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First CAR T-cell therapy approved in Canada
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Regimens produce similar results in FL
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in the treatment of follicular lymphoma (FL) in a phase 3 trial.
Patients with previously untreated FL had similar complete response (CR) rates and progression-free survival (PFS) rates whether they received rituximab-based chemotherapy or rituximab plus lenalidomide.
These results were published in The New England Journal of Medicine.
The trial, RELEVANCE, included 1,030 patients with previously untreated FL. They were randomized to receive rituximab plus chemotherapy (n=517) or rituximab plus lenalidomide (n=513) for 18 cycles.
Patients in the chemotherapy arm received one of three regimens—R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), rituximab and bendamustine, or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone).
Patients in both treatment arms went on to receive rituximab maintenance every 8 weeks for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years.
The coprimary endpoints were CR (confirmed or unconfirmed) and PFS. After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the treatment arms.
CR was observed in 48% of the rituximab-lenalidomide arm and 53% of the rituximab-chemotherapy arm (P=0.13).
The interim 3-year PFS rate was 77% in the rituximab-lenalidomide arm and 78% in the rituximab-chemotherapy arm. The hazard ratio for progression or death from any cause was 1.10 (P=0.48).
The efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose disease was Ann Arbor stage I or II, whereas the efficacy of rituximab-lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some adverse events (AEs) being more common in one arm than the other.
AEs that were more common with rituximab-lenalidomide include cutaneous reactions (43% vs 24%), diarrhea (37% vs 19%), rash (29% vs 8%), abdominal pain (15% vs 9%), peripheral edema (14% vs 9%), muscle spasms (13% vs 4%), myalgia (14% vs 6%), and tumor flare reaction (6% vs <1%).
AEs that were more common with rituximab-chemotherapy were anemia (89% vs 66%), fatigue (29% vs 23%), nausea (42% vs 20%), vomiting (19% vs 7%), febrile neutropenia (7% vs 2%), leukopenia (10% vs 4%), and peripheral neuropathy (16% vs 7%).
Grade 3/4 cutaneous reactions were more common with rituximab-lenalidomide (7% vs 1%), and grade 3/4 neutropenia was more common with rituximab-chemotherapy (50% vs 32%).
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in the treatment of follicular lymphoma (FL) in a phase 3 trial.
Patients with previously untreated FL had similar complete response (CR) rates and progression-free survival (PFS) rates whether they received rituximab-based chemotherapy or rituximab plus lenalidomide.
These results were published in The New England Journal of Medicine.
The trial, RELEVANCE, included 1,030 patients with previously untreated FL. They were randomized to receive rituximab plus chemotherapy (n=517) or rituximab plus lenalidomide (n=513) for 18 cycles.
Patients in the chemotherapy arm received one of three regimens—R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), rituximab and bendamustine, or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone).
Patients in both treatment arms went on to receive rituximab maintenance every 8 weeks for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years.
The coprimary endpoints were CR (confirmed or unconfirmed) and PFS. After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the treatment arms.
CR was observed in 48% of the rituximab-lenalidomide arm and 53% of the rituximab-chemotherapy arm (P=0.13).
The interim 3-year PFS rate was 77% in the rituximab-lenalidomide arm and 78% in the rituximab-chemotherapy arm. The hazard ratio for progression or death from any cause was 1.10 (P=0.48).
The efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose disease was Ann Arbor stage I or II, whereas the efficacy of rituximab-lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some adverse events (AEs) being more common in one arm than the other.
AEs that were more common with rituximab-lenalidomide include cutaneous reactions (43% vs 24%), diarrhea (37% vs 19%), rash (29% vs 8%), abdominal pain (15% vs 9%), peripheral edema (14% vs 9%), muscle spasms (13% vs 4%), myalgia (14% vs 6%), and tumor flare reaction (6% vs <1%).
AEs that were more common with rituximab-chemotherapy were anemia (89% vs 66%), fatigue (29% vs 23%), nausea (42% vs 20%), vomiting (19% vs 7%), febrile neutropenia (7% vs 2%), leukopenia (10% vs 4%), and peripheral neuropathy (16% vs 7%).
Grade 3/4 cutaneous reactions were more common with rituximab-lenalidomide (7% vs 1%), and grade 3/4 neutropenia was more common with rituximab-chemotherapy (50% vs 32%).
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in the treatment of follicular lymphoma (FL) in a phase 3 trial.
Patients with previously untreated FL had similar complete response (CR) rates and progression-free survival (PFS) rates whether they received rituximab-based chemotherapy or rituximab plus lenalidomide.
These results were published in The New England Journal of Medicine.
The trial, RELEVANCE, included 1,030 patients with previously untreated FL. They were randomized to receive rituximab plus chemotherapy (n=517) or rituximab plus lenalidomide (n=513) for 18 cycles.
Patients in the chemotherapy arm received one of three regimens—R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), rituximab and bendamustine, or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone).
Patients in both treatment arms went on to receive rituximab maintenance every 8 weeks for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years.
The coprimary endpoints were CR (confirmed or unconfirmed) and PFS. After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the treatment arms.
CR was observed in 48% of the rituximab-lenalidomide arm and 53% of the rituximab-chemotherapy arm (P=0.13).
The interim 3-year PFS rate was 77% in the rituximab-lenalidomide arm and 78% in the rituximab-chemotherapy arm. The hazard ratio for progression or death from any cause was 1.10 (P=0.48).
The efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose disease was Ann Arbor stage I or II, whereas the efficacy of rituximab-lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some adverse events (AEs) being more common in one arm than the other.
AEs that were more common with rituximab-lenalidomide include cutaneous reactions (43% vs 24%), diarrhea (37% vs 19%), rash (29% vs 8%), abdominal pain (15% vs 9%), peripheral edema (14% vs 9%), muscle spasms (13% vs 4%), myalgia (14% vs 6%), and tumor flare reaction (6% vs <1%).
AEs that were more common with rituximab-chemotherapy were anemia (89% vs 66%), fatigue (29% vs 23%), nausea (42% vs 20%), vomiting (19% vs 7%), febrile neutropenia (7% vs 2%), leukopenia (10% vs 4%), and peripheral neuropathy (16% vs 7%).
Grade 3/4 cutaneous reactions were more common with rituximab-lenalidomide (7% vs 1%), and grade 3/4 neutropenia was more common with rituximab-chemotherapy (50% vs 32%).
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
Rituximab/lenalidomide similar to rituximab/chemotherapy for follicular lymphoma
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in treatment of follicular lymphoma, according to results from a phase 3 trial.
RELEVANCE (NCT01476787) was a multicenter, international, randomized, open-label trial designed to determine the superiority of rituximab/lenalidomide over rituximab/chemotherapy.
This trial randomized 1,030 patients with previously untreated follicular lymphoma to receive either rituximab plus lenalidomide (n = 513) or rituximab plus chemotherapy (n = 517) for 18 cycles; both groups then went on to receive rituximab maintenance therapy for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years. The study was published in the New England Journal of Medicine.
One of the coprimary endpoints was complete response (confirmed or unconfirmed) by the end of the treatment period; the other was progression-free survival, which was planned to be assessed through three analyses, including two interim analyses, the first of which was reported in this study.
After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the two groups. Complete response (confirmed or unconfirmed) was seen in 48% of the rituximab/lenalidomide group (95% confidence interval [CI], 44-53) and in 53% of the rituximab/chemotherapy group (95% CI, 49-57; P = .13). The hazard ratio for progression or death from any cause was 1.10 (95% CI, 0.85-1.43; P = .48).
In the subgroup analyses, the efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose follicular lymphoma was Ann Arbor stage I or II, whereas efficacy of rituximab/lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some events being more common in one group than in the other. For example, cutaneous reactions, diarrhea, rash, and myalgia were more common with rituximab/lenalidomide treatment, whereas anemia, fatigue, nausea, and febrile neutropenia were more common with rituximab/chemotherapy treatment. Among grade 3 or 4 events, cutaneous reactions were more common with rituximab/lenalidomide, and grade 3 or 4 neutropenia was more common with rituximab/chemotherapy.
“Overall, both treatment groups showed good outcomes, and a median has not yet been reached for either progression-free survival or overall survival,” the study authors wrote.
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
SOURCE: Morschhauser F et al. N Engl J Med. 2018;379:934-47.
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in treatment of follicular lymphoma, according to results from a phase 3 trial.
RELEVANCE (NCT01476787) was a multicenter, international, randomized, open-label trial designed to determine the superiority of rituximab/lenalidomide over rituximab/chemotherapy.
This trial randomized 1,030 patients with previously untreated follicular lymphoma to receive either rituximab plus lenalidomide (n = 513) or rituximab plus chemotherapy (n = 517) for 18 cycles; both groups then went on to receive rituximab maintenance therapy for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years. The study was published in the New England Journal of Medicine.
