Lymphoma & Plasma Cell Disorders

John F. Seymour, MBBS, PhD

ATLANTA—The combination of venetoclax and rituximab (VR) should be a standard treatment option for adults with relapsed/refractory chronic lymphocytic leukemia (CLL), according to a speaker at the 2017 ASH Annual Meeting.

Data from the phase 3 MURANO study showed that patients with relapsed/refractory CLL who received VR had significantly longer progression-free survival (PFS) than those who received bendamustine and rituximab (BR).

In addition, “secondary endpoints were consistently in favor of venetoclax-rituximab,” said study investigator John F. Seymour, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Adverse events (AEs) were largely consistent with the known safety profiles of the drugs studied, but tumor lysis syndrome (TLS) was infrequent and occurred at a similar frequency in both treatment arms.

“Thus, overall, I believe venetoclax and rituximab should be considered as a suitable standard therapeutic option in patients with relapsed/refractory CLL,” Dr Seymour said.

It is important to note, however, that patients in the VR arm of this study could receive venetoclax for up to 2 years, whereas patients in the BR arm received study treatment for a maximum of six 28-day cycles.

Dr Seymour presented results from MURANO as a late-breaking abstract at ASH (LBA-2). The study was sponsored by Hoffman-La Roche and AbbVie.

MURANO enrolled 389 CLL patients who had received 1 to 3 prior therapies. Patients were randomized to receive VR (n=194) or BR (n=195). Baseline characteristics were similar between the treatment arms.

In both arms, patients received a single monthly dose of rituximab for 6 cycles. The first dose was 375 mg/m², and all subsequent doses were 500 mg/m².

In the VR arm, patients received a 4-week or 5-week dose ramp-up of venetoclax from 20 mg to 400 mg daily. This was intended to mitigate the risk of TLS, which has been observed in previous studies of venetoclax.

Patients in the VR arm continued with daily venetoclax at 400 mg for a maximum of 2 years or until disease progression or cessation due to toxicity. They started receiving rituximab after the ramp-up period (at week 6).

In the BR arm, patients received bendamustine at 70 mg/m² on days 1 and 2 of each 28-day cycle for 6 cycles. Patients could proceed to subsequent therapy if they progressed.

The median follow-up was 23.8 months (range, 0-37.4 months).

Twenty-five percent of patients in the VR arm and 17% in the BR arm discontinued treatment ahead of schedule. Reasons for discontinuation (in the VR and BR arms, respectively) were disease progression (5% and 3%), AEs (12% and 6%), death (1% and 2%), and “other” (6% and 7%).

Survival

The study’s primary endpoint was investigator-assessed PFS. PFS according to an independent review committee (IRC) was a secondary endpoint.

According to investigators, the median PFS was not reached in the VR arm and was 17.0 months in the BR arm (hazard ratio [HR]=0.17, P<0.0001). According to the IRC, the median PFS was not reached in the VR arm and was 18.1 months in the BR arm (HR=0.17, P<0.0001).

According to investigators, the estimated PFS at 24 months was 84.9% in the VR arm and 36.3% in the BR arm. According to the IRC, the 24-month PFS was 82.8% and 37.4%, respectively.

The benefit with VR was consistent across subgroups. Patients had a PFS benefit regardless of their number of prior therapies, deletion 17p status, TP53 mutational status, baseline IGHV mutational status, and whether they had relapsed or refractory disease.

Dr Seymour acknowledged that the differences in treatment duration between the BR and VR arms may have affected the interpretation of these results.

“[T]he treatment duration differed, although, of course, the capacity to deliver more than 6 cycles of bendamustine-rituximab would have been problematic,” he said. “There is some data that antibody treatment may prolong progression-free survival. However, when this study was designed, in 2013, that data was certainly not available. And I believe, currently, maintenance antibody is not an accepted standard of treatment.”

The median overall survival (OS) was not reached in either treatment arm. The 1-year OS rate was 95.9% in the VR arm and 91.1% in the BR arm. The 2-year OS rate was 91.9% and 86.6%, respectively (HR=0.48, P=0.0186).

“[W]ith median follow-up of just on 2 years, there is already a clinically meaningful difference [in OS between the treatment arms],” Dr Seymour said.

“This is not attributable to any difference in availability of novel therapies. Of the 54 patients who received subsequent therapy after progression on the bendamustine-rituximab arm, 40 of those received novel targeted agents.”

Response and MRD

According to investigators, the overall response rate was 93.3% (181/194) in the VR arm and 67.7% (312/195) in the BR arm (P<0.0001). According to the IRC, the overall response rate was 92.3% (179/194) and 72.3% (141/195), respectively (P<0.0001).

According to investigators, the rate of complete response (CR) or CR with incomplete marrow recovery (CRi) was 26.8% (n=52) in the VR arm and 8.2% (n=16) in the BR arm. According to the IRC, the CR/CRi rate was 8.2% (n=16) and 3.6% (n=7), respectively.

Dr Seymour acknowledged the differences in CR/CRi between investigator and IRC assessments. He said 28 of the 42 discrepancies in the VR arm “were attributable to residual CT scan nodal abnormalities in the 16- to 30-mm size.” However, he also noted that 88% of these patients were negative for minimal residual disease (MRD) in the peripheral blood at that time point.

MRD was assessed every 3 months. Patients were counted as MRD-positive if they were positive by either allele-specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Patients were also counted as MRD-positive if there was a failure to collect a sample.

The proportion of patients who were MRD-negative in the VR and BR arms, respectively, was:

• 45% and 6% at 4 months
• 62% and 13% at 9 months
• 60% and 10% at 12 months
• 57% and 9% at 15 months
• 60% and 5% at 18 months.

Dr Seymour pointed out that 65 patients in the VR arm surpassed the maximum treatment duration for venetoclax (2 years) and therefore stopped receiving the drug, but only 12 of these patients have follow-up beyond 3 months.

“So information about the durability of response after cessation remains immature at the moment,” he said.

Safety

All patients in the VR arm and 98% in the BR arm had at least 1 AE. The rate of serious AEs was 46% and 43%, respectively. The rate of grade 3/4 AEs was 82% and 70%, respectively.

Grade 3/4 AEs with at least a 2% difference in incidence between the treatment arms (in the VR and BR arms, respectively) were neutropenia (58% and 39%), anemia (11% and 14%), thrombocytopenia (6% and 10%), febrile neutropenia (4% and 10%), pneumonia (5% and 8%), infusion-related reactions (2% and 5%), TLS (3% and 1%), hypotension (0% and 3%), hyperglycemia (2% and 0%), and hypogammaglobulinemia (2% and 0%).

