Lymphoma & Plasma Cell Disorders

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Photo by Rhoda Baer

BOSTON—A pair of preclinical studies suggest the FLT3/BTK inhibitor CG’806 is active in a range of hematologic malignancies.

In one of the studies, CG’806 proved particularly effective against acute myeloid leukemia (AML) cells harboring mutant forms of FLT3, and the compound was able to eradicate AML in mice.

In another study, researchers found CG’806 exhibited “broad potency” against leukemias, lymphomas, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPNs).

Both studies were presented as posters at Hematologic Malignancies: Translating Discoveries to Novel Therapies (poster 25 and poster 44).

Both studies involved researchers from Aptose Biosciences, the company developing CG’806.

Poster 25

Weiguo Zhang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues presented poster 25, “CG’806, a first-in-class FLT3/BTK inhibitor, exerts superior potency against AML cells harboring ITD, TKD and gatekeeper mutated FLT3 or wild-type FLT3.”

The researchers tested CG’806 and other FLT3 inhibitors in human or murine leukemia cell lines with wild-type (WT) FLT3, FLT3-ITD mutations, FLT3 TKD domain mutations, or ITD plus TKD mutations.

Compared to second-generation FLT3 inhibitors (quizartinib, gilteritinib, or crenolanib), CG’806 showed more pronounced anti-proliferative effects in leukemia cells with ITD mutations, D835 mutations, ITD plus F691I/Y842D/D835 mutations, or in FLT3 WT cells.

With CG’086, the IC50s in human AML cell lines were 0.17 nM for MV4-11 (FLT3-ITD) and 0.82 nM for MOLM13 (FLT3-ITD).

The IC50s in the murine leukemia cell lines were 9.49 nM for Ba/F3 (FLT3-WT), 0.30 nM for Ba/F3 (FLT3-ITD), 8.26 nM for Ba/F3 (FLT3-D835Y), 9.72 nM for Ba/F3 (FLT3-ITD+D835Y), and 0.43 nM for Ba/F3 (FLT3-ITD+F691L).

The researchers also found that CG’806 “triggers marked apoptosis” in FLT3-ITD-mutated primary AML samples but minimal apoptosis in normal bone marrow cells.

Another finding was that once-daily oral dosing of CG’806 in a murine model of AML (MV4-11) resulted in sustained micromolar plasma concentration over a 24-hour period.

This was accompanied by complete elimination of AML FLT3-ITD tumors without toxicity, the researchers said.

Poster 44

Stephen E. Kurtz, PhD, of Oregon Health & Science University in Portland, and his colleagues presented poster 44, “CG’806, a First-in-Class FLT3/BTK Inhibitor, Exhibits Potent Activity against AML Patient Samples with Mutant or Wild-Type FLT3, as well as Other Hematologic Malignancy Subtypes.”

The researchers tested CG’806 in samples from patients with AML (n=82), MDS/MPNs (n=15), acute lymphoblastic leukemia (ALL, n=17), chronic lymphocytic leukemia (CLL, n=58), and chronic myeloid leukemia (CML, n=4).

The team observed “broad sensitivity” to CG’806, with 59% (48/82) of AML, 53% (8/15) of MDS/MPN, 40% (23/58) of CLL, 29% (5/17) of ALL, and 25% (1/4) of CML cases exhibiting an IC50 of less than 100 nM.

Among the 38 tested AML samples with known FLT3 mutational status, the FLT3-ITD+ AML samples tended to have enhanced sensitivity to CG’806 (median IC50 = 20 nM, n=8) relative to the FLT3-WT samples (median IC50 = 120 nM, n=30).

The researchers also found that CG’806 exerted potent anti-proliferative activity against human AML, B-ALL, mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cell lines.

“The analyses of CG’806 against primary hematologic malignancy patient samples and cultured cell lines show evidence of potent and broad drug activity in AML and other disease subtypes and support further development of this agent for hematologic malignancies,” Dr Kurtz said. 

Vials and a syringe

In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).

Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.

Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.

Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.

Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.

The study was funded by Roche, which markets rituximab as Rituxan and MabThera.

The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.

Patients were randomized to receive IV rituximab at 375 mg/m² (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.

Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.

Patients then received rituximab maintenance every 8 weeks.

The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.

Efficacy

In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the treatment arms at cycle 7.

The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).

In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.

At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.

At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.

At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).

Safety

The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.

Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).

Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.

Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.

The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL. 

Vials and a syringe

In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).

Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.

Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.

Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.

Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.

The study was funded by Roche, which markets rituximab as Rituxan and MabThera.

The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.

Patients were randomized to receive IV rituximab at 375 mg/m² (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.

Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.

Patients then received rituximab maintenance every 8 weeks.

The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.

Efficacy

In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the treatment arms at cycle 7.

The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).

In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.

At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.

At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.

At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).

Safety

The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.

Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).

Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.

Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.

The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL. 

Vials and a syringe

In a phase 3 trial, subcutaneous (SC) and intravenous (IV) rituximab produced comparable results as part of a first-line treatment regimen for follicular lymphoma (FL).

Overall response rates (ORR) were similar in patients who received SC rituximab and those who received IV rituximab, first in combination with chemotherapy and then alone as maintenance therapy.