One of the coprimary endpoints was complete response (confirmed or unconfirmed) by the end of the treatment period; the other was progression-free survival, which was planned to be assessed through three analyses, including two interim analyses, the first of which was reported in this study.
After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the two groups. Complete response (confirmed or unconfirmed) was seen in 48% of the rituximab/lenalidomide group (95% confidence interval [CI], 44-53) and in 53% of the rituximab/chemotherapy group (95% CI, 49-57; P = .13). The hazard ratio for progression or death from any cause was 1.10 (95% CI, 0.85-1.43; P = .48).
In the subgroup analyses, the efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose follicular lymphoma was Ann Arbor stage I or II, whereas efficacy of rituximab/lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some events being more common in one group than in the other. For example, cutaneous reactions, diarrhea, rash, and myalgia were more common with rituximab/lenalidomide treatment, whereas anemia, fatigue, nausea, and febrile neutropenia were more common with rituximab/chemotherapy treatment. Among grade 3 or 4 events, cutaneous reactions were more common with rituximab/lenalidomide, and grade 3 or 4 neutropenia was more common with rituximab/chemotherapy.
“Overall, both treatment groups showed good outcomes, and a median has not yet been reached for either progression-free survival or overall survival,” the study authors wrote.
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
SOURCE: Morschhauser F et al. N Engl J Med. 2018;379:934-47.
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in treatment of follicular lymphoma, according to results from a phase 3 trial.
RELEVANCE (NCT01476787) was a multicenter, international, randomized, open-label trial designed to determine the superiority of rituximab/lenalidomide over rituximab/chemotherapy.
This trial randomized 1,030 patients with previously untreated follicular lymphoma to receive either rituximab plus lenalidomide (n = 513) or rituximab plus chemotherapy (n = 517) for 18 cycles; both groups then went on to receive rituximab maintenance therapy for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years. The study was published in the New England Journal of Medicine.
One of the coprimary endpoints was complete response (confirmed or unconfirmed) by the end of the treatment period; the other was progression-free survival, which was planned to be assessed through three analyses, including two interim analyses, the first of which was reported in this study.
After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the two groups. Complete response (confirmed or unconfirmed) was seen in 48% of the rituximab/lenalidomide group (95% confidence interval [CI], 44-53) and in 53% of the rituximab/chemotherapy group (95% CI, 49-57; P = .13). The hazard ratio for progression or death from any cause was 1.10 (95% CI, 0.85-1.43; P = .48).
In the subgroup analyses, the efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose follicular lymphoma was Ann Arbor stage I or II, whereas efficacy of rituximab/lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some events being more common in one group than in the other. For example, cutaneous reactions, diarrhea, rash, and myalgia were more common with rituximab/lenalidomide treatment, whereas anemia, fatigue, nausea, and febrile neutropenia were more common with rituximab/chemotherapy treatment. Among grade 3 or 4 events, cutaneous reactions were more common with rituximab/lenalidomide, and grade 3 or 4 neutropenia was more common with rituximab/chemotherapy.
“Overall, both treatment groups showed good outcomes, and a median has not yet been reached for either progression-free survival or overall survival,” the study authors wrote.
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
SOURCE: Morschhauser F et al. N Engl J Med. 2018;379:934-47.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Complete responses were seen in 48% of rituximab/lenalidomide patients versus 53% in the rituximab/chemotherapy patients (P = .13).
Study details: A phase 3 superiority trial of 1,030 patients with previously untreated follicular lymphoma.
Disclosures: Celgene and the Lymphoma Academic Research Organization funded the study. The authors reported various disclosures, including financial ties to Celgene.
Source: Morschhauser F et al. N Engl J Med. 2018;379:934-47.
New BTK inhibitor under review in China
for the treatment of relapsed/refractory mantle cell lymphoma (MCL).
The U.S. Food and Drug Administration recently granted the drug fast track designation for the treatment of patients with Waldenström’s macroglobulinemia.
The application in China is supported by results from a phase 2, single-arm trial of 86 patients with relapsed/refractory MCL who received 160 mg zanubrutinib orally twice daily. The overall response rate was 84%, which included 59% of patients with a complete response. At 8.3 months of follow-up, the median duration of response had not been reached, according to the drug’s sponsor BeiGene.
Zanubrutinib is being studied in several ongoing trials, including for the treatment of untreated chronic lymphocytic leukemia (CLL), for relapsed/refractory follicular lymphoma in combination with obinutuzumab, and comparing it to ibrutinib in Waldenström’s macroglobulinemia and CLL/small lymphocytic lymphoma.
for the treatment of relapsed/refractory mantle cell lymphoma (MCL).
The U.S. Food and Drug Administration recently granted the drug fast track designation for the treatment of patients with Waldenström’s macroglobulinemia.
The application in China is supported by results from a phase 2, single-arm trial of 86 patients with relapsed/refractory MCL who received 160 mg zanubrutinib orally twice daily. The overall response rate was 84%, which included 59% of patients with a complete response. At 8.3 months of follow-up, the median duration of response had not been reached, according to the drug’s sponsor BeiGene.
Zanubrutinib is being studied in several ongoing trials, including for the treatment of untreated chronic lymphocytic leukemia (CLL), for relapsed/refractory follicular lymphoma in combination with obinutuzumab, and comparing it to ibrutinib in Waldenström’s macroglobulinemia and CLL/small lymphocytic lymphoma.
for the treatment of relapsed/refractory mantle cell lymphoma (MCL).
The U.S. Food and Drug Administration recently granted the drug fast track designation for the treatment of patients with Waldenström’s macroglobulinemia.
The application in China is supported by results from a phase 2, single-arm trial of 86 patients with relapsed/refractory MCL who received 160 mg zanubrutinib orally twice daily. The overall response rate was 84%, which included 59% of patients with a complete response. At 8.3 months of follow-up, the median duration of response had not been reached, according to the drug’s sponsor BeiGene.
Zanubrutinib is being studied in several ongoing trials, including for the treatment of untreated chronic lymphocytic leukemia (CLL), for relapsed/refractory follicular lymphoma in combination with obinutuzumab, and comparing it to ibrutinib in Waldenström’s macroglobulinemia and CLL/small lymphocytic lymphoma.
EC approves CAR T-cell therapy for DLBCL, PMBCL
The European Commission (EC) has approved the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®) to treat two types of lymphoma.
Axicabtagene ciloleucel is now approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy.
The approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC’s approval of axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival rate was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome.
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher cytokine release syndrome occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
The European Commission (EC) has approved the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®) to treat two types of lymphoma.
Axicabtagene ciloleucel is now approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy.
The approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC’s approval of axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival rate was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome.
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher cytokine release syndrome occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
The European Commission (EC) has approved the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®) to treat two types of lymphoma.
Axicabtagene ciloleucel is now approved to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma (PMBCL) after two or more lines of systemic therapy.
The approval extends to all member countries of the European Union, as well as Norway, Iceland, and Liechtenstein.
The EC’s approval of axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival rate was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome.
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher cytokine release syndrome occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
First CAR T-cell therapy approvals bolster booming immunotherapy market
There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).1 CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.
Tisagenlecleucel
Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.2 Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.
The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 106 transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.
The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.3
To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.
In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.
Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.
The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.
Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.4
Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 106 CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 108 cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.
Axicabtagene ciloleucel
Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.5 It is not indicated for the treatment of patients with primary central nervous system lymphoma.
Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.6 Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.
Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.
Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.
A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.
The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.
To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.
Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).7
Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 106 CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.
1. Bosserman LD. Cancer care in 2017: the promise of more cures with the challenges of an unstable health care system. JCSO 2017;15(6):e283-e290.
2. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA News Release. August 30, 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/
ucm574154.htm. Accessed March 31, 2018.
3. Maude S.L, Laetsch T.W, Buechner S, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-48.
4. Kymriah (tisagenlecleucel) suspension for intravenous use. Prescribing information. Novartis Pharmaceuticals Corporation, August, 2017. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.
com/files/kymriah.pdf. Accessed March 31, 2018.
5. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. FDA News Release. October 18, 2017. https://www.fda.gov/Drugs/
InformationOnDrugs/ApprovedDrugs/ucm581296.htm. Accessed March 31, 2018.
6. Neelapu, S.S, Locke F.L, Bartlett, L.J, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377:2531-44.
7. Kymriah (tisagenlecleucel) suspension for intravenous use. Prescribing information. Kite Pharma Inc. October 2017. https://www.yescarta.com/wp-content/uploads/yescarta-pi.pdf. Accessed March 31, 2018.
There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).1 CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.
Tisagenlecleucel
Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.2 Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.
The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 106 transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.
The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.3
To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.
In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.
Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.
The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.
Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.4
Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 106 CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 108 cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.