The rate of grade 5 AEs was 5% in the VR arm and 6% in the BR arm.

Grade 5 AEs in the VR arm were pneumonia (n=3), sepsis (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1).

Grade 5 AEs in the BR arm included sepsis (n=2), lung cancer (n=2), Listeria sepsis (n=1), Scedosporium infection (n=1), lymphoma (n=1), hemorrhagic stroke (n=1), pulmonary embolism (n=1), acute myeloid leukemia (n=1), and sudden death (n=1).

John F. Seymour, MBBS, PhD

ATLANTA—The combination of venetoclax and rituximab (VR) should be a standard treatment option for adults with relapsed/refractory chronic lymphocytic leukemia (CLL), according to a speaker at the 2017 ASH Annual Meeting.

Data from the phase 3 MURANO study showed that patients with relapsed/refractory CLL who received VR had significantly longer progression-free survival (PFS) than those who received bendamustine and rituximab (BR).

In addition, “secondary endpoints were consistently in favor of venetoclax-rituximab,” said study investigator John F. Seymour, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Adverse events (AEs) were largely consistent with the known safety profiles of the drugs studied, but tumor lysis syndrome (TLS) was infrequent and occurred at a similar frequency in both treatment arms.

“Thus, overall, I believe venetoclax and rituximab should be considered as a suitable standard therapeutic option in patients with relapsed/refractory CLL,” Dr Seymour said.

It is important to note, however, that patients in the VR arm of this study could receive venetoclax for up to 2 years, whereas patients in the BR arm received study treatment for a maximum of six 28-day cycles.

Dr Seymour presented results from MURANO as a late-breaking abstract at ASH (LBA-2). The study was sponsored by Hoffman-La Roche and AbbVie.

MURANO enrolled 389 CLL patients who had received 1 to 3 prior therapies. Patients were randomized to receive VR (n=194) or BR (n=195). Baseline characteristics were similar between the treatment arms.

In both arms, patients received a single monthly dose of rituximab for 6 cycles. The first dose was 375 mg/m², and all subsequent doses were 500 mg/m².

In the VR arm, patients received a 4-week or 5-week dose ramp-up of venetoclax from 20 mg to 400 mg daily. This was intended to mitigate the risk of TLS, which has been observed in previous studies of venetoclax.

Patients in the VR arm continued with daily venetoclax at 400 mg for a maximum of 2 years or until disease progression or cessation due to toxicity. They started receiving rituximab after the ramp-up period (at week 6).

In the BR arm, patients received bendamustine at 70 mg/m² on days 1 and 2 of each 28-day cycle for 6 cycles. Patients could proceed to subsequent therapy if they progressed.

The median follow-up was 23.8 months (range, 0-37.4 months).

Twenty-five percent of patients in the VR arm and 17% in the BR arm discontinued treatment ahead of schedule. Reasons for discontinuation (in the VR and BR arms, respectively) were disease progression (5% and 3%), AEs (12% and 6%), death (1% and 2%), and “other” (6% and 7%).

Survival

The study’s primary endpoint was investigator-assessed PFS. PFS according to an independent review committee (IRC) was a secondary endpoint.

According to investigators, the median PFS was not reached in the VR arm and was 17.0 months in the BR arm (hazard ratio [HR]=0.17, P<0.0001). According to the IRC, the median PFS was not reached in the VR arm and was 18.1 months in the BR arm (HR=0.17, P<0.0001).

According to investigators, the estimated PFS at 24 months was 84.9% in the VR arm and 36.3% in the BR arm. According to the IRC, the 24-month PFS was 82.8% and 37.4%, respectively.

The benefit with VR was consistent across subgroups. Patients had a PFS benefit regardless of their number of prior therapies, deletion 17p status, TP53 mutational status, baseline IGHV mutational status, and whether they had relapsed or refractory disease.

Dr Seymour acknowledged that the differences in treatment duration between the BR and VR arms may have affected the interpretation of these results.

“[T]he treatment duration differed, although, of course, the capacity to deliver more than 6 cycles of bendamustine-rituximab would have been problematic,” he said. “There is some data that antibody treatment may prolong progression-free survival. However, when this study was designed, in 2013, that data was certainly not available. And I believe, currently, maintenance antibody is not an accepted standard of treatment.”

The median overall survival (OS) was not reached in either treatment arm. The 1-year OS rate was 95.9% in the VR arm and 91.1% in the BR arm. The 2-year OS rate was 91.9% and 86.6%, respectively (HR=0.48, P=0.0186).

“[W]ith median follow-up of just on 2 years, there is already a clinically meaningful difference [in OS between the treatment arms],” Dr Seymour said.

“This is not attributable to any difference in availability of novel therapies. Of the 54 patients who received subsequent therapy after progression on the bendamustine-rituximab arm, 40 of those received novel targeted agents.”

Response and MRD

According to investigators, the overall response rate was 93.3% (181/194) in the VR arm and 67.7% (312/195) in the BR arm (P<0.0001). According to the IRC, the overall response rate was 92.3% (179/194) and 72.3% (141/195), respectively (P<0.0001).

According to investigators, the rate of complete response (CR) or CR with incomplete marrow recovery (CRi) was 26.8% (n=52) in the VR arm and 8.2% (n=16) in the BR arm. According to the IRC, the CR/CRi rate was 8.2% (n=16) and 3.6% (n=7), respectively.

Dr Seymour acknowledged the differences in CR/CRi between investigator and IRC assessments. He said 28 of the 42 discrepancies in the VR arm “were attributable to residual CT scan nodal abnormalities in the 16- to 30-mm size.” However, he also noted that 88% of these patients were negative for minimal residual disease (MRD) in the peripheral blood at that time point.

MRD was assessed every 3 months. Patients were counted as MRD-positive if they were positive by either allele-specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Patients were also counted as MRD-positive if there was a failure to collect a sample.

The proportion of patients who were MRD-negative in the VR and BR arms, respectively, was:

• 45% and 6% at 4 months
• 62% and 13% at 9 months
• 60% and 10% at 12 months
• 57% and 9% at 15 months
• 60% and 5% at 18 months.