Although patients who received SC rituximab had administration-related reactions that weren’t observed in the IV rituximab group, these events were largely mild-to-moderate local injection-site reactions.

Andrew Davies, PhD, of the University of Southampton in the UK, and his colleagues reported these results in The Lancet Haematology.

Data from stage 1 of this study, known as SABRINA, were previously published in The Lancet Oncology. The current publication includes stage 2 data.

The study was funded by Roche, which markets rituximab as Rituxan and MabThera.

The trial enrolled 410 patients with previously untreated, grade 1-3a, CD20-positive FL.

Patients were randomized to receive IV rituximab at 375 mg/m² (n=205) or SC rituximab at 1400 mg (n=205) plus chemotherapy.

Chemotherapy consisted of 6 to 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) every 3 weeks during induction.

Patients then received rituximab maintenance every 8 weeks.

The researchers said baseline characteristics were balanced between the treatment arms, although there were more females in the SC arm than the IV arm—120 (59%) and 99 (48%), respectively.

Efficacy

In stage 1 of this study, the primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the treatment arms at cycle 7.

The results suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio=1.62).

In stage 2, the primary endpoint was efficacy, or ORR, at the end of induction based on the researchers’ assessments and confirmed by an independent review panel of radiologists.

At the end of induction, the ORR was 84.9% (174/205) in the IV arm and 84.4% (173/205) in the SC arm. The complete response rate was 32.2% (n=66) in both arms.

At the end of maintenance therapy, the ORR was 78.1% (139/178) in the IV arm and 77.9% (134/172) in the SC arm. The complete response rates were 56.2% (n=100) and 50.6% (n=87), respectively.

At a median follow-up of 37 months, there was no significant difference between the arms with regard to progression-free survival (hazard ratio[HR]=0.84), event-free survival (HR=0.91), or overall survival (HR=0.81).

Safety

The incidence of adverse events (AEs) was similar between the treatment arms—95% in the IV arm and 96% in the SC arm. The incidence of grade 3 or higher AEs was 55% and 56%, respectively, and the incidence of serious AEs was 34% and 37%, respectively.

Overall, the most common AEs were gastrointestinal disorders (60% in the IV arm and 66% in the SC arm), infections and infestations (64% and 67%, respectively), and general or administration site conditions (50% and 60%, respectively).

Administration-related reactions were more common in the SC arm than the IV arm—48% and 35%, respectively. The most common of these reactions were chills (7%) and pruritus (6%) in the IV arm and injection-site erythema (11%), pruritus (6%), rash (5%), and injection-site pain (5%) in the SC arm.

Neutropenia was the most common grade 3 or higher AE, occurring in 34% of patients in the IV arm and 37% in the SC arm. Febrile neutropenia was the most frequent serious AE, occurring in 5% and 6%, respectively.

The researchers said these results suggest the SC formulation of rituximab has similar efficacy and a similar safety profile as IV rituximab in the first-line treatment of FL. 

Photo courtesy of Merck

The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).

The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.

The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).

This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.

The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.

Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.

KEYNOTE-087

In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.

In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.

In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.

For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths. 

Photo courtesy of Merck

The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).

The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.

The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).

This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.

The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.

Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.

KEYNOTE-087

In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.

In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.

In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.

For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths. 

Photo courtesy of Merck

The European Commission (EC) has approved the anti-PD-1 therapy pembrolizumab (Keytruda) for use in patients with classical Hodgkin lymphoma (cHL).

The drug is now approved to treat adults with relapsed or refractory cHL who have failed autologous stem cell transplant (auto-SCT) and brentuximab vedotin (BV) or who are transplant-ineligible and have failed treatment with BV.

The approval allows marketing of pembrolizumab for this indication in the European Economic Area (EEA).

This is the first approval for pembrolizumab in a hematologic malignancy in the EEA. The drug was previously approved there as a treatment for melanoma and non-small-cell lung cancer.

The new approval for pembrolizumab was based on data from the KEYNOTE-087 and KEYNOTE-013 trials.

Results from KEYNOTE-013 were presented at the 2016 ASH Annual Meeting (abstract 1108), and results from KEYNOTE-087 were recently published in the Journal of Clinical Oncology.

KEYNOTE-087

In this phase 2 trial, researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%, and the CR rate was 21.7%.

In Cohort 2 (n=81), the ORR was 64.2%, and the CR rate was 24.7%.

In Cohort 3 (n=60), the ORR was 70.0%, and the CR rate was 20%.

For the entire study cohort, the median duration of response was not reached, and the median overall survival (OS) was not reached. At 9 months, the OS was 97.5%, and the progression-free survival (PFS) was 63.4%.

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%, and the CR rate was 19%. The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median PFS was 11.4 months (range, 4.9-27.8 months). The 6-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median OS was not reached. Six-month and 12-month OS rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths. 

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

Micrograph showing CLL

Long-term follow-up of a phase 1 study suggests the BTK inhibitor ONO/GS-4059 can stave off progression in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Roughly 60% of the patients studied were progression-free and still taking ONO/GS-4059 at last follow-up, with the longest time on treatment exceeding 3 years.