Axicabtagene ciloleucel
Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.5 It is not indicated for the treatment of patients with primary central nervous system lymphoma.
Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.6 Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.
Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.
Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.
A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.
The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.
To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.
Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).7
Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 106 CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.
There were a number of landmark approvals by the US Food and Drug Administration (FDA) in 2017 for cancer therapies, among them, the approval of the first two chimeric antigen receptor (CAR) T-cell therapies for cancer: tisagenlecleucel (in August) and axicabtagene ciloluecel (in October).1 CAR T-cells are a type of adoptive cell therapy or immunotherapy, in which the patient’s own immune cells are genetically engineered to target a tumor-associated antigen, in this case CD19. In tisagenlecleucel, CD19 proteins on B cells are targeted in the treatment of B-cell precursor acute lymphoblastic leukemia. Axicabtagene ciloluecel, the second anti-CD19 CAR T-cell therapy, was approved for the treatment of refractory, aggressive B-cell non-Hodgkin lymphoma.
Tisagenlecleucel
Tisagenlecleucel was approved for the treatment of pediatric patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) whose disease is refractory to treatment or who have relapsed after second-line therapy or beyond.2 Approval was based on the pivotal ELIANA trial, a single-arm, global phase 2 trial conducted at 25 centers worldwide during April 2015 through April 2017. Patients were eligible for enrollment if they had relapsed or refractory B-cell ALL and were at least 3 years of age at screening and no older than 21 years of age at diagnosis, had at least 5% lymphoblasts in the bone marrow at screening, had tumor expression of CD19, had adequate organ function, and a Karnofsky (adult) or Lansky (child) Performance Status of ≥50 (with the worst allowable score, 50, indicating a patient who requires considerable assistance and frequent medical care [Karnofsky] and lying around much of the day, but gets dressed; no active playing but participates in all quiet play and activities [Lansky]). Exclusion criteria included previous receipt of anti-CD19 therapy, concomitant genetic syndromes associated with bone marrow failure, previous malignancy, and/or active or latent hepatitis B or C virus (HBV/HCV) infection.
The overall remission rate (ORR) was evaluated in 75 patients who were given a single dose of tisagenlecleucel (a median weight-adjusted dose of 3.1 x 106 transduced viable T cells per kg of body weight) within 14 days of completing a lymphodepleting chemotherapy regimen. The confirmed ORR after at least 3 months of follow-up, as assessed by independent central review, was 81%, which included 60% of patients in complete remission (CR) and 21% in complete remission with incomplete hematologic recovery, all of whom were negative for minimal residual disease.
The most common adverse events (AEs) associated with tisagenlecleucel treatment were cytokine release syndrome (CRS), hypogammaglobulinemia, infection, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, and delirium. AEs were of grade 3/4 severity in 84% of patients.3
To combat serious safety issues, including CRS and neurologic toxicities, the FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (REMS) that, in part, requires health care providers who administer the drug to be trained in their management. It also requires the facility where treatment is administered to have immediate, onsite access to the drug tocilizumab, which was approved in conjunction with tisagenlecleucel for the treatment of patients who experience CRS.
In addition to information about the REMS, the prescribing information details warnings and precautions relating to several other common toxicities. These include hypersensitivity reactions, serious infections, prolonged cytopenias, and hypogammaglobulinemia.
Patients should be monitored for signs and symptoms of infection and treated appropriately. Viral reactivation can occur after tisagenlecleucel treatment, so patients should be screened for HBV, HCV, and human immunodeficiency virus before collection of cells.
The administration of myeloid growth factors is not recommended during the first 3 weeks after infusion or until CRS has resolved. Immunoglobulin levels should be monitored after treatment and hypogammaglobulinemia managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement according to standard guidelines.
Patients treated with tisagenlecleucel should also be monitored for life for secondary malignancies, should not be treated with live vaccines from 2 weeks before the start of lymphodepleting chemotherapy until immune recovery after tisagenlecleucel infusion, and should be aware of the potential for neurological events to impact their ability to drive and use dangerous machinery.4
Tisagenlecleucel is marketed as Kymriah by Novartis Pharmaceuticals. The recommended dose is 1 infusion of 0.2-5 x 106 CAR-positive viable T cells per kilogram of body weight intravenously (for patients ≤50kg) and 0.1-2.5 x 108 cells/kg (for patients >50kg), administered 2-14 days after lymphodepleting chemotherapy.
Axicabtagene ciloleucel
Axicabtagene ciloleucel was approved for the treatment of adult patients with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.5 It is not indicated for the treatment of patients with primary central nervous system lymphoma.
Approval followed positive results from the phase 2 single-arm, multicenter ZUMA-1 trial.6 Patients were included if they were aged 18 years of age and older, had histologically confirmed aggressive B-cell non-Hodgkin lymphoma that was chemotherapy refractory, had received adequate previous therapy, had at least 1 measurable lesion, had completed radiation or systemic therapy at least 2 weeks before, had resolved toxicities related to previous therapy, and had an Eastern Cooperative Oncology Group Performance Status of 0 (asymptomatic) or 1 (symptomatic), an absolute neutrophil count of ≥1000/µL, a platelet count of ≥50,000/µL, and adequate hepatic, renal and cardiac function. They were treated with a single infusion of axicabtagene ciloleucel after lymphodepleting chemotherapy.
Patients who had received previous CD19-targeted therapy, who had concomitant genetic syndromes associated with bone marrow failure, who had previous malignancy, and who had active or latent HBV/HCV infection were among those excluded from the study.
Patients were enrolled in 2 cohorts; those with DLBCL (n = 77) and those with PMBCL or transformed follicular lymphoma (n = 24). The primary endpoint was objective response rate, and after a primary analysis at a minimum of 6 months follow-up, the objective response rate was 82%, with a CR rate of 52%. Among patients who achieved CR, the median duration of response was not reached after a median follow-up of 7.9 months.
A subsequent updated analysis was performed when 108 patients had been followed for a minimum of 1 year. The objective response rate was 82%, and the CR rate was 58%, with some patients having CR in the absence of additional therapies as late as 15 months after treatment. At this updated analysis, 42% of patients continued to have a response, 40% of whom remained in CR.
The most common grade 3 or higher AEs included febrile neutropenia, fever, CRS, encephalopathy, infections, hypotension, and hypoxia. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias, and serious infections. Grade 3 or higher CRS or neurologic toxicities occurred in 13% and 28% of patients, respectively. Three patients died during treatment.
To mitigate the risk of CRS and neurologic toxicity, axicabtagene ciloleucel is approved with an REMS that requires appropriate certification and training before hospitals are cleared to administer the therapy.
Other warnings and precautions in the prescribing information relate to serious infections (monitor for signs and symptoms and treat appropriately), prolonged cytopenias (monitor blood counts), hypogammaglobulinemia (monitor immunoglobulin levels and manage appropriately), secondary malignancies (life-long monitoring), and the potential effects of neurologic events on a patient’s ability to drive and operate dangerous machinery (avoid for at least 8 weeks after infusion).7
Axicabtagene ciloleucel is marketed as Yescarta by Kite Pharma Inc. The recommended dose is a single intravenous infusion with a target of 2 x 106 CAR-positive viable T cells per kilogram of body weight, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.
1. Bosserman LD. Cancer care in 2017: the promise of more cures with the challenges of an unstable health care system. JCSO 2017;15(6):e283-e290.
2. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA News Release. August 30, 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/
ucm574154.htm. Accessed March 31, 2018.
3. Maude S.L, Laetsch T.W, Buechner S, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-48.
4. Kymriah (tisagenlecleucel) suspension for intravenous use. Prescribing information. Novartis Pharmaceuticals Corporation, August, 2017. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.
com/files/kymriah.pdf. Accessed March 31, 2018.
5. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. FDA News Release. October 18, 2017. https://www.fda.gov/Drugs/
InformationOnDrugs/ApprovedDrugs/ucm581296.htm. Accessed March 31, 2018.
6. Neelapu, S.S, Locke F.L, Bartlett, L.J, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377:2531-44.
7. Kymriah (tisagenlecleucel) suspension for intravenous use. Prescribing information. Kite Pharma Inc. October 2017. https://www.yescarta.com/wp-content/uploads/yescarta-pi.pdf. Accessed March 31, 2018.
1. Bosserman LD. Cancer care in 2017: the promise of more cures with the challenges of an unstable health care system. JCSO 2017;15(6):e283-e290.
2. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA News Release. August 30, 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/
ucm574154.htm. Accessed March 31, 2018.
3. Maude S.L, Laetsch T.W, Buechner S, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-48.
4. Kymriah (tisagenlecleucel) suspension for intravenous use. Prescribing information. Novartis Pharmaceuticals Corporation, August, 2017. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.
com/files/kymriah.pdf. Accessed March 31, 2018.
5. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. FDA News Release. October 18, 2017. https://www.fda.gov/Drugs/
InformationOnDrugs/ApprovedDrugs/ucm581296.htm. Accessed March 31, 2018.
6. Neelapu, S.S, Locke F.L, Bartlett, L.J, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377:2531-44.
7. Kymriah (tisagenlecleucel) suspension for intravenous use. Prescribing information. Kite Pharma Inc. October 2017. https://www.yescarta.com/wp-content/uploads/yescarta-pi.pdf. Accessed March 31, 2018.
Immunotherapies shape the treatment landscape for hematologic malignancies
The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.
Exploiting T cells
The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.1,2
Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.
Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.1,3,4
Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.
CARs are formed by fusing part of the single-chain variable fragment of a monoclonal antibody to part of the TCR and one or more costimulatory molecules. In this way, the T cell is guided to the tumor through antibody recognition of a particular tumor-associated antigen, whereupon its effector functions are activated by engagement of the TCR and costimulatory signal.5
Headlining advancements with CAR T cells
CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.4,5
CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.6
It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.7
Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.8 Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.9
Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).10
Antibodies evolve
Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.
Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).11 Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.12
The use of ofatumumab as maintenance therapy is supported by the results of the phase 3 PROLONG study in which 474 patients were randomly assigned to ofatumumab maintenance for 2 years or observation. Over a median follow-up of close to 20 months, ofatumumab-treated patients experienced improved progression-free survival (PFS; median PFS: 29.4 months vs 15.2 months; hazard ratio [HR], 0.50; P < .0001).13 Obinutuzumab’s new indication is based on data from the phase 3 GADOLIN trial, in which the obinutuzumab arm showed improved 3-year PFS compared with rituximab.14Until recently, multiple myeloma had proven relatively resistant to mAb therapy, but two new drug targets have dramatically altered the treatment landscape for this type of hematologic malignancy. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells and only at low levels on other lymphoid and myeloid cells.15
Several antibodies directed at these targets are in clinical development, but daratumumab and elotuzumab, targeting CD38 and CS1, respectively, are both newly approved by the FDA for relapsed/refractory disease, daratumumab as monotherapy and elotuzumab in combination with lenalidomide and dexamethasone.
The indication for daratumumab was subsequently expanded to include its use in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Support for this new indication came from 2 pivotal phase 3 trials. In the CASTOR trial, the combination of daratumumab with bortezomib–dexamethasone reduced the risk of disease progression or death by 61%, compared with bortezomib–dexamethasone alone, whereas daratumumab with lenalidomide–dexamethasone reduced the risk of disease progression or death by 63% in the POLLUX trial.16,17
Numerous clinical trials for both drugs are ongoing, including in the front-line setting in multiple myeloma, as well as trials in other types of B-cell malignancy, and several other CD38-targeting mAbs are also in development, including isatuximab, which has reached the phase 3 stage (NCT02990338).
Innovative design
Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.
The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.18
Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.19 Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.20
Bispecific antibodies that link natural killer (NK) cells to tumor cells, by targeting the NK-cell receptor CD16, known as BiKEs, are also in development in an attempt to harness the power of the innate immune response.
B-cell signaling a ripe target
Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.
A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.
More than 100 clinical trials of ibrutinib are ongoing in an effort to further clarify its role in a variety of different disease settings. Furthermore, in an effort to address some of the toxicity concerns with ibrutinib, more specific BTK inhibitors are also being developed.
Other kinases that orchestrate the BCR pathway, including phosphatidylinositol-3-kinase (PI3K) and SYK, are also being targeted. The delta isoform of PI3K is expressed exclusively in hematopoietic cells and a number of PI3K delta inhibitors have been developed. Idelalisib received regulatory approval for the treatment of patients with CLL in combination with rituximab, and for patients with follicular lymphoma and small lymphocytic leukemia.
As with ibrutinib, a plethora of clinical trials are ongoing, however a major setback was suffered in the frontline setting when Gilead Sciences halted 6 clinical trials due to reports of increased rates of adverse events, including deaths.26 Meanwhile, SYK inhibitors have lagged behind somewhat in their development, but one such offering, entospletinib, is showing promise in patients with AML.27
Finally, there has been some success in targeting one of the downstream targets of the BCR signaling pathway, the Bcl2 protein that is involved in the regulation of apoptosis. Venetoclax was approved last year for the treatment of patients with relapsed/refractory CLL in patients who have a chromosome 17p deletion, based on the demonstration of impressive, durable responses.28
1. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ. Haemato- logical malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer. 2015;15(4):201-215.
2. Im A, Pavletic SZ. Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol. 2017;10(1):94.
3. Gill S. Planes, trains, and automobiles: perspectives on CAR T cells and other cellular therapies for hematologic malignancies. Curr Hematol Malig Rep. 2016;11(4):318-325.
4. Ye B, Stary CM, Gao Q, et al. Genetically modified T-cell-based adoptive immunotherapy in hematological malignancies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237740/. Published January 2, 2017. Accessed July 22, 2017.
5. Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337-350.
6. Novartis. Novartis personalized cell therapy CTL019 receives FDA breakthrough therapy designation. https://www.novartis.com/news/media-releases/novartis-personalized-cell-therapy-ctl019-receivesfda-breakthrough-therapy. Published July 7, 2014. Accessed June 19,
2017.
7. Novartis. Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL. https://www.novartis.com/news/media-releases/novartis-presentsresults-first-global-registration-trial-ctl019-pediatric-and. Published December 4, 2016. Accessed June 19, 2017.
8. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA1: a multicenter study of KTE-C19 Anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285-295.
9. Abramson JS, Palomba L, Gordon L. Transcend NHL 001: immunotherapy with the CD19-Directd CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Paper presented at 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, CA.
10. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35(suppl;):Abstr LBA3001.
11. Okroj M, Osterborg A, Blom AM. Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies. Cancer Treat Rev. 2013;39(6):632-639.
12. Safdari Y, Ahmadzadeh V, Farajnia S. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies. Invest New Drugs. 2016;34(4):497-512.
13. van Oers MH, Kuliczkowski K, Smolej L, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015;16(13):1370-1379.
14. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093.
15. Touzeau C, Moreau P, Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31(5):1039-1047.
16. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
17. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
18. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.
19. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.
20. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.
21. Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol. 2015;93(3):290-296.
22. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
23. Koehrer S, Burger JA. B-cell receptor signaling in chronic lymphocytic leukemia and other B-cell malignancies. Clin Adv Hematol Oncol. 2016;14(1):55-65.
24. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015;94(3):193-205.
25. Bojarczuk K, Bobrowicz M, Dwojak M, et al. B-cell receptor signaling in the pathogenesis of lymphoid malignancies. Blood Cells Mol Dis. 2015;55(3):255-265.
26. Medscape Medical News. Gilead stops six trials adding idelalisib to other drugs. http://www.medscape.com/viewarticle/860372. Published March 14, 2016. Accessed June 19, 2017.
27. Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016;7(3):157-170.
28. Food and Drug Administration. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. Released April 11, 2016. Accessed June 19, 2017.
The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.
Exploiting T cells
The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.1,2
Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.
Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.1,3,4
Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.
CARs are formed by fusing part of the single-chain variable fragment of a monoclonal antibody to part of the TCR and one or more costimulatory molecules. In this way, the T cell is guided to the tumor through antibody recognition of a particular tumor-associated antigen, whereupon its effector functions are activated by engagement of the TCR and costimulatory signal.5
Headlining advancements with CAR T cells
CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.4,5
CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.6
It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.7
Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.8 Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.9
Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).10
Antibodies evolve
Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.
Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).11 Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.12
The use of ofatumumab as maintenance therapy is supported by the results of the phase 3 PROLONG study in which 474 patients were randomly assigned to ofatumumab maintenance for 2 years or observation. Over a median follow-up of close to 20 months, ofatumumab-treated patients experienced improved progression-free survival (PFS; median PFS: 29.4 months vs 15.2 months; hazard ratio [HR], 0.50; P < .0001).13 Obinutuzumab’s new indication is based on data from the phase 3 GADOLIN trial, in which the obinutuzumab arm showed improved 3-year PFS compared with rituximab.14Until recently, multiple myeloma had proven relatively resistant to mAb therapy, but two new drug targets have dramatically altered the treatment landscape for this type of hematologic malignancy. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells and only at low levels on other lymphoid and myeloid cells.15
Several antibodies directed at these targets are in clinical development, but daratumumab and elotuzumab, targeting CD38 and CS1, respectively, are both newly approved by the FDA for relapsed/refractory disease, daratumumab as monotherapy and elotuzumab in combination with lenalidomide and dexamethasone.