Dr Seymour pointed out that 65 patients in the VR arm surpassed the maximum treatment duration for venetoclax (2 years) and therefore stopped receiving the drug, but only 12 of these patients have follow-up beyond 3 months.

“So information about the durability of response after cessation remains immature at the moment,” he said.

Safety

All patients in the VR arm and 98% in the BR arm had at least 1 AE. The rate of serious AEs was 46% and 43%, respectively. The rate of grade 3/4 AEs was 82% and 70%, respectively.

Grade 3/4 AEs with at least a 2% difference in incidence between the treatment arms (in the VR and BR arms, respectively) were neutropenia (58% and 39%), anemia (11% and 14%), thrombocytopenia (6% and 10%), febrile neutropenia (4% and 10%), pneumonia (5% and 8%), infusion-related reactions (2% and 5%), TLS (3% and 1%), hypotension (0% and 3%), hyperglycemia (2% and 0%), and hypogammaglobulinemia (2% and 0%).

The rate of grade 5 AEs was 5% in the VR arm and 6% in the BR arm.

Grade 5 AEs in the VR arm were pneumonia (n=3), sepsis (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1).

Grade 5 AEs in the BR arm included sepsis (n=2), lung cancer (n=2), Listeria sepsis (n=1), Scedosporium infection (n=1), lymphoma (n=1), hemorrhagic stroke (n=1), pulmonary embolism (n=1), acute myeloid leukemia (n=1), and sudden death (n=1).

John F. Seymour, MBBS, PhD

ATLANTA—The combination of venetoclax and rituximab (VR) should be a standard treatment option for adults with relapsed/refractory chronic lymphocytic leukemia (CLL), according to a speaker at the 2017 ASH Annual Meeting.

Data from the phase 3 MURANO study showed that patients with relapsed/refractory CLL who received VR had significantly longer progression-free survival (PFS) than those who received bendamustine and rituximab (BR).

In addition, “secondary endpoints were consistently in favor of venetoclax-rituximab,” said study investigator John F. Seymour, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.

Adverse events (AEs) were largely consistent with the known safety profiles of the drugs studied, but tumor lysis syndrome (TLS) was infrequent and occurred at a similar frequency in both treatment arms.

“Thus, overall, I believe venetoclax and rituximab should be considered as a suitable standard therapeutic option in patients with relapsed/refractory CLL,” Dr Seymour said.

It is important to note, however, that patients in the VR arm of this study could receive venetoclax for up to 2 years, whereas patients in the BR arm received study treatment for a maximum of six 28-day cycles.

Dr Seymour presented results from MURANO as a late-breaking abstract at ASH (LBA-2). The study was sponsored by Hoffman-La Roche and AbbVie.

MURANO enrolled 389 CLL patients who had received 1 to 3 prior therapies. Patients were randomized to receive VR (n=194) or BR (n=195). Baseline characteristics were similar between the treatment arms.

In both arms, patients received a single monthly dose of rituximab for 6 cycles. The first dose was 375 mg/m², and all subsequent doses were 500 mg/m².

In the VR arm, patients received a 4-week or 5-week dose ramp-up of venetoclax from 20 mg to 400 mg daily. This was intended to mitigate the risk of TLS, which has been observed in previous studies of venetoclax.

Patients in the VR arm continued with daily venetoclax at 400 mg for a maximum of 2 years or until disease progression or cessation due to toxicity. They started receiving rituximab after the ramp-up period (at week 6).

In the BR arm, patients received bendamustine at 70 mg/m² on days 1 and 2 of each 28-day cycle for 6 cycles. Patients could proceed to subsequent therapy if they progressed.

The median follow-up was 23.8 months (range, 0-37.4 months).

Twenty-five percent of patients in the VR arm and 17% in the BR arm discontinued treatment ahead of schedule. Reasons for discontinuation (in the VR and BR arms, respectively) were disease progression (5% and 3%), AEs (12% and 6%), death (1% and 2%), and “other” (6% and 7%).

Survival

The study’s primary endpoint was investigator-assessed PFS. PFS according to an independent review committee (IRC) was a secondary endpoint.

According to investigators, the median PFS was not reached in the VR arm and was 17.0 months in the BR arm (hazard ratio [HR]=0.17, P<0.0001). According to the IRC, the median PFS was not reached in the VR arm and was 18.1 months in the BR arm (HR=0.17, P<0.0001).

According to investigators, the estimated PFS at 24 months was 84.9% in the VR arm and 36.3% in the BR arm. According to the IRC, the 24-month PFS was 82.8% and 37.4%, respectively.

The benefit with VR was consistent across subgroups. Patients had a PFS benefit regardless of their number of prior therapies, deletion 17p status, TP53 mutational status, baseline IGHV mutational status, and whether they had relapsed or refractory disease.

Dr Seymour acknowledged that the differences in treatment duration between the BR and VR arms may have affected the interpretation of these results.

“[T]he treatment duration differed, although, of course, the capacity to deliver more than 6 cycles of bendamustine-rituximab would have been problematic,” he said. “There is some data that antibody treatment may prolong progression-free survival. However, when this study was designed, in 2013, that data was certainly not available. And I believe, currently, maintenance antibody is not an accepted standard of treatment.”

The median overall survival (OS) was not reached in either treatment arm. The 1-year OS rate was 95.9% in the VR arm and 91.1% in the BR arm. The 2-year OS rate was 91.9% and 86.6%, respectively (HR=0.48, P=0.0186).

“[W]ith median follow-up of just on 2 years, there is already a clinically meaningful difference [in OS between the treatment arms],” Dr Seymour said.

“This is not attributable to any difference in availability of novel therapies. Of the 54 patients who received subsequent therapy after progression on the bendamustine-rituximab arm, 40 of those received novel targeted agents.”

Response and MRD

According to investigators, the overall response rate was 93.3% (181/194) in the VR arm and 67.7% (312/195) in the BR arm (P<0.0001). According to the IRC, the overall response rate was 92.3% (179/194) and 72.3% (141/195), respectively (P<0.0001).

According to investigators, the rate of complete response (CR) or CR with incomplete marrow recovery (CRi) was 26.8% (n=52) in the VR arm and 8.2% (n=16) in the BR arm. According to the IRC, the CR/CRi rate was 8.2% (n=16) and 3.6% (n=7), respectively.

Dr Seymour acknowledged the differences in CR/CRi between investigator and IRC assessments. He said 28 of the 42 discrepancies in the VR arm “were attributable to residual CT scan nodal abnormalities in the 16- to 30-mm size.” However, he also noted that 88% of these patients were negative for minimal residual disease (MRD) in the peripheral blood at that time point.