In addition, researchers said the extended follow-up revealed no new safety concerns, and the maximum tolerated dose of ONO/GS-4059 has not been reached.

Martin Dyer, DPhil, of the University of Leicester in the UK, and his colleagues reported these results in Blood.

The research was funded by Gilead Sciences, Inc., and ONO Pharmaceuticals helped with data analysis.

The study enrolled 90 patients with relapsed or refractory B-cell malignancies, 28 of whom had CLL. Dr Dyer and his colleagues reported follow-up results in CLL patients only.

The patients’ median number of prior treatments was 4 (range, 2-9), and 11 patients were refractory to their last line of therapy. None had received prior treatment with a BTK inhibitor.

The patients received ONO/GS-4059 at varying doses, from 20 mg once daily (QD) to 600 mg QD and a twice-daily (BID) regimen of 300 mg. Six patients were also taking anticoagulant therapy while on study.

Patients were allowed to continue treatment with ONO/GS-4059 if they responded to the drug or maintained stable disease.

Initially, 25 patients were evaluable for response, and 24 of them responded to ONO/GS-4059, for an overall response rate of 96%.

At last follow-up on June 8, 2016, 17 patients were still receiving ONO/GS-4059, and all had a very good partial response.

Dr Dyer said the responses have been similar to those seen with other irreversible BTK inhibitors. Most have involved rapid and almost complete resolution of lymph node masses and rapid improvement in hematological indexes.

“It is clear . . . that the major responses occur rapidly, within the first 3 months of drug, and that, thereafter, improvement occurs at a much slower rate,” Dr Dyer said. “It will be of interest, I think, to look at the remaining patients on study to assess whether responses deepen with time on drug.”

The duration of treatment for these patients ranged from 302 days to 1160 days at last follow-up. They were receiving ONO/GS-4059 at doses ranging from 40 mg QD to 600 mg QD or 300 mg BID, and no maximum tolerated dose had been identified.

Eleven patients (39.3%) discontinued ONO/GS-4059 due to death (n=3), disease progression (n=4), adverse events (AEs, n=3), and sponsor decision due to extended drug interruption (n=1). One of the patients included in the AE group also had concurrent disease progression.

The median progression-free survival was 38.5 months, and the median overall survival was 44.9 months. The median time on study was 32.5 months.

The most common treatment-emergent AEs were bruising (35.7%), neutropenia (35.7%), anemia (32.1%), nasopharyngitis (32.1%), fall (32.1%), cough (28.6%), arthralgia (28.6%), and basal cell carcinoma (28.6%).

The most common grade 3/4 AEs included neutropenia (25%), thrombocytopenia (14.3%), lower respiratory tract infection (14.3%), and anemia (10.7%).

“Our long-term follow-up shows maintained efficacy without toxicity,” Dr Dyer said. “This study is the first report of long-term follow-up of a selective BTK inhibitor, and it is excellent news for patients. We are now doing studies of ONO/GS-4059 in combination with other precision medicines to assess whether these results can be enhanced in patients with CLL and other B-cell malignancies.” 

Lower-intensity radiation regimens for patients with early-stage Hodgkin lymphoma (HL) did not shorten progression-free survival (PFS), according to a long-term analysis. Further, for patients with unfavorable early-stage disease, a more intense chemotherapy or radiation regimen conferred no survival benefit.

The German Hodgkin Study Group included patients with early-stage HL who had both early-stage favorable HL and early-stage unfavorable HL. Stephanie Sasse, MD, and her study group colleagues published long-term follow-up findings from multiple trials, conducted from 1993 to 2003, that evaluated risk-adapted treatment strategies to reduce radiation field size and chemotherapy intensity, “aiming at achieving sufficient tumor control while potentially reducing treatment-associated toxicity,” wrote Dr. Sasse and her colleagues of the University Hospital of Cologne (Ger.) (J Clin Oncol. 2017 Apr 18. doi: JCO2016709410).

Trials in favorable HL

Of the 627 patients in the HD7 trial in patients with favorable HL, combined-modality therapy resulted in better rates of PFS (73%) over a 15-year period, compared with extended-field radiotherapy (RT) alone (52%) (hazard ratio, 0.5; 95% confidence interval, 0.3-0.6; P less than 0.001). Another study, called HD10, was in early-stage favorable HL patients. It compared a lower-intensity regimen of two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus 20 Gy involved-field RT with a four-cycle ABVD regimen combined with 30 Gy involved-field RT. The 1,190-patient study achieved a median follow-up of 98 months, finding that the less-intense regimen was not inferior with an identical 10-year PFS of 87% in both arms (HR 1.0; 95% CI 0.6-1.5). Overall survival (OS) was nearly identical as well, at 94% in each arm (HR 0.9; 95% CI, 0.5-1.6).

Both trials HD7 and HD10 tracked the incidence of secondary neoplasias and detected no significant differences between groups, though there was a nonsignificant trend toward more secondary neoplasias for the HD7 patients who received extended-field radiotherapy. These analyses “strongly support the current risk-adapted treatment strategy in early-stage favorable HL,” wrote Dr. Sasse and her coinvestigators.