The indication for daratumumab was subsequently expanded to include its use in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Support for this new indication came from 2 pivotal phase 3 trials. In the CASTOR trial, the combination of daratumumab with bortezomib–dexamethasone reduced the risk of disease progression or death by 61%, compared with bortezomib–dexamethasone alone, whereas daratumumab with lenalidomide–dexamethasone reduced the risk of disease progression or death by 63% in the POLLUX trial.16,17
Numerous clinical trials for both drugs are ongoing, including in the front-line setting in multiple myeloma, as well as trials in other types of B-cell malignancy, and several other CD38-targeting mAbs are also in development, including isatuximab, which has reached the phase 3 stage (NCT02990338).
Innovative design
Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.
The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.18
Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.19 Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.20
Bispecific antibodies that link natural killer (NK) cells to tumor cells, by targeting the NK-cell receptor CD16, known as BiKEs, are also in development in an attempt to harness the power of the innate immune response.
B-cell signaling a ripe target
Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.
A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.
More than 100 clinical trials of ibrutinib are ongoing in an effort to further clarify its role in a variety of different disease settings. Furthermore, in an effort to address some of the toxicity concerns with ibrutinib, more specific BTK inhibitors are also being developed.
Other kinases that orchestrate the BCR pathway, including phosphatidylinositol-3-kinase (PI3K) and SYK, are also being targeted. The delta isoform of PI3K is expressed exclusively in hematopoietic cells and a number of PI3K delta inhibitors have been developed. Idelalisib received regulatory approval for the treatment of patients with CLL in combination with rituximab, and for patients with follicular lymphoma and small lymphocytic leukemia.
As with ibrutinib, a plethora of clinical trials are ongoing, however a major setback was suffered in the frontline setting when Gilead Sciences halted 6 clinical trials due to reports of increased rates of adverse events, including deaths.26 Meanwhile, SYK inhibitors have lagged behind somewhat in their development, but one such offering, entospletinib, is showing promise in patients with AML.27
Finally, there has been some success in targeting one of the downstream targets of the BCR signaling pathway, the Bcl2 protein that is involved in the regulation of apoptosis. Venetoclax was approved last year for the treatment of patients with relapsed/refractory CLL in patients who have a chromosome 17p deletion, based on the demonstration of impressive, durable responses.28
The treatment landscape for hematologic malignancies is evolving faster than ever before, with a range of available therapeutic options that is now almost as diverse as this group of tumors. Immunotherapy in particular is front and center in the battle to control these diseases. Here, we describe the latest promising developments.
Exploiting T cells
The treatment landscape for hematologic malignancies is diverse, but one particular type of therapy has led the charge in improving patient outcomes. Several features of hematologic malignancies may make them particularly amenable to immunotherapy, including the fact that they are derived from corrupt immune cells and come into constant contact with other immune cells within the hematopoietic environment in which they reside. One of the oldest forms of immunotherapy, hematopoietic stem-cell transplantation (HSCT), remains the only curative option for many patients with hematologic malignancies.1,2
Given the central role of T lymphocytes in antitumor immunity, research efforts have focused on harnessing their activity for cancer treatment. One example of this is adoptive cellular therapy (ACT), in which T cells are collected from a patient, grown outside the body to increase their number and then reinfused back to the patient. Allogeneic HSCT, in which the stem cells are collected from a matching donor and transplanted into the patient, is a crude example of ACT. The graft-versus-tumor effect is driven by donor cells present in the transplant, but is limited by the development of graft-versus-host disease (GvHD), whereby the donor T cells attack healthy host tissue.
Other types of ACT have been developed in an effort to capitalize on the anti-tumor effects of the patients own T cells and thus avoid the potentially fatal complication of GvHD. Tumor-infiltrating lymphocyte (TIL) therapy was developed to exploit the presence of tumor-specific T cells in the tumor microenvironment. To date, the efficacy of TIL therapy has been predominantly limited to melanoma.1,3,4
Most recently, there has been a substantial buzz around the idea of genetically engineering T cells before they are reintroduced into the patient, to increase their anti-tumor efficacy and minimize damage to healthy tissue. This is achieved either by manipulating the antigen binding portion of the T-cell receptor to alter its specificity (TCR T cells) or by generating artificial fusion receptors known as chimeric antigen receptors (CAR T cells; Figure 1). The former is limited by the need for the TCR to be genetically matched to the patient’s immune type, whereas the latter is more flexible in this regard and has proved most successful.
CARs are formed by fusing part of the single-chain variable fragment of a monoclonal antibody to part of the TCR and one or more costimulatory molecules. In this way, the T cell is guided to the tumor through antibody recognition of a particular tumor-associated antigen, whereupon its effector functions are activated by engagement of the TCR and costimulatory signal.5
Headlining advancements with CAR T cells
CAR T cells directed against the CD19 antigen, found on the surface of many hematologic malignancies, are the most clinically advanced in this rapidly evolving field (Table 1). Durable remissions have been demonstrated in patients with relapsed and refractory hematologic malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and acute lymphoblastic lymphoma (ALL), with efficacy in both the pre- and posttransplant setting and in patients with chemotherapy-refractory disease.4,5
CTL019, a CD19-targeted CAR-T cell therapy, also known as tisagenlecleucel-T, has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with relapsed/refractory B-cell ALL and, more recently, for the treatment of adult patients with relapsed/refractory diffuse large B cell lymphoma.6
It is edging closer to FDA approval for the ALL indication, having been granted priority review in March on the basis of the phase 2 ELIANA trial, in which 50 patients received a single infusion of CTL019. Data presented at the American Society of Hematology annual meeting in December 2016 showed that 82% of patients achieved either complete remission (CR) or CR with incomplete blood count recovery (CRi) 3 months after treatment.7
Meanwhile, Kite Pharma has a rolling submission with the FDA for KTE-C19 (axicabtagene ciloleucel) for the treatment of patients with relapsed/refractory B-cell NHL who are ineligible for HSCT. In the ZUMA-1 trial, this therapy demonstrated an overall response rate (ORR) of 71%.8 Juno Therapeutics is developing several CAR T-cell therapies, including JCAR017, which elicited CR in 60% of patients with relapsed/refractory NHL.9
Target antigens other than CD19 are being explored, but these are mostly in the early stages of clinical development. While the focus has predominantly been on the treatment of lymphoma and leukemia, a presentation at the American Society for Clinical Oncology annual meeting in June reported the efficacy of a CAR-T cell therapy targeting the B-cell maturation antigen in patients with multiple myeloma. Results from 19 patients enrolled in an ongoing phase 1 trial in China showed that 14 had achieved stringent CR, 1 partial remission (PR) and 4 very good partial remission (VGPR).10
Antibodies evolve
Another type of immunotherapy that has revolutionized the treatment of hematologic malignancies is monoclonal antibodies (mAbs), targeting antigens on the surface of malignant B and T cells, in particular CD20. The approval of CD20-targeting mAb rituximab in 1997 was the first coup for the development of immunotherapy for the treatment of hematologic malignancies. It has become part of the standard treatment regimen for B-cell malignancies, including NHL and CLL, in combination with various types of chemotherapy.
Several other CD20-targeting antibodies have been developed (Table 2), some of which work in the same way as rituximab (eg, ofatumumab) and some that have a slightly different mechanism of action (eg, obinutuzumab).11 Both types of antibody have proved highly effective; ofatumumab is FDA approved for the treatment of advanced CLL and is being evaluated in phase 3 trials in other hematologic malignancies, while obinutuzumab has received regulatory approval for the first-line treatment of CLL, replacing the standard rituximab-containing regimen.12
The use of ofatumumab as maintenance therapy is supported by the results of the phase 3 PROLONG study in which 474 patients were randomly assigned to ofatumumab maintenance for 2 years or observation. Over a median follow-up of close to 20 months, ofatumumab-treated patients experienced improved progression-free survival (PFS; median PFS: 29.4 months vs 15.2 months; hazard ratio [HR], 0.50; P < .0001).13 Obinutuzumab’s new indication is based on data from the phase 3 GADOLIN trial, in which the obinutuzumab arm showed improved 3-year PFS compared with rituximab.14Until recently, multiple myeloma had proven relatively resistant to mAb therapy, but two new drug targets have dramatically altered the treatment landscape for this type of hematologic malignancy. CD2 subset 1 (CS1), also known as signaling lymphocytic activation molecule 7 (SLAMF7), and CD38 are glycoproteins expressed highly and nearly uniformly on the surface of multiple myeloma cells and only at low levels on other lymphoid and myeloid cells.15
Several antibodies directed at these targets are in clinical development, but daratumumab and elotuzumab, targeting CD38 and CS1, respectively, are both newly approved by the FDA for relapsed/refractory disease, daratumumab as monotherapy and elotuzumab in combination with lenalidomide and dexamethasone.