MRD was assessed every 3 months. Patients were counted as MRD-positive if they were positive by either allele-specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Patients were also counted as MRD-positive if there was a failure to collect a sample.

The proportion of patients who were MRD-negative in the VR and BR arms, respectively, was:

• 45% and 6% at 4 months
• 62% and 13% at 9 months
• 60% and 10% at 12 months
• 57% and 9% at 15 months
• 60% and 5% at 18 months.

Dr Seymour pointed out that 65 patients in the VR arm surpassed the maximum treatment duration for venetoclax (2 years) and therefore stopped receiving the drug, but only 12 of these patients have follow-up beyond 3 months.

“So information about the durability of response after cessation remains immature at the moment,” he said.

Safety

All patients in the VR arm and 98% in the BR arm had at least 1 AE. The rate of serious AEs was 46% and 43%, respectively. The rate of grade 3/4 AEs was 82% and 70%, respectively.

Grade 3/4 AEs with at least a 2% difference in incidence between the treatment arms (in the VR and BR arms, respectively) were neutropenia (58% and 39%), anemia (11% and 14%), thrombocytopenia (6% and 10%), febrile neutropenia (4% and 10%), pneumonia (5% and 8%), infusion-related reactions (2% and 5%), TLS (3% and 1%), hypotension (0% and 3%), hyperglycemia (2% and 0%), and hypogammaglobulinemia (2% and 0%).

The rate of grade 5 AEs was 5% in the VR arm and 6% in the BR arm.

Grade 5 AEs in the VR arm were pneumonia (n=3), sepsis (n=1), cardiac failure (n=1), myocardial infarction (n=1), sudden cardiac death (n=1), colorectal cancer (n=1), status epilepticus (n=1), and acute respiratory failure (n=1).

Grade 5 AEs in the BR arm included sepsis (n=2), lung cancer (n=2), Listeria sepsis (n=1), Scedosporium infection (n=1), lymphoma (n=1), hemorrhagic stroke (n=1), pulmonary embolism (n=1), acute myeloid leukemia (n=1), and sudden death (n=1).

© Scott Morgan 2017

ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.

In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.

If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.

TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.

Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.

Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).

Study design

Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.

Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.

Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.

Patients then had a PET scan and lab tests prior to lymphodepletion.

“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . .  that could help us figure out which patients are at higher risk of toxicity, potentially.”

Lymphodepletion consisted of fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m² for 3 days).

Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.

Dose levels were 5 x 10⁷ cells as a single or double dose (DL1S) and 1 x 10⁸ cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.

“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”

At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.

Results

Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.

“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.

At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).

At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.

The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.

Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.

“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”

Dr Saddiqi focused the presentation on patient factors.

Patient factors

The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.

Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.

However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.

Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD)  ≥ 50 cm² at baseline had an 8-fold increase in risk of CRS and neurotoxicity.

“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”

Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.

The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.

“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.

And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.

“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.

The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.

The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.

“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.

"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”

The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.

*Data in the presentation differ from the abstract.

© Scott Morgan 2017

ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.

In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.

If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.

TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.

Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.

Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).

Study design

Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.

Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.

Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.

Patients then had a PET scan and lab tests prior to lymphodepletion.

“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . .  that could help us figure out which patients are at higher risk of toxicity, potentially.”

Lymphodepletion consisted of fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m² for 3 days).

Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.

Dose levels were 5 x 10⁷ cells as a single or double dose (DL1S) and 1 x 10⁸ cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.

“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”

At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.

Results

Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.

“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.

At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).

At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.

The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.

Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.

“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”

Dr Saddiqi focused the presentation on patient factors.

Patient factors

The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.

Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.

However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.

Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD)  ≥ 50 cm² at baseline had an 8-fold increase in risk of CRS and neurotoxicity.

“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”

Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.

The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.

“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.

And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.

“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.

The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.

The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.

“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.

"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”

The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.

*Data in the presentation differ from the abstract.

© Scott Morgan 2017

ATLANTA—Data suggest a therapeutic window may exist for chimeric antigen receptor (CAR) T-cell expansion with JCAR017, according to a preliminary model.

In a core set of 67 patients with diffuse large B-cell lymphoma (DLBCL) who had received JCAR017 in the TRANSCEND NHL 001 trial, investigators observed that baseline high tumor burden and inflammatory biomarkers were associated with high CAR T-cell expansion and increased rates of cytokine release syndrome (CRS) and neurotoxicity.

If the model holds up, researchers say they could potentially identify patients at risk for low or high T-cell expansion levels and develop a strategy to enhance or limit the expansion.

TRANSCEND NHL 001 (NCT02631044) is a multicenter, phase 1 trial in relapsed or refractory non-Hodgkin lymphoma evaluating 2 dose levels of JCAR017, also known as lisocabtagene maraleucel, or liso-cel for short.

Liso-cel is a CD19-directed 4-1BB CAR T cell administered at precise doses of CD4+ and CD8+ CAR T cells. It had previously demonstrated high complete remission (CR) rates and low incidences of CRS and neurotoxicity.

Tanya Saddiqi, MD, of City of Hope National Medical Center in Duarte, California, presented data from the dose-finding and expansion cohorts at the 2017 ASH Annual Meeting (abstract 193*).

Study design

Patients with DLBCL after 2 lines of prior therapy or mantle cell lymphoma after 1 prior line of therapy were eligible to enroll in TRANSCEND NHL 001.

Patients with de novo DLBCL, those who transformed from follicular lymphoma, or those with high-grade B-cell lymphoma made up the pivotal or core population. All DLBCL patients enrolled on the trial comprised the full population.

Patients were screened, enrolled, and underwent apheresis. Bridging therapy was permitted while their CAR T cells were being manufactured.

Patients then had a PET scan and lab tests prior to lymphodepletion.

“This is the time point of our interest,” Dr Saddiqi said, “to see if there are any patient characteristics or biomarkers that we can identify . . .  that could help us figure out which patients are at higher risk of toxicity, potentially.”

Lymphodepletion consisted of fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m² for 3 days).

Patients received the JCAR017 infusion, and, at specific time points thereafter, cytokine, pharmacokinetic (PK), and clinical lab evaluations were conducted. PK evaluation and scans were performed every 3 months for the first year after JCAR017 infusion, and safety and viral vector follow-up for 15 years.