Trials in unfavorable HL

The HD8 trial enrolled 1,064 patients and followed them for a median 153 months to compare the efficacy of involved-field RT with extended-field RT, finding involved-field RT noninferior for PFS (HR, 1.0; 95% CI, 0.8-1.2). However, the overall 15-year PFS rate of 74% and OS rate of 82% “leave room for improvement,” said the investigators.

Finally, trial HD11 compared two different chemotherapy regimens and two different radiation doses. Patients received four cycles of either ABVD or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline dosage (BEACOPP_baseline), followed by 20 or 30 Gy involved-field RT. The study, which followed 1,395 patients for a median of 106 months, had a 2x2 factorial design.

Following the HD11 cohort longitudinally showed that BEACOPP_baseline did not confer a PFS advantage over ABVD for patients receiving the 30 Gy RT regimen (HR 1.1; 95% CI, 0.7-1.5). Nor did patients who received 20 Gy RT have significantly longer PFS with the more intense BEACOPPbaseline chemotherapy regimen (HR 0.8; 95% CI, 0.6-1.1).

Overall survival and the incidence of secondary neoplasias did not differ between trial arms in HD11, said Dr. Sasse and her coinvestigators.

To further explore whether more intense chemotherapy might result in better PFS rates for patients with early-stage unfavorable HL, Dr. Sasse and her colleagues are following long-term results from more recent trial, HD14, that combined two cycles of BEACOPP_escalated and two cycles of ABVD. More short-term toxicity was seen, but patients in this trial arm have significantly better 5-year PFS rates than do those receiving four cycles of ABVD. “The improved tumor control is a relevant outcome parameter for patients,” wrote Dr. Sasse and her colleagues.

The investigators are reserving judgment about whether more radiation exposure and higher doses of alkylating agents and etoposide may eventually result in higher rates of secondary neoplasms. “Subsequent analyses with even longer follow-up will have to confirm that the reduction of RT field size or dose indeed translates into a reduced risk of [secondary neoplasms],” they wrote.

Several of the authors reported multiple relationships with pharmaceutical companies. The study was funded by a grant from the German Cancer Aid.

koakes@frontlinemedcom.com

On Twitter @karioakes

Lower-intensity radiation regimens for patients with early-stage Hodgkin lymphoma (HL) did not shorten progression-free survival (PFS), according to a long-term analysis. Further, for patients with unfavorable early-stage disease, a more intense chemotherapy or radiation regimen conferred no survival benefit.

The German Hodgkin Study Group included patients with early-stage HL who had both early-stage favorable HL and early-stage unfavorable HL. Stephanie Sasse, MD, and her study group colleagues published long-term follow-up findings from multiple trials, conducted from 1993 to 2003, that evaluated risk-adapted treatment strategies to reduce radiation field size and chemotherapy intensity, “aiming at achieving sufficient tumor control while potentially reducing treatment-associated toxicity,” wrote Dr. Sasse and her colleagues of the University Hospital of Cologne (Ger.) (J Clin Oncol. 2017 Apr 18. doi: JCO2016709410).

Trials in favorable HL

Of the 627 patients in the HD7 trial in patients with favorable HL, combined-modality therapy resulted in better rates of PFS (73%) over a 15-year period, compared with extended-field radiotherapy (RT) alone (52%) (hazard ratio, 0.5; 95% confidence interval, 0.3-0.6; P less than 0.001). Another study, called HD10, was in early-stage favorable HL patients. It compared a lower-intensity regimen of two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus 20 Gy involved-field RT with a four-cycle ABVD regimen combined with 30 Gy involved-field RT. The 1,190-patient study achieved a median follow-up of 98 months, finding that the less-intense regimen was not inferior with an identical 10-year PFS of 87% in both arms (HR 1.0; 95% CI 0.6-1.5). Overall survival (OS) was nearly identical as well, at 94% in each arm (HR 0.9; 95% CI, 0.5-1.6).

Both trials HD7 and HD10 tracked the incidence of secondary neoplasias and detected no significant differences between groups, though there was a nonsignificant trend toward more secondary neoplasias for the HD7 patients who received extended-field radiotherapy. These analyses “strongly support the current risk-adapted treatment strategy in early-stage favorable HL,” wrote Dr. Sasse and her coinvestigators.

Trials in unfavorable HL

The HD8 trial enrolled 1,064 patients and followed them for a median 153 months to compare the efficacy of involved-field RT with extended-field RT, finding involved-field RT noninferior for PFS (HR, 1.0; 95% CI, 0.8-1.2). However, the overall 15-year PFS rate of 74% and OS rate of 82% “leave room for improvement,” said the investigators.

Finally, trial HD11 compared two different chemotherapy regimens and two different radiation doses. Patients received four cycles of either ABVD or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline dosage (BEACOPP_baseline), followed by 20 or 30 Gy involved-field RT. The study, which followed 1,395 patients for a median of 106 months, had a 2x2 factorial design.

Following the HD11 cohort longitudinally showed that BEACOPP_baseline did not confer a PFS advantage over ABVD for patients receiving the 30 Gy RT regimen (HR 1.1; 95% CI, 0.7-1.5). Nor did patients who received 20 Gy RT have significantly longer PFS with the more intense BEACOPPbaseline chemotherapy regimen (HR 0.8; 95% CI, 0.6-1.1).