The indication for daratumumab was subsequently expanded to include its use in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Support for this new indication came from 2 pivotal phase 3 trials. In the CASTOR trial, the combination of daratumumab with bortezomib–dexamethasone reduced the risk of disease progression or death by 61%, compared with bortezomib–dexamethasone alone, whereas daratumumab with lenalidomide–dexamethasone reduced the risk of disease progression or death by 63% in the POLLUX trial.16,17
Numerous clinical trials for both drugs are ongoing, including in the front-line setting in multiple myeloma, as well as trials in other types of B-cell malignancy, and several other CD38-targeting mAbs are also in development, including isatuximab, which has reached the phase 3 stage (NCT02990338).
Innovative design
Newer drug designs, which have sought to take mAb therapy to the next level, have also shown significant efficacy in hematologic malignancies. Antibody-drug conjugates (ADCs) combine the cytotoxic efficacy of chemotherapeutic agents with the specificity of a mAb targeting a tumor-specific antigen. This essentially creates a targeted payload that improves upon the efficacy of mAb monotherapy but mitigates some of the side effects of chemotherapy related to their indiscriminate killing of both cancerous and healthy cells.
The development of ADCs has been somewhat of a rollercoaster ride, with the approval and subsequent withdrawal of the first-in-class drug gemtuzumab ozogamicin in 2010, but the field was reinvigorated with the successful development of brentuximab vedotin, which targets the CD30 antigen and is approved for the treatment of multiple different hematologic malignancies, including, most recently, for posttransplant consolidation therapy in patients with Hodgkin lymphoma at high risk of relapse or progression.18
Brentuximab vedotin may soon be joined by another FDA-approved ADC, this one targeting CD22. Inotuzumab ozogamicin was recently granted priority review for the treatment of relapsed/refractory ALL. The FDA is reviewing data from the phase 3 INO-VATE study in which inotuzumab ozogamicin reduced the risk of disease progression or death by 55% compared with standard therapy, and a decision is expected by August.19 Other ADC targets being investigated in clinical trials include CD138, CD19, and CD33 (Table 3). Meanwhile, a meta-analysis of randomized trials suggested that the withdrawal of gemtuzumab ozogamicin may have been premature, indicating that it does improve long-term overall survival (OS) and reduces the risk of relapse.20
Bispecific antibodies that link natural killer (NK) cells to tumor cells, by targeting the NK-cell receptor CD16, known as BiKEs, are also in development in an attempt to harness the power of the innate immune response.
B-cell signaling a ripe target
Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.
A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.
More than 100 clinical trials of ibrutinib are ongoing in an effort to further clarify its role in a variety of different disease settings. Furthermore, in an effort to address some of the toxicity concerns with ibrutinib, more specific BTK inhibitors are also being developed.
Other kinases that orchestrate the BCR pathway, including phosphatidylinositol-3-kinase (PI3K) and SYK, are also being targeted. The delta isoform of PI3K is expressed exclusively in hematopoietic cells and a number of PI3K delta inhibitors have been developed. Idelalisib received regulatory approval for the treatment of patients with CLL in combination with rituximab, and for patients with follicular lymphoma and small lymphocytic leukemia.
As with ibrutinib, a plethora of clinical trials are ongoing, however a major setback was suffered in the frontline setting when Gilead Sciences halted 6 clinical trials due to reports of increased rates of adverse events, including deaths.26 Meanwhile, SYK inhibitors have lagged behind somewhat in their development, but one such offering, entospletinib, is showing promise in patients with AML.27
Finally, there has been some success in targeting one of the downstream targets of the BCR signaling pathway, the Bcl2 protein that is involved in the regulation of apoptosis. Venetoclax was approved last year for the treatment of patients with relapsed/refractory CLL in patients who have a chromosome 17p deletion, based on the demonstration of impressive, durable responses.28
1. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ. Haemato- logical malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer. 2015;15(4):201-215.
2. Im A, Pavletic SZ. Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol. 2017;10(1):94.
3. Gill S. Planes, trains, and automobiles: perspectives on CAR T cells and other cellular therapies for hematologic malignancies. Curr Hematol Malig Rep. 2016;11(4):318-325.
4. Ye B, Stary CM, Gao Q, et al. Genetically modified T-cell-based adoptive immunotherapy in hematological malignancies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237740/. Published January 2, 2017. Accessed July 22, 2017.
5. Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337-350.
6. Novartis. Novartis personalized cell therapy CTL019 receives FDA breakthrough therapy designation. https://www.novartis.com/news/media-releases/novartis-personalized-cell-therapy-ctl019-receivesfda-breakthrough-therapy. Published July 7, 2014. Accessed June 19,
2017.
7. Novartis. Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL. https://www.novartis.com/news/media-releases/novartis-presentsresults-first-global-registration-trial-ctl019-pediatric-and. Published December 4, 2016. Accessed June 19, 2017.
8. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA1: a multicenter study of KTE-C19 Anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285-295.
9. Abramson JS, Palomba L, Gordon L. Transcend NHL 001: immunotherapy with the CD19-Directd CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Paper presented at 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, CA.
10. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35(suppl;):Abstr LBA3001.
11. Okroj M, Osterborg A, Blom AM. Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies. Cancer Treat Rev. 2013;39(6):632-639.
12. Safdari Y, Ahmadzadeh V, Farajnia S. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies. Invest New Drugs. 2016;34(4):497-512.
13. van Oers MH, Kuliczkowski K, Smolej L, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015;16(13):1370-1379.
14. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093.
15. Touzeau C, Moreau P, Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31(5):1039-1047.
16. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
17. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
18. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.
19. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.
20. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.
21. Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol. 2015;93(3):290-296.
22. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
23. Koehrer S, Burger JA. B-cell receptor signaling in chronic lymphocytic leukemia and other B-cell malignancies. Clin Adv Hematol Oncol. 2016;14(1):55-65.
24. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015;94(3):193-205.
25. Bojarczuk K, Bobrowicz M, Dwojak M, et al. B-cell receptor signaling in the pathogenesis of lymphoid malignancies. Blood Cells Mol Dis. 2015;55(3):255-265.
26. Medscape Medical News. Gilead stops six trials adding idelalisib to other drugs. http://www.medscape.com/viewarticle/860372. Published March 14, 2016. Accessed June 19, 2017.
27. Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016;7(3):157-170.
28. Food and Drug Administration. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. Released April 11, 2016. Accessed June 19, 2017.
1. Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ. Haemato- logical malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer. 2015;15(4):201-215.
2. Im A, Pavletic SZ. Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol. 2017;10(1):94.
3. Gill S. Planes, trains, and automobiles: perspectives on CAR T cells and other cellular therapies for hematologic malignancies. Curr Hematol Malig Rep. 2016;11(4):318-325.
4. Ye B, Stary CM, Gao Q, et al. Genetically modified T-cell-based adoptive immunotherapy in hematological malignancies. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237740/. Published January 2, 2017. Accessed July 22, 2017.
5. Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech. 2015;8(4):337-350.
6. Novartis. Novartis personalized cell therapy CTL019 receives FDA breakthrough therapy designation. https://www.novartis.com/news/media-releases/novartis-personalized-cell-therapy-ctl019-receivesfda-breakthrough-therapy. Published July 7, 2014. Accessed June 19,
2017.
7. Novartis. Novartis presents results from first global registration trial of CTL019 in pediatric and young adult patients with r/r B-ALL. https://www.novartis.com/news/media-releases/novartis-presentsresults-first-global-registration-trial-ctl019-pediatric-and. Published December 4, 2016. Accessed June 19, 2017.
8. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA1: a multicenter study of KTE-C19 Anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285-295.
9. Abramson JS, Palomba L, Gordon L. Transcend NHL 001: immunotherapy with the CD19-Directd CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Paper presented at 58th American Society of Hematology Annual Meeting; December 3-6, 2016; San Diego, CA.
10. Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35(suppl;):Abstr LBA3001.
11. Okroj M, Osterborg A, Blom AM. Effector mechanisms of anti-CD20 monoclonal antibodies in B cell malignancies. Cancer Treat Rev. 2013;39(6):632-639.
12. Safdari Y, Ahmadzadeh V, Farajnia S. CD20-targeting in B-cell malignancies: novel prospects for antibodies and combination therapies. Invest New Drugs. 2016;34(4):497-512.
13. van Oers MH, Kuliczkowski K, Smolej L, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015;16(13):1370-1379.
14. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093.
15. Touzeau C, Moreau P, Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31(5):1039-1047.
16. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
17. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
18. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16(5):315-337.
19. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.
20. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.
21. Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol. 2015;93(3):290-296.
22. Kantarjian H, Stein A, Gokbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
23. Koehrer S, Burger JA. B-cell receptor signaling in chronic lymphocytic leukemia and other B-cell malignancies. Clin Adv Hematol Oncol. 2016;14(1):55-65.
24. Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015;94(3):193-205.
25. Bojarczuk K, Bobrowicz M, Dwojak M, et al. B-cell receptor signaling in the pathogenesis of lymphoid malignancies. Blood Cells Mol Dis. 2015;55(3):255-265.