Dose levels were 5 x 10⁷ cells as a single or double dose (DL1S) and 1 x 10⁸ cells as a single dose (DL2S). Dose level 2 was chosen for further study, and double dosing was discontinued.

“Double dosing was actually not pursued further,” Dr Saddiqi explained, “because it did not seem to add any benefit over single dosing.”

At the time of the presentation, 91 total patients were treated, 67 of whom were the core population.

Results

Dr Saddiqi reported that patients treated with JCAR017 achieved a relatively high best overall response rate (ORR) and high durable CR rates.

“And this seems to be especially true for the core set of patients and particularly for patients at dose level 2,” she added.

At all dose levels, the core patients had a best ORR of 84% (41/49) and a CR rate of 61% (30/49).

At follow-up of 3 months or longer, the core group had an ORR of 65% (26/40) for all dose levels, 52% (11/21) for dose level 1, and 80% (12/15) for dose level 2.

The 3-month CR rate was 53% (21/40) for all dose levels in the core group, 33% (7/21) in dose level 1, and 73% (11/15) in dose level 2.

Dr Saddiqi noted that CRS and neurotoxicity did not differ by dose level or schedule, and there were no grade 5 events of CRS or neurotoxicity.

“Among the core group, dose level change did not add to their toxicity,” she said. “And so the question is: Is it patient factors, is it tumor factors? What is it that is actually causing the toxicities in these patients?”

Dr Saddiqi focused the presentation on patient factors.

Patient factors

The data showed that tumor burden and lactose dehydrogenase (LDH) levels were higher in patients with CRS and neurotoxicity.

Univariate analysis revealed that CRS and neurotoxicity were associated with a shorter time since diagnosis.

However, prior number of therapies, patient weight, and disease stage were not associated with CRS or neurotoxicity.

Investigators were able to identify preliminary risk boundaries. Core patients with high LDH levels (≥ 500 U/L) and sum of the products of diameters (SPD)  ≥ 50 cm² at baseline had an 8-fold increase in risk of CRS and neurotoxicity.

“Inversely, if these patients did not meet the cutoff for LDH or SPD,” Dr Saddiqi pointed out, “if they were lower than that, they have significantly lower CRS and neurotoxicity events.”

Investigators also observed that baseline markers of inflammation and inflammatory cytokines trended higher in patients with CRS and neurotoxicity. For CRS, this includes ferritin, C-reactive protein (CRP), IL-10, IL-15, IL-16, TNFα, and MIP-1β. For neurotoxicity, this includes ferritin, CRP, d-Dimer, IL-6, IL-15, TNFα, and MIP-1α.

The team also observed that tumor burden, baseline markers of inflammation, and inflammatory cytokines trended lower in core patients with durable responses.

“Interestingly, it’s inversely true that patients who did have these higher levels [of inflammation markers], and higher tumor burden, and higher LDH, actually were the ones that were either showing no response at 3 months or had lost their response by the 3-month assessment point,” Dr Saddiqi explained.

And in patients with higher baseline tumor burden and inflammatory cytokine levels, JCAR017 T-cell expansion trended higher.

“Some were deemed to be super expanders because their CAR T-cell levels were very high in their blood,” she added.

The investigators created a preliminary logistic model based on the data that suggests a therapeutic window might be able to limit toxicity and optimize efficacy.

The model indicates that patients with higher tumor burden, higher LDH, and higher inflammatory state at baseline seem to be the ones who are having more CRS and more neurotoxicity after CAR T-cell infusion.

“They are expanding their cells much more, yet their responses at 3 months seem to be affected adversely by this entire situation,” Dr Saddiqi said.

"One explanation, potentially, could be that these CAR T cells are seeing a lot of antigen when they go into the body. They have the perfect cytokine milieu to grow, expand, and go crazy in the body, if you will, and very quickly peter out as well because there’s T-cell exhaustion that happens rather rapidly and clinical responses are then then lost.”

The investigators believe that if they can identify those patients ahead of time who may be at risk of too high expansion or too low expansion of their CAR T cells, they may be able to find strategies to push expansion into the “sweet spot of CAR T-cell expansion and ultimately get the holy grail of having durable responses for all with minimal toxicity,” Dr Saddiqi concluded.

TRANSCEND NHL 001 is sponsored by Juno Therapeutics, Inc. Dr Saddiqi has served on a steering committee for JCAR017.

*Data in the presentation differ from the abstract.

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for the anti-PD-1 therapy pembrolizumab (KEYTRUDA).

With this sBLA, Merck is seeking approval for pembrolizumab to treat adult and pediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL) or patients with PMBCL who have relapsed after 2 or more prior lines of therapy.

The FDA expects to make a decision on the sBLA by April 3, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Pembrolizumab is currently FDA-approved to treat classical Hodgkin lymphoma, melanoma, lung cancer, head and neck cancer, urothelial carcinoma, microsatellite instability-high cancer, and gastric cancer.

The sBLA for pembrolizumab as a treatment for PMBCL is supported by the phase 2 KEYNOTE-170 trial. Results from this trial were presented at the 2017 ASH Annual Meeting (abstract 2833).

KEYNOTE-170 is an ongoing study in which researchers are evaluating pembrolizumab (given at a 200 mg fixed dose every 3 weeks) in patients with relapsed/refractory PMBCL or relapsed/refractory Richter syndrome.

The PMBCL cohort enrolled patients who relapsed after autologous stem cell transplant (ASCT), were refractory to ASCT, or were ineligible for ASCT. Patients ineligible for ASCT had to have received 2 or more lines of prior therapy.

The median duration of follow-up was 10.5 months (range, 0.1-17.7).

In the efficacy population (n=29), the overall response rate was 41% (n=12), and the complete response rate was 24% (n=7).

The median time to response was 2.8 months (range, 2.4-5.5), and the median duration of response was not reached (range, 1.1+ to 13.6+ months).

Of the 53 patients evaluated for safety, 57% (n=30) experienced treatment-related adverse events (TRAEs), including 21% (n=11) who experienced grade 3-4 TRAEs.

The most common TRAEs (occurring in at least 5% of patients) were neutropenia (n=11), hypothyroidism (n=4), asthenia (n=3), and pyrexia (n=3).

Immune-mediated adverse events of all grades occurred in 11% (n=6) of patients. These include hypothyroidism (n=4), hyperthyroidism (n=2), pneumonitis (n=1), and thyroiditis (n=1). There were no treatment-related deaths.