Overall survival and the incidence of secondary neoplasias did not differ between trial arms in HD11, said Dr. Sasse and her coinvestigators.

To further explore whether more intense chemotherapy might result in better PFS rates for patients with early-stage unfavorable HL, Dr. Sasse and her colleagues are following long-term results from more recent trial, HD14, that combined two cycles of BEACOPP_escalated and two cycles of ABVD. More short-term toxicity was seen, but patients in this trial arm have significantly better 5-year PFS rates than do those receiving four cycles of ABVD. “The improved tumor control is a relevant outcome parameter for patients,” wrote Dr. Sasse and her colleagues.

The investigators are reserving judgment about whether more radiation exposure and higher doses of alkylating agents and etoposide may eventually result in higher rates of secondary neoplasms. “Subsequent analyses with even longer follow-up will have to confirm that the reduction of RT field size or dose indeed translates into a reduced risk of [secondary neoplasms],” they wrote.

Several of the authors reported multiple relationships with pharmaceutical companies. The study was funded by a grant from the German Cancer Aid.

koakes@frontlinemedcom.com

On Twitter @karioakes

Lower-intensity radiation regimens for patients with early-stage Hodgkin lymphoma (HL) did not shorten progression-free survival (PFS), according to a long-term analysis. Further, for patients with unfavorable early-stage disease, a more intense chemotherapy or radiation regimen conferred no survival benefit.

The German Hodgkin Study Group included patients with early-stage HL who had both early-stage favorable HL and early-stage unfavorable HL. Stephanie Sasse, MD, and her study group colleagues published long-term follow-up findings from multiple trials, conducted from 1993 to 2003, that evaluated risk-adapted treatment strategies to reduce radiation field size and chemotherapy intensity, “aiming at achieving sufficient tumor control while potentially reducing treatment-associated toxicity,” wrote Dr. Sasse and her colleagues of the University Hospital of Cologne (Ger.) (J Clin Oncol. 2017 Apr 18. doi: JCO2016709410).

Trials in favorable HL

Of the 627 patients in the HD7 trial in patients with favorable HL, combined-modality therapy resulted in better rates of PFS (73%) over a 15-year period, compared with extended-field radiotherapy (RT) alone (52%) (hazard ratio, 0.5; 95% confidence interval, 0.3-0.6; P less than 0.001). Another study, called HD10, was in early-stage favorable HL patients. It compared a lower-intensity regimen of two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) plus 20 Gy involved-field RT with a four-cycle ABVD regimen combined with 30 Gy involved-field RT. The 1,190-patient study achieved a median follow-up of 98 months, finding that the less-intense regimen was not inferior with an identical 10-year PFS of 87% in both arms (HR 1.0; 95% CI 0.6-1.5). Overall survival (OS) was nearly identical as well, at 94% in each arm (HR 0.9; 95% CI, 0.5-1.6).

Both trials HD7 and HD10 tracked the incidence of secondary neoplasias and detected no significant differences between groups, though there was a nonsignificant trend toward more secondary neoplasias for the HD7 patients who received extended-field radiotherapy. These analyses “strongly support the current risk-adapted treatment strategy in early-stage favorable HL,” wrote Dr. Sasse and her coinvestigators.

Trials in unfavorable HL

The HD8 trial enrolled 1,064 patients and followed them for a median 153 months to compare the efficacy of involved-field RT with extended-field RT, finding involved-field RT noninferior for PFS (HR, 1.0; 95% CI, 0.8-1.2). However, the overall 15-year PFS rate of 74% and OS rate of 82% “leave room for improvement,” said the investigators.

Finally, trial HD11 compared two different chemotherapy regimens and two different radiation doses. Patients received four cycles of either ABVD or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline dosage (BEACOPP_baseline), followed by 20 or 30 Gy involved-field RT. The study, which followed 1,395 patients for a median of 106 months, had a 2x2 factorial design.

Following the HD11 cohort longitudinally showed that BEACOPP_baseline did not confer a PFS advantage over ABVD for patients receiving the 30 Gy RT regimen (HR 1.1; 95% CI, 0.7-1.5). Nor did patients who received 20 Gy RT have significantly longer PFS with the more intense BEACOPPbaseline chemotherapy regimen (HR 0.8; 95% CI, 0.6-1.1).

Overall survival and the incidence of secondary neoplasias did not differ between trial arms in HD11, said Dr. Sasse and her coinvestigators.

To further explore whether more intense chemotherapy might result in better PFS rates for patients with early-stage unfavorable HL, Dr. Sasse and her colleagues are following long-term results from more recent trial, HD14, that combined two cycles of BEACOPP_escalated and two cycles of ABVD. More short-term toxicity was seen, but patients in this trial arm have significantly better 5-year PFS rates than do those receiving four cycles of ABVD. “The improved tumor control is a relevant outcome parameter for patients,” wrote Dr. Sasse and her colleagues.

The investigators are reserving judgment about whether more radiation exposure and higher doses of alkylating agents and etoposide may eventually result in higher rates of secondary neoplasms. “Subsequent analyses with even longer follow-up will have to confirm that the reduction of RT field size or dose indeed translates into a reduced risk of [secondary neoplasms],” they wrote.