26. Medscape Medical News. Gilead stops six trials adding idelalisib to other drugs. http://www.medscape.com/viewarticle/860372. Published March 14, 2016. Accessed June 19, 2017.
27. Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016;7(3):157-170.
28. Food and Drug Administration. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. Released April 11, 2016. Accessed June 19, 2017.
Insurance status linked to survival in FL patients
Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.
The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.
“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”
Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.
The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.
“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”
Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
Having health insurance can mean the difference between life and death for US patients with follicular lymphoma (FL), according to research published in Blood.
The study showed that patients with private health insurance had nearly 2-fold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 FL patients showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket were 1.96 for those with no insurance, 1.83 for those with Medicaid, and 1.96 for those with Medicare (P<0.0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL,” Christopher R. Flowers, MD, of Emory University in Atlanta, Georgia, and his colleagues wrote in Blood.
“Future studies on outcomes in FL should include insurance status as an important predictor. Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability.”
Earlier research showed that patients with Medicaid or no insurance were more likely than privately insured patients to be diagnosed with cancers at advanced stages, and some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, Dr Flowers and his colleagues extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
The investigators identified 43,648 patients, age 18 and older, who were diagnosed with FL from 2004 through 2014. The team looked at patients ages 18 to 64 as well as patients age 65 and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients age 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P<0.0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and patients with a score of 2 or greater had an HR of 3.1 (P<0.0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality healthcare may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
Insurance is a matter of life or death for lymphoma patients
Having health insurance can mean the difference between life and death for patients with follicular lymphoma, suggest results of a study showing that patients with private health insurance had nearly twofold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 patients with follicular lymphoma (FL) in a national cancer registry showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket with either no insurance, Medicaid, or Medicare were, respectively, 1.96, 1.83, and 1.96 (P less than .0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL. Future studies on outcomes in FL should include insurance status as an important predictor,” Christopher R. Flowers, MD, of Emory University in Atlanta and his colleagues wrote in Blood.
“Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability,” they added.
The investigators noted that earlier research found that patients with Medicaid or no insurance were more likely than privately-insured patients to be diagnosed with cancers at advanced stages, and that some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, they extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
They identified a total of 43,648 patients aged 18 years or older who were diagnosed with FL from 2004 through 2014. They looked at both patients 18-64 years and those 65 years and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than age 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients aged 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P less than .0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and that patients with a score of 2 or greater had a HR of 3.1 (P less than .0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality health care may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr. Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
SOURCE: Goldstein JS et al. Blood. 2018 Jul 24. doi: 10.1182/blood-2018-03-839035.
Having health insurance can mean the difference between life and death for patients with follicular lymphoma, suggest results of a study showing that patients with private health insurance had nearly twofold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 patients with follicular lymphoma (FL) in a national cancer registry showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket with either no insurance, Medicaid, or Medicare were, respectively, 1.96, 1.83, and 1.96 (P less than .0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL. Future studies on outcomes in FL should include insurance status as an important predictor,” Christopher R. Flowers, MD, of Emory University in Atlanta and his colleagues wrote in Blood.
“Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability,” they added.
The investigators noted that earlier research found that patients with Medicaid or no insurance were more likely than privately-insured patients to be diagnosed with cancers at advanced stages, and that some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, they extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
They identified a total of 43,648 patients aged 18 years or older who were diagnosed with FL from 2004 through 2014. They looked at both patients 18-64 years and those 65 years and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than age 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients aged 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P less than .0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and that patients with a score of 2 or greater had a HR of 3.1 (P less than .0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality health care may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr. Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
SOURCE: Goldstein JS et al. Blood. 2018 Jul 24. doi: 10.1182/blood-2018-03-839035.
Having health insurance can mean the difference between life and death for patients with follicular lymphoma, suggest results of a study showing that patients with private health insurance had nearly twofold better survival outcomes than patients without insurance or those who were covered by Medicare or Medicaid.
A review of records on more than 43,000 patients with follicular lymphoma (FL) in a national cancer registry showed that, compared with patients under age 65 with private insurance, the hazard ratios (HR) for death among patients in the same age bracket with either no insurance, Medicaid, or Medicare were, respectively, 1.96, 1.83, and 1.96 (P less than .0001 for each comparison).
“Our study finds that insurance status contributes to survival disparities in FL. Future studies on outcomes in FL should include insurance status as an important predictor,” Christopher R. Flowers, MD, of Emory University in Atlanta and his colleagues wrote in Blood.
“Further research on prognosis for FL should examine the impact of public policy, such as the passage of the [Affordable Care Act], on FL outcomes, as well as examine other factors that influence access to care, such as individual-level socioeconomic status, regular primary care visits, access to prescription medications, and care affordability,” they added.
The investigators noted that earlier research found that patients with Medicaid or no insurance were more likely than privately-insured patients to be diagnosed with cancers at advanced stages, and that some patients with aggressive non-Hodgkin lymphomas have been shown to have insurance-related disparities in treatments and outcomes.
To see whether the same could be true for patients with indolent-histology lymphomas such as FL, they extracted data from the National Cancer Database, a nationwide hospital-based cancer registry sponsored jointly by the American College of Surgeons and the American Cancer Society.
They identified a total of 43,648 patients aged 18 years or older who were diagnosed with FL from 2004 through 2014. They looked at both patients 18-64 years and those 65 years and older to account for changes in insurance with Medicare eligibility.
Overall survival among patients younger than age 65 was significantly worse for patients with public insurance (Medicaid or Medicare) or no insurance in Cox proportional hazard models controlling for available data on sociodemographic factors and prognostic indicators.
However, compared with patients aged 65 and older with private insurance, only patients with Medicare as their sole source of insurance had significantly worse overall survival (HR, 1.28; P less than .0001).
Patients who were uninsured or had Medicaid were more likely than others to have lower socioeconomic status, present with advanced-stage disease, have systemic symptoms, and have multiple comorbidities that persisted after controlling for known sociodemographic and prognostic factors.
The investigators found that, among patients under age 65, those with a comorbidity score of 1 had an HR for death of 1.71, compared with patients with no comorbidities, and that patients with a score of 2 or greater had a HR of 3.1 (P less than .0001 for each comparison).
“The findings of the study indicate that improving access to affordable, quality health care may reduce disparities in survival for those currently lacking coverage,” the investigators wrote.
The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr. Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
SOURCE: Goldstein JS et al. Blood. 2018 Jul 24. doi: 10.1182/blood-2018-03-839035.
FROM BLOOD
Key clinical point:
Major finding: The risk for death among patients under age 65 with no insurance, Medicaid, or Medicare was nearly twice that of similar patients with private health insurance.
Study details: Review of data on 43,648 patients with follicular lymphoma in the National Cancer Database.
Disclosures: The study was supported by Emory University, the National Institutes of Health, and the National Center for Advancing Translational Sciences. Dr. Flowers reported financial relationships with AbbVie, Spectrum, Celgene, and several other companies. The other authors reported having nothing to disclose.
Source: Goldstein JS et al. Blood. 2018 Jul 24. doi: 10.1182/blood-2018-03-839035.
Treatment improves PFS in early stage FL
A multidrug regimen can improve upon involved-field radiotherapy (IFRT) in patients with early stage follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.
FL patients who received IFRT plus cyclophosphamide, vincristine, and prednisolone (CVP)—with or without rituximab—had a significant improvement in progression-free survival (PFS) compared to patients who received standard treatment with IFRT alone.
However, there was no significant difference in overall survival (OS) between the treatment arms.
“This is the first successful randomized study ever to be conducted in early stage follicular lymphoma comparing standard therapy to standard therapy plus effective chemotherapy or immunochemotherapy,” said Michael MacManus, MBBCh, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
“It shows that the initial treatment received by patients can significantly affect their long-term chance of staying free from disease. Moving forward, we are interested in determining whether there is a benefit in overall long-term survival for patients treated with the combination with further follow-up, and if there is any way to predict if a person will benefit from combined treatment based on analyses of blood or biopsy specimens.”
Dr MacManus and his colleagues studied 150 patients with stage I to II, low-grade FL who were enrolled in this trial between 2000 and 2012.
At randomization, the patients’ median age was 57, 52% were male, 75% had stage I disease, and 48% had PET staging.
Half of patients (n=75) were randomized to receive IFRT (30-36 Gy) alone, and half were randomized to IFRT (30-36 Gy) plus 6 cycles of CVP. From 2006 on, patients in the CVP arm received rituximab (R) as well (n=31).
Baseline characteristics were well-balanced between the treatment arms.
Efficacy
The median follow-up was 9.6 years (range, 3.1 to 15.8 years).
PFS was significantly better among patients randomized to receive CVP±R (hazard ratio [HR]=0.57; P=0.033). The estimated 10-year PFS rate was 41% in the IFRT arm and 59% in the CVP±R arm.