*Data in the abstract differ from the presentation.

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for the anti-PD-1 therapy pembrolizumab (KEYTRUDA).

With this sBLA, Merck is seeking approval for pembrolizumab to treat adult and pediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL) or patients with PMBCL who have relapsed after 2 or more prior lines of therapy.

The FDA expects to make a decision on the sBLA by April 3, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Pembrolizumab is currently FDA-approved to treat classical Hodgkin lymphoma, melanoma, lung cancer, head and neck cancer, urothelial carcinoma, microsatellite instability-high cancer, and gastric cancer.

The sBLA for pembrolizumab as a treatment for PMBCL is supported by the phase 2 KEYNOTE-170 trial. Results from this trial were presented at the 2017 ASH Annual Meeting (abstract 2833).

KEYNOTE-170 is an ongoing study in which researchers are evaluating pembrolizumab (given at a 200 mg fixed dose every 3 weeks) in patients with relapsed/refractory PMBCL or relapsed/refractory Richter syndrome.

The PMBCL cohort enrolled patients who relapsed after autologous stem cell transplant (ASCT), were refractory to ASCT, or were ineligible for ASCT. Patients ineligible for ASCT had to have received 2 or more lines of prior therapy.

The median duration of follow-up was 10.5 months (range, 0.1-17.7).

In the efficacy population (n=29), the overall response rate was 41% (n=12), and the complete response rate was 24% (n=7).

The median time to response was 2.8 months (range, 2.4-5.5), and the median duration of response was not reached (range, 1.1+ to 13.6+ months).

Of the 53 patients evaluated for safety, 57% (n=30) experienced treatment-related adverse events (TRAEs), including 21% (n=11) who experienced grade 3-4 TRAEs.

The most common TRAEs (occurring in at least 5% of patients) were neutropenia (n=11), hypothyroidism (n=4), asthenia (n=3), and pyrexia (n=3).

Immune-mediated adverse events of all grades occurred in 11% (n=6) of patients. These include hypothyroidism (n=4), hyperthyroidism (n=2), pneumonitis (n=1), and thyroiditis (n=1). There were no treatment-related deaths.

*Data in the abstract differ from the presentation.

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted priority review to a supplemental biologics license application (sBLA) for the anti-PD-1 therapy pembrolizumab (KEYTRUDA).

With this sBLA, Merck is seeking approval for pembrolizumab to treat adult and pediatric patients with refractory primary mediastinal B-cell lymphoma (PMBCL) or patients with PMBCL who have relapsed after 2 or more prior lines of therapy.

The FDA expects to make a decision on the sBLA by April 3, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Pembrolizumab is currently FDA-approved to treat classical Hodgkin lymphoma, melanoma, lung cancer, head and neck cancer, urothelial carcinoma, microsatellite instability-high cancer, and gastric cancer.

The sBLA for pembrolizumab as a treatment for PMBCL is supported by the phase 2 KEYNOTE-170 trial. Results from this trial were presented at the 2017 ASH Annual Meeting (abstract 2833).

KEYNOTE-170 is an ongoing study in which researchers are evaluating pembrolizumab (given at a 200 mg fixed dose every 3 weeks) in patients with relapsed/refractory PMBCL or relapsed/refractory Richter syndrome.

The PMBCL cohort enrolled patients who relapsed after autologous stem cell transplant (ASCT), were refractory to ASCT, or were ineligible for ASCT. Patients ineligible for ASCT had to have received 2 or more lines of prior therapy.

The median duration of follow-up was 10.5 months (range, 0.1-17.7).

In the efficacy population (n=29), the overall response rate was 41% (n=12), and the complete response rate was 24% (n=7).

The median time to response was 2.8 months (range, 2.4-5.5), and the median duration of response was not reached (range, 1.1+ to 13.6+ months).

Of the 53 patients evaluated for safety, 57% (n=30) experienced treatment-related adverse events (TRAEs), including 21% (n=11) who experienced grade 3-4 TRAEs.

The most common TRAEs (occurring in at least 5% of patients) were neutropenia (n=11), hypothyroidism (n=4), asthenia (n=3), and pyrexia (n=3).

Immune-mediated adverse events of all grades occurred in 11% (n=6) of patients. These include hypothyroidism (n=4), hyperthyroidism (n=2), pneumonitis (n=1), and thyroiditis (n=1). There were no treatment-related deaths.

*Data in the abstract differ from the presentation.

© Phil McCarten 2017

ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.

They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).

Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.

At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.

Researchers believe these results confirm the durable clinical benefit reported previously.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).

“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”

The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.

The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.

Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.

The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.

Study design and enrollment

Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.

Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.

“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”

When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 10⁸ to 6.0 x 10⁸ CAR-positive T cells.

The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.

As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.

Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.

There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.

Patient characteristics

Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.

Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.

Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.

Forty-seven percent had undergone prior auto-SCT.

Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.

Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.

Efficacy

The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.

The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.

“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”

The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.

The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.

“The effect of the T cells becomes evident as you follow these patients over time,” he said.

The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.

“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.

Safety

Adverse events of special interest that occurred within 8 weeks of the infusion included:

• Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
• Neurologic events—21% all grades, 8% grade 3, 4% grade 4
• Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
• Infections—34% all grades, 18% grade 3, 2% grade 4
• Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4

No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.

Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).

Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.

Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.

They also noted that dose and exposure were independent.

Dr Schuster indicated that these data are the basis for global regulatory submissions.

Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.

Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.

Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.

© Phil McCarten 2017

ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.

They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).

Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.

At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.

Researchers believe these results confirm the durable clinical benefit reported previously.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).

“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”

The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.

The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.

Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.

The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.

Study design and enrollment

Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.

Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.

“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”

When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 10⁸ to 6.0 x 10⁸ CAR-positive T cells.

The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.

As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.

Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.

There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.

Patient characteristics

Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.

Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.

Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.

Forty-seven percent had undergone prior auto-SCT.

Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.

Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.

Efficacy

The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.

The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.

“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”

The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.

The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.

“The effect of the T cells becomes evident as you follow these patients over time,” he said.

The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.

“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.

Safety

Adverse events of special interest that occurred within 8 weeks of the infusion included:

• Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
• Neurologic events—21% all grades, 8% grade 3, 4% grade 4
• Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
• Infections—34% all grades, 18% grade 3, 2% grade 4
• Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4

No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.

Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).

Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.

Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.

They also noted that dose and exposure were independent.