Several of the authors reported multiple relationships with pharmaceutical companies. The study was funded by a grant from the German Cancer Aid.

koakes@frontlinemedcom.com

On Twitter @karioakes

The emerging role for immunotherapies as an essential component of multiple myeloma therapy is examined in a review article in Leukemia by Cyrille Touzeau, MD, and his colleagues.

The reviewers detail research examining a string of monoclonal antibodies that fell short in earlier evaluations. They focus on the two approved agents that target CD38 (daratumumab) and SLAMF7 (elotuzumab) and have succeeded in combination therapies for patients with relapsed myeloma. These two antibodies, and other immunotherapy possibilities in the pipeline, are expected to have a strong impact on treatment modalities and outcomes in patients with multiple myeloma, including transplant eligible and elderly patients, Dr. Touzeau, of the service d’hématologie clinique, Nantes, France, and his fellow researchers wrote.

Peter Anderson/ Pathology Education Informational Resource (PEIR) Digital Library/ © University of Alabama at Birmingham, Department of Pathology

mdales@frontlinemedcom.com

On Twitter @maryjodales

The emerging role for immunotherapies as an essential component of multiple myeloma therapy is examined in a review article in Leukemia by Cyrille Touzeau, MD, and his colleagues.

The reviewers detail research examining a string of monoclonal antibodies that fell short in earlier evaluations. They focus on the two approved agents that target CD38 (daratumumab) and SLAMF7 (elotuzumab) and have succeeded in combination therapies for patients with relapsed myeloma. These two antibodies, and other immunotherapy possibilities in the pipeline, are expected to have a strong impact on treatment modalities and outcomes in patients with multiple myeloma, including transplant eligible and elderly patients, Dr. Touzeau, of the service d’hématologie clinique, Nantes, France, and his fellow researchers wrote.

Peter Anderson/ Pathology Education Informational Resource (PEIR) Digital Library/ © University of Alabama at Birmingham, Department of Pathology

mdales@frontlinemedcom.com

On Twitter @maryjodales

The emerging role for immunotherapies as an essential component of multiple myeloma therapy is examined in a review article in Leukemia by Cyrille Touzeau, MD, and his colleagues.

The reviewers detail research examining a string of monoclonal antibodies that fell short in earlier evaluations. They focus on the two approved agents that target CD38 (daratumumab) and SLAMF7 (elotuzumab) and have succeeded in combination therapies for patients with relapsed myeloma. These two antibodies, and other immunotherapy possibilities in the pipeline, are expected to have a strong impact on treatment modalities and outcomes in patients with multiple myeloma, including transplant eligible and elderly patients, Dr. Touzeau, of the service d’hématologie clinique, Nantes, France, and his fellow researchers wrote.

Peter Anderson/ Pathology Education Informational Resource (PEIR) Digital Library/ © University of Alabama at Birmingham, Department of Pathology

mdales@frontlinemedcom.com

On Twitter @maryjodales

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

hematologynews@frontlinemedcom.com

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

hematologynews@frontlinemedcom.com

MONTREAL – A combination of placenta-derived stem cells and umbilical cord blood was associated with early engraftment and high degrees of cord blood donor chimerism in the treatment of children with both malignant and nonmalignant hematologic conditions requiring stem cell transplantation, updated results of a pilot study show.

Among 16 children treated with the combination, the probability of neutrophil engraftment was 87.5%, and all patients who had neutrophil engraftment went on to have platelet engraftment. The probability of 12-month overall survival was 81.2%, reported Allyson Flower, MD, from Boston Children’s Health Physicians in Hawthorne, N.Y. “The probability of grade II-IV acute graft vs. host disease was 12.5%, compared with 32.5% seen with unrelated cord blood in our group’s previous studies. Cellular immune reconstitution was robust,” she said at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Augmenting cord blood

Although unrelated donor cord blood transplantation expands the donor pool, is rapidly available, and is associated with decreases in both severe acute graft vs. host disease (GVHD) and chronic GVHD, compared with other stem cell sources, the technique is hampered by limited cell doses, prolonged immune reconstitution time, delays in hematopoietic recovery, and a higher incidence of graft failure.

Early studies of myeloablative conditioning followed by unrelated umbilical or placental blood transplantation showed a median of 22-24 days to neutrophil engraftment (Blood 1996 88:795-802; N Engl J Med. 1996;335:157-66), Dr. Flower noted.

More recently, a multivariate analysis of patients who underwent reduced-intensity conditioning followed by hematopoietic stem cell transplant with unrelated cord blood showed that graft failure was an independent risk factor for worse overall survival (Biol Blood Marrow Transplant. 2013 Apr;19:4;552-61).

Multiple groups have shown that adding human placenta–derived stem cells (HPDSC) to cord blood transplantation can facilitate more rapid hematopoietic engraftment by increasing the number of stem cells, increasing the proportion of hematopoietic progenitor cells, and providing additional, immature CD34+/CD45– progenitor cells.

In a single-arm, nonrandomized study, the investigators enrolled 16 patients ranging in age from 0.3 to 15.7 years with inborn errors of metabolism, marrow failure syndromes, severe immunodeficiency states, or hematologic malignancies.