Patients randomized to receive CVP plus R (n=31) had significantly better PFS than patients randomized to receive IFRT alone (n=31) over the same time period (HR=0.26; P=0.045).
There were 10 deaths in the IRFT arm and 5 in the CVP±R arm, but there was no significant difference in OS between the arms (HR=0.62; P=0.40). The 10-year OS rate was 86% in the IFRT arm and 95% in the CVP±R arm.
There was no significant between-arm difference in transformation to aggressive lymphoma (P=0.1). Transformation occurred in 10 patients in the IFRT arm and 4 in the CVP±R arm.
Safety
There were 148 patients from both arms who ultimately received IFRT, and 69 patients who received CVP±R.
Grade 2 toxicities occurring in more than 10% of IFRT recipients included upper gastrointestinal (n=27; 18%), skin (n=21; 14%), and mucous membrane (n=19; 12%) toxicity. One IFRT recipient had grade 3 mucositis, and 1 had grade 4 esophageal/pharyngeal mucosal toxicity.
Grade 3 toxicities occurring in at least 2 patients in the CVP±R arm included neutropenia (n=10; 14%), infection (n=8; 12%), diarrhea (n=3; 4%), elevated gamma-glutamyl transferase (n=3; 4%), fatigue (n=3; 4%), and febrile neutropenia (n=3; 4%).
Three patients (4%) in the CVP±R arm had acute grade 3 neuropathy related to vincristine. Ten patients (14%) had grade 4 neutropenia.
The most common late toxicities for the entire patient cohort were salivary gland (n=8; 5%) and skin (n=4; 3%) toxicities.
Grade 3 lung and menopausal toxicities occurred in 1 patient each. Two patients had late grade 3 vincristine neuropathy. One patient who had grade 3 neuropathy during chemotherapy progressed to grade 4.
A multidrug regimen can improve upon involved-field radiotherapy (IFRT) in patients with early stage follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.
FL patients who received IFRT plus cyclophosphamide, vincristine, and prednisolone (CVP)—with or without rituximab—had a significant improvement in progression-free survival (PFS) compared to patients who received standard treatment with IFRT alone.
However, there was no significant difference in overall survival (OS) between the treatment arms.
“This is the first successful randomized study ever to be conducted in early stage follicular lymphoma comparing standard therapy to standard therapy plus effective chemotherapy or immunochemotherapy,” said Michael MacManus, MBBCh, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
“It shows that the initial treatment received by patients can significantly affect their long-term chance of staying free from disease. Moving forward, we are interested in determining whether there is a benefit in overall long-term survival for patients treated with the combination with further follow-up, and if there is any way to predict if a person will benefit from combined treatment based on analyses of blood or biopsy specimens.”
Dr MacManus and his colleagues studied 150 patients with stage I to II, low-grade FL who were enrolled in this trial between 2000 and 2012.
At randomization, the patients’ median age was 57, 52% were male, 75% had stage I disease, and 48% had PET staging.
Half of patients (n=75) were randomized to receive IFRT (30-36 Gy) alone, and half were randomized to IFRT (30-36 Gy) plus 6 cycles of CVP. From 2006 on, patients in the CVP arm received rituximab (R) as well (n=31).
Baseline characteristics were well-balanced between the treatment arms.
Efficacy
The median follow-up was 9.6 years (range, 3.1 to 15.8 years).
PFS was significantly better among patients randomized to receive CVP±R (hazard ratio [HR]=0.57; P=0.033). The estimated 10-year PFS rate was 41% in the IFRT arm and 59% in the CVP±R arm.
Patients randomized to receive CVP plus R (n=31) had significantly better PFS than patients randomized to receive IFRT alone (n=31) over the same time period (HR=0.26; P=0.045).
There were 10 deaths in the IRFT arm and 5 in the CVP±R arm, but there was no significant difference in OS between the arms (HR=0.62; P=0.40). The 10-year OS rate was 86% in the IFRT arm and 95% in the CVP±R arm.
There was no significant between-arm difference in transformation to aggressive lymphoma (P=0.1). Transformation occurred in 10 patients in the IFRT arm and 4 in the CVP±R arm.
Safety
There were 148 patients from both arms who ultimately received IFRT, and 69 patients who received CVP±R.
Grade 2 toxicities occurring in more than 10% of IFRT recipients included upper gastrointestinal (n=27; 18%), skin (n=21; 14%), and mucous membrane (n=19; 12%) toxicity. One IFRT recipient had grade 3 mucositis, and 1 had grade 4 esophageal/pharyngeal mucosal toxicity.
Grade 3 toxicities occurring in at least 2 patients in the CVP±R arm included neutropenia (n=10; 14%), infection (n=8; 12%), diarrhea (n=3; 4%), elevated gamma-glutamyl transferase (n=3; 4%), fatigue (n=3; 4%), and febrile neutropenia (n=3; 4%).
Three patients (4%) in the CVP±R arm had acute grade 3 neuropathy related to vincristine. Ten patients (14%) had grade 4 neutropenia.
The most common late toxicities for the entire patient cohort were salivary gland (n=8; 5%) and skin (n=4; 3%) toxicities.
Grade 3 lung and menopausal toxicities occurred in 1 patient each. Two patients had late grade 3 vincristine neuropathy. One patient who had grade 3 neuropathy during chemotherapy progressed to grade 4.
A multidrug regimen can improve upon involved-field radiotherapy (IFRT) in patients with early stage follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.
FL patients who received IFRT plus cyclophosphamide, vincristine, and prednisolone (CVP)—with or without rituximab—had a significant improvement in progression-free survival (PFS) compared to patients who received standard treatment with IFRT alone.
However, there was no significant difference in overall survival (OS) between the treatment arms.
“This is the first successful randomized study ever to be conducted in early stage follicular lymphoma comparing standard therapy to standard therapy plus effective chemotherapy or immunochemotherapy,” said Michael MacManus, MBBCh, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
“It shows that the initial treatment received by patients can significantly affect their long-term chance of staying free from disease. Moving forward, we are interested in determining whether there is a benefit in overall long-term survival for patients treated with the combination with further follow-up, and if there is any way to predict if a person will benefit from combined treatment based on analyses of blood or biopsy specimens.”
Dr MacManus and his colleagues studied 150 patients with stage I to II, low-grade FL who were enrolled in this trial between 2000 and 2012.
At randomization, the patients’ median age was 57, 52% were male, 75% had stage I disease, and 48% had PET staging.
Half of patients (n=75) were randomized to receive IFRT (30-36 Gy) alone, and half were randomized to IFRT (30-36 Gy) plus 6 cycles of CVP. From 2006 on, patients in the CVP arm received rituximab (R) as well (n=31).
Baseline characteristics were well-balanced between the treatment arms.
Efficacy
The median follow-up was 9.6 years (range, 3.1 to 15.8 years).
PFS was significantly better among patients randomized to receive CVP±R (hazard ratio [HR]=0.57; P=0.033). The estimated 10-year PFS rate was 41% in the IFRT arm and 59% in the CVP±R arm.
Patients randomized to receive CVP plus R (n=31) had significantly better PFS than patients randomized to receive IFRT alone (n=31) over the same time period (HR=0.26; P=0.045).
There were 10 deaths in the IRFT arm and 5 in the CVP±R arm, but there was no significant difference in OS between the arms (HR=0.62; P=0.40). The 10-year OS rate was 86% in the IFRT arm and 95% in the CVP±R arm.
There was no significant between-arm difference in transformation to aggressive lymphoma (P=0.1). Transformation occurred in 10 patients in the IFRT arm and 4 in the CVP±R arm.
Safety
There were 148 patients from both arms who ultimately received IFRT, and 69 patients who received CVP±R.
Grade 2 toxicities occurring in more than 10% of IFRT recipients included upper gastrointestinal (n=27; 18%), skin (n=21; 14%), and mucous membrane (n=19; 12%) toxicity. One IFRT recipient had grade 3 mucositis, and 1 had grade 4 esophageal/pharyngeal mucosal toxicity.
Grade 3 toxicities occurring in at least 2 patients in the CVP±R arm included neutropenia (n=10; 14%), infection (n=8; 12%), diarrhea (n=3; 4%), elevated gamma-glutamyl transferase (n=3; 4%), fatigue (n=3; 4%), and febrile neutropenia (n=3; 4%).
Three patients (4%) in the CVP±R arm had acute grade 3 neuropathy related to vincristine. Ten patients (14%) had grade 4 neutropenia.
The most common late toxicities for the entire patient cohort were salivary gland (n=8; 5%) and skin (n=4; 3%) toxicities.
Grade 3 lung and menopausal toxicities occurred in 1 patient each. Two patients had late grade 3 vincristine neuropathy. One patient who had grade 3 neuropathy during chemotherapy progressed to grade 4.