Dr Schuster indicated that these data are the basis for global regulatory submissions.

Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.

Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.

Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.

© Phil McCarten 2017

ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.

They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).

Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.

At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.

Researchers believe these results confirm the durable clinical benefit reported previously.

Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).

“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”

The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.

The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.

Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.

The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.

Study design and enrollment

Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.

Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.

“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”

When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 10⁸ to 6.0 x 10⁸ CAR-positive T cells.

The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.

As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.

Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.

There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.

Patient characteristics

Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.

Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.

Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.

Forty-seven percent had undergone prior auto-SCT.

Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.

Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.

Efficacy

The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.

The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.

“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”

The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.

The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.

“The effect of the T cells becomes evident as you follow these patients over time,” he said.

The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.

“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.

Safety

Adverse events of special interest that occurred within 8 weeks of the infusion included:

• Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
• Neurologic events—21% all grades, 8% grade 3, 4% grade 4
• Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
• Infections—34% all grades, 18% grade 3, 2% grade 4
• Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4

No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.

Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).

Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.

Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.

They also noted that dose and exposure were independent.

Dr Schuster indicated that these data are the basis for global regulatory submissions.

Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.

Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.

Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.

Photo by Bill Branson

A survey of nearly 300 US medical providers revealed that many were open to helping children with cancer access medical marijuana (MM).

However, most of the providers surveyed did not know state-specific regulations pertaining to MM.

Providers who were legally eligible to certify (ETC) for MM were less open to endorsing its use.

The lack of standards on formulations, dosing, and potency of MM was identified as the greatest barrier to recommending MM for children with cancer.

Kelly Michelson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois, and her colleagues reported these findings in Pediatrics.

The researchers used a 32-item survey to assess MM practices, knowledge, attitudes, and barriers for pediatric oncology providers in Illinois, Massachusetts, and Washington.

The survey was sent to providers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Seattle Children’s Cancer and Blood Disorders Center, and Lurie Children’s Center for Cancer and Blood Disorders.

There were 288 respondents, and 33% were legally ETC for MM. Eighty-six percent of ETC providers were physicians, and 14% were nurse practitioners or physician assistants.

Of the non-ETC providers, 89% were nurses, 8% were nurse practitioners or physician assistants, 2% were psychosocial providers, and 2% were “other” providers.

Thirty percent of all providers said they had received at least 1 request for MM in the previous month. And 14% of these providers facilitated patient access to MM.

Ninety-two percent of providers said they were willing to help pediatric cancer patients access MM. Fifty-seven percent of providers approved of patients smoking MM, 89% approved of oral formulations, 67% approved of using MM as cancer-directed therapy, and 92% approved of using MM to manage symptoms.

Fifty-nine percent of providers knew that MM is against federal laws, and 86% knew that their state had legalized MM, but only 5% knew state-specific regulations.

ETC providers were less likely to report willingness to help patients access MM. These providers were also less likely to approve of MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms.

“It is not surprising that providers who are eligible to certify for medical marijuana were more cautious about recommending it, given that their licensure could be jeopardized due to federal prohibition,” Dr Michelson said.

“Institutional policies also may have influenced their attitudes. Lurie Children’s, for example, prohibits pediatric providers from facilitating medical marijuana access in accordance with the federal law, even though it is legal in Illinois.”

Most providers considered MM more permissible for use in children with advanced cancer or near the end of life than in earlier stages of cancer treatment. This is consistent with the current American Academy of Pediatrics position that sanctions MM use for “children with life-limiting or seriously debilitating conditions.”

Only 2% of providers reported that MM was never appropriate for a child with cancer.

Most providers (63%) were not concerned about substance abuse in children who receive MM or about being prosecuted for helping patients access MM (80%).

The greatest concern (listed by 46% of providers) was the absence of standards around prescribing MM to children with cancer.

“In addition to unclear dosage guidelines, the lack of high quality scientific data that medical marijuana benefits outweigh possible harm is a huge concern for providers accustomed to evidence-based practice,” Dr Michelson said. “We need rigorously designed clinical trials on the use of medical marijuana in children with cancer.”

Photo by Bill Branson

A survey of nearly 300 US medical providers revealed that many were open to helping children with cancer access medical marijuana (MM).

However, most of the providers surveyed did not know state-specific regulations pertaining to MM.

Providers who were legally eligible to certify (ETC) for MM were less open to endorsing its use.

The lack of standards on formulations, dosing, and potency of MM was identified as the greatest barrier to recommending MM for children with cancer.

Kelly Michelson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois, and her colleagues reported these findings in Pediatrics.

The researchers used a 32-item survey to assess MM practices, knowledge, attitudes, and barriers for pediatric oncology providers in Illinois, Massachusetts, and Washington.

The survey was sent to providers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Seattle Children’s Cancer and Blood Disorders Center, and Lurie Children’s Center for Cancer and Blood Disorders.

There were 288 respondents, and 33% were legally ETC for MM. Eighty-six percent of ETC providers were physicians, and 14% were nurse practitioners or physician assistants.

Of the non-ETC providers, 89% were nurses, 8% were nurse practitioners or physician assistants, 2% were psychosocial providers, and 2% were “other” providers.

Thirty percent of all providers said they had received at least 1 request for MM in the previous month. And 14% of these providers facilitated patient access to MM.

Ninety-two percent of providers said they were willing to help pediatric cancer patients access MM. Fifty-seven percent of providers approved of patients smoking MM, 89% approved of oral formulations, 67% approved of using MM as cancer-directed therapy, and 92% approved of using MM to manage symptoms.

Fifty-nine percent of providers knew that MM is against federal laws, and 86% knew that their state had legalized MM, but only 5% knew state-specific regulations.

ETC providers were less likely to report willingness to help patients access MM. These providers were also less likely to approve of MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms.

“It is not surprising that providers who are eligible to certify for medical marijuana were more cautious about recommending it, given that their licensure could be jeopardized due to federal prohibition,” Dr Michelson said.

“Institutional policies also may have influenced their attitudes. Lurie Children’s, for example, prohibits pediatric providers from facilitating medical marijuana access in accordance with the federal law, even though it is legal in Illinois.”

Most providers considered MM more permissible for use in children with advanced cancer or near the end of life than in earlier stages of cancer treatment. This is consistent with the current American Academy of Pediatrics position that sanctions MM use for “children with life-limiting or seriously debilitating conditions.”

Only 2% of providers reported that MM was never appropriate for a child with cancer.

Most providers (63%) were not concerned about substance abuse in children who receive MM or about being prosecuted for helping patients access MM (80%).

The greatest concern (listed by 46% of providers) was the absence of standards around prescribing MM to children with cancer.

“In addition to unclear dosage guidelines, the lack of high quality scientific data that medical marijuana benefits outweigh possible harm is a huge concern for providers accustomed to evidence-based practice,” Dr Michelson said. “We need rigorously designed clinical trials on the use of medical marijuana in children with cancer.”

Photo by Bill Branson

A survey of nearly 300 US medical providers revealed that many were open to helping children with cancer access medical marijuana (MM).

However, most of the providers surveyed did not know state-specific regulations pertaining to MM.

Providers who were legally eligible to certify (ETC) for MM were less open to endorsing its use.

The lack of standards on formulations, dosing, and potency of MM was identified as the greatest barrier to recommending MM for children with cancer.

Kelly Michelson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois, and her colleagues reported these findings in Pediatrics.

The researchers used a 32-item survey to assess MM practices, knowledge, attitudes, and barriers for pediatric oncology providers in Illinois, Massachusetts, and Washington.

The survey was sent to providers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Seattle Children’s Cancer and Blood Disorders Center, and Lurie Children’s Center for Cancer and Blood Disorders.

There were 288 respondents, and 33% were legally ETC for MM. Eighty-six percent of ETC providers were physicians, and 14% were nurse practitioners or physician assistants.

Of the non-ETC providers, 89% were nurses, 8% were nurse practitioners or physician assistants, 2% were psychosocial providers, and 2% were “other” providers.

Thirty percent of all providers said they had received at least 1 request for MM in the previous month. And 14% of these providers facilitated patient access to MM.

Ninety-two percent of providers said they were willing to help pediatric cancer patients access MM. Fifty-seven percent of providers approved of patients smoking MM, 89% approved of oral formulations, 67% approved of using MM as cancer-directed therapy, and 92% approved of using MM to manage symptoms.

Fifty-nine percent of providers knew that MM is against federal laws, and 86% knew that their state had legalized MM, but only 5% knew state-specific regulations.

ETC providers were less likely to report willingness to help patients access MM. These providers were also less likely to approve of MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms.

“It is not surprising that providers who are eligible to certify for medical marijuana were more cautious about recommending it, given that their licensure could be jeopardized due to federal prohibition,” Dr Michelson said.

“Institutional policies also may have influenced their attitudes. Lurie Children’s, for example, prohibits pediatric providers from facilitating medical marijuana access in accordance with the federal law, even though it is legal in Illinois.”

Most providers considered MM more permissible for use in children with advanced cancer or near the end of life than in earlier stages of cancer treatment. This is consistent with the current American Academy of Pediatrics position that sanctions MM use for “children with life-limiting or seriously debilitating conditions.”

Only 2% of providers reported that MM was never appropriate for a child with cancer.

Most providers (63%) were not concerned about substance abuse in children who receive MM or about being prosecuted for helping patients access MM (80%).

The greatest concern (listed by 46% of providers) was the absence of standards around prescribing MM to children with cancer.

“In addition to unclear dosage guidelines, the lack of high quality scientific data that medical marijuana benefits outweigh possible harm is a huge concern for providers accustomed to evidence-based practice,” Dr Michelson said. “We need rigorously designed clinical trials on the use of medical marijuana in children with cancer.”

ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.

At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.

In this video interview, Helen Heslop, MD, provided her perspective on the current use and future directions of three of these treatments: axicabtagene ciloleucel (Yescarta), acalabrutinib (Calquence), and copanlisib (Aliqopa).

“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.

Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.

“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.

However, while the findings are encouraging, only 30%-40% are having a durable response, she added.

“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.

With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.

Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.

“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.

She reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.

At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.

In this video interview, Helen Heslop, MD, provided her perspective on the current use and future directions of three of these treatments: axicabtagene ciloleucel (Yescarta), acalabrutinib (Calquence), and copanlisib (Aliqopa).

“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.

Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.

“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.

However, while the findings are encouraging, only 30%-40% are having a durable response, she added.

“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.

With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.

Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.

“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.

She reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

ATLANTA – 2017 was a banner year for the approval of new drugs to treat hematologic disorders.

At a special interest session at the annual meeting of American Society of Hematology, representatives from the Food and Drug Administration joined forces with clinicians to discuss the use of the newly approved treatments in the real-world setting.

In this video interview, Helen Heslop, MD, provided her perspective on the current use and future directions of three of these treatments: axicabtagene ciloleucel (Yescarta), acalabrutinib (Calquence), and copanlisib (Aliqopa).

“This is extremely exciting,” she said regarding the pace of new approvals for hematologic malignancies.

Axicabtagene ciloleucel, a CAR T-cell product approved in October for the treatment of relapsed/refractory large B-cell lymphoma in adults, is particularly interesting, she said.

“The data shows that if you look at a population of diffuse large B-cell lymphoma patients, that historically have a very poor outcome, there is definitely an impressive response rate and improved survival, compared to the natural history cohort,” said Dr. Heslop of Baylor College of Medicine, Houston.

However, while the findings are encouraging, only 30%-40% are having a durable response, she added.

“So I think there’ll be lots of efforts to try and improve the response rate by combination with other agents such as checkpoint inhibitors or other immunomodulators,” she said.

With respect to the second-generation Bruton’s tyrosine kinase inhibitor acalabrutinib, which was approved in October for adults with mantle cell lymphoma who have been treated with at least one prior therapy, she discussed the potential for improved outcomes and the importance of looking further into its use in patients who have failed ibrutinib therapy, as well as its use in combination with other agents, such as bendamustine and rituximab early in the course of disease.

Copanlisib, a PI3 kinase inhibitor approved in September, is an addition to the armamentarium for adult patients with relapsed follicular lymphoma after two lines of previous therapy.

“It still does have some side effects, as do other drugs in this class, so I think it’s place will still need to be defined,” Dr. Heslop said.

She reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

Adult patients with mycosis fungoides (MF) have a higher risk of secondary malignancies, according to a 20-year population-based cohort study. The researchers, from Bezmialem Vakif University in Istanbul, Turkey, say their findings support earlier research about a higher risk of, for instance, Hodgkin lymphoma, chronic leukemia, and lung cancer.

Between 1998 and 2015, the researchers documented 143 cases of cutaneous T-cell lymphoma (CTCL). The majority of patients had