Malignant conditions included B-cell precursor acute lymphoblastic leukemia (B-ALL; four patients), acute myeloid leukemia (AML; two), and T-cell ALL (one) in first complete remission, and T-cell lymphoblastic lymphoma following induction failure (one). Nonmalignant conditions included adrenoleukodystrophy (two patients), amegakaryotic thrombocytopenia (one), severe combined immunodeficiency (SCID; two), dyskeratosis congenita (one), chronic granulomatous disease (one), and severe congenital neutropenia (one).

The patients first underwent either myeloablative or reduced-intensity conditioning, followed 10 days later by infusion of unrelated cord blood and HPDSCs. Prior to HPDSC infusion, patients were medicated with diphenhydramine and hydrocortisone to prevent or reduce potential sensitivity reactions. HPDSCs were infused no sooner than 4 hours after the end of the cord blood infusion.

Patients received GVHD prophylaxis with either tacrolimus or cyclosporine, plus mycophenolate mofetil.

The combination appeared to be safe, with no cases of grade 3 or 4 toxicity secondary to HPDSC infusion.

The probability of neutrophil engraftment was 87.5%, with engraftment occurring at a median of 23 days (range 13-53). As noted before, all patients who had neutrophil engraftment had platelet engraftment, which was achieved at a median of 47 days (range, 20-98). In the group’s previous studies, median time to platelet engraftment was 53 days for patients who had undergone reduced-intensity conditioning, and 118 days for patients who had undergone myeloablation.

The probability of grade 2-4 acute GVHD within 100 days was 12.5%, and there were no cases of chronic GVHD.

Respective percentages of cord blood donor chimerism at days 30, 60, 100, and 180 were 88%, 98%, 99%, and 99%.

Immune reconstitution was strong, with normalization of mean CD3+, CD19+, and CD56+ cells occurring by day 100, CD8+ cells by day 180, and CD4+ cells by day 270.

There were three patient deaths: one from adenoviremia in a patient with B-ALL and CNS relapse, who had neutrophil engraftment at day 21; one in a patient with SCID, from adenoviremia and multiple system organ failure, who did not have engraftment before death; and one in a patient with severe congenital neutrophilia, who also did not have neutrophil engraftment.

None of the eight patients with malignant disease have experienced relapse to date, Dr. Flower noted.

The study was funded by a grant from Celgene Cellular Therapeutics. Dr. Flower reported having no conflicts of interest.

hematologynews@frontlinemedcom.com

Ibrutinib is active in patients with previously treated marginal zone lymphoma (MZL) and has a good safety profile, the results of a multicenter, open-label phase II trial published in Blood suggest.

Nearly half of 63 patients responded to monotherapy with the once-daily oral inhibitor of Bruton tyrosine kinase, and ibrutinib was generally well tolerated, according to the study (Blood. 2017;129:2224-32). The results prompted the U.S. Food and Drug Administration to grant accelerated approval of ibrutinib for patients with MZL who were previously treated with at least one prior anti-CD20–based therapy.

“MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation,” note the investigators, who were led by Ariela Noy, MD, a hematologic oncologist with the Lymphoma Service at the Memorial Sloan-Kettering Cancer Center, New York. “Single-agent ibrutinib induced durable responses with a favorable benefit–risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy.”

“As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL,” they maintain. “Future studies will investigate ibrutinib in treatment-naive patients or as combination strategies in relapsed/refractory MZL.”

In the trial, which was funded by Pharmacyclics, an AbbVie Company, patients with MZL of all subtypes who had received at least one prior therapy with an anti-CD20 antibody–containing regimen were treated with 560 mg ibrutinib (Imbruvica) orally once daily. The median number of prior systemic therapies was two, and 63% had received prior chemoimmunotherapy.

The overall response rate, as assessed by an independent review committee using 2007 International Working Group criteria – the trial’s primary endpoint – was 48%, according to the published results. Benefit was similar across patients who differed regarding MZL subtype, number of prior regimen, and previous receipt of chemoimmunotherapy

After a 19.4-month median follow-up, the median duration of response was not reached, and median progression-free survival was 14.2 months.

The most common grade 3 or worse adverse events were anemia (14%), pneumonia (8%), and fatigue (6%). Serious adverse events of any grade affected 44% of patients. The most common was grade 3 or 4 pneumonia. Adverse events led to treatment discontinuation in 17% of patients and dose reductions in 10%.

“Due to evidence of pseudoprogression in our trial … biopsies may be warranted to differentiate between true lymphoma progression and immune-mediated antitumor response,” the investigators note.

Dr. Noy disclosed that she has received research funding from Pharmacyclics.

hematologynews@frontlinemedcom.com

Ibrutinib is active in patients with previously treated marginal zone lymphoma (MZL) and has a good safety profile, the results of a multicenter, open-label phase II trial published in Blood suggest.

Nearly half of 63 patients responded to monotherapy with the once-daily oral inhibitor of Bruton tyrosine kinase, and ibrutinib was generally well tolerated, according to the study (Blood. 2017;129:2224-32). The results prompted the U.S. Food and Drug Administration to grant accelerated approval of ibrutinib for patients with MZL who were previously treated with at least one prior anti-CD20–based therapy.

“MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation,” note the investigators, who were led by Ariela Noy, MD, a hematologic oncologist with the Lymphoma Service at the Memorial Sloan-Kettering Cancer Center, New York. “Single-agent ibrutinib induced durable responses with a favorable benefit–risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy.”

“As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL,” they maintain. “Future studies will investigate ibrutinib in treatment-naive patients or as combination strategies in relapsed/refractory MZL.”

In the trial, which was funded by Pharmacyclics, an AbbVie Company, patients with MZL of all subtypes who had received at least one prior therapy with an anti-CD20 antibody–containing regimen were treated with 560 mg ibrutinib (Imbruvica) orally once daily. The median number of prior systemic therapies was two, and 63% had received prior chemoimmunotherapy.

The overall response rate, as assessed by an independent review committee using 2007 International Working Group criteria – the trial’s primary endpoint – was 48%, according to the published results. Benefit was similar across patients who differed regarding MZL subtype, number of prior regimen, and previous receipt of chemoimmunotherapy

After a 19.4-month median follow-up, the median duration of response was not reached, and median progression-free survival was 14.2 months.

The most common grade 3 or worse adverse events were anemia (14%), pneumonia (8%), and fatigue (6%). Serious adverse events of any grade affected 44% of patients. The most common was grade 3 or 4 pneumonia. Adverse events led to treatment discontinuation in 17% of patients and dose reductions in 10%.

“Due to evidence of pseudoprogression in our trial … biopsies may be warranted to differentiate between true lymphoma progression and immune-mediated antitumor response,” the investigators note.

Dr. Noy disclosed that she has received research funding from Pharmacyclics.

hematologynews@frontlinemedcom.com

Ibrutinib is active in patients with previously treated marginal zone lymphoma (MZL) and has a good safety profile, the results of a multicenter, open-label phase II trial published in Blood suggest.

Nearly half of 63 patients responded to monotherapy with the once-daily oral inhibitor of Bruton tyrosine kinase, and ibrutinib was generally well tolerated, according to the study (Blood. 2017;129:2224-32). The results prompted the U.S. Food and Drug Administration to grant accelerated approval of ibrutinib for patients with MZL who were previously treated with at least one prior anti-CD20–based therapy.

“MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation,” note the investigators, who were led by Ariela Noy, MD, a hematologic oncologist with the Lymphoma Service at the Memorial Sloan-Kettering Cancer Center, New York. “Single-agent ibrutinib induced durable responses with a favorable benefit–risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy.”

“As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL,” they maintain. “Future studies will investigate ibrutinib in treatment-naive patients or as combination strategies in relapsed/refractory MZL.”

In the trial, which was funded by Pharmacyclics, an AbbVie Company, patients with MZL of all subtypes who had received at least one prior therapy with an anti-CD20 antibody–containing regimen were treated with 560 mg ibrutinib (Imbruvica) orally once daily. The median number of prior systemic therapies was two, and 63% had received prior chemoimmunotherapy.

The overall response rate, as assessed by an independent review committee using 2007 International Working Group criteria – the trial’s primary endpoint – was 48%, according to the published results. Benefit was similar across patients who differed regarding MZL subtype, number of prior regimen, and previous receipt of chemoimmunotherapy

After a 19.4-month median follow-up, the median duration of response was not reached, and median progression-free survival was 14.2 months.

The most common grade 3 or worse adverse events were anemia (14%), pneumonia (8%), and fatigue (6%). Serious adverse events of any grade affected 44% of patients. The most common was grade 3 or 4 pneumonia. Adverse events led to treatment discontinuation in 17% of patients and dose reductions in 10%.

“Due to evidence of pseudoprogression in our trial … biopsies may be warranted to differentiate between true lymphoma progression and immune-mediated antitumor response,” the investigators note.

Dr. Noy disclosed that she has received research funding from Pharmacyclics.

hematologynews@frontlinemedcom.com

The immune checkpoint inhibitor pembrolizumab has good antitumor activity and a favorable safety profile when used to treat relapsed or refractory classic Hodgkin lymphoma, according to findings from the KEYNOTE-087 trial.

Pembrolizumab has garnered interest for this population because Hodgkin Reed-Sternberg cells have a chromosomal alteration leading to overexpression of both programmed death ligand 1 and programmed death ligand 2.

Neil Osterweil

The immune checkpoint inhibitor pembrolizumab has good antitumor activity and a favorable safety profile when used to treat relapsed or refractory classic Hodgkin lymphoma, according to findings from the KEYNOTE-087 trial.

Pembrolizumab has garnered interest for this population because Hodgkin Reed-Sternberg cells have a chromosomal alteration leading to overexpression of both programmed death ligand 1 and programmed death ligand 2.

Neil Osterweil

The immune checkpoint inhibitor pembrolizumab has good antitumor activity and a favorable safety profile when used to treat relapsed or refractory classic Hodgkin lymphoma, according to findings from the KEYNOTE-087 trial.

Pembrolizumab has garnered interest for this population because Hodgkin Reed-Sternberg cells have a chromosomal alteration leading to overexpression of both programmed death ligand 1 and programmed death ligand 2.

Neil Osterweil

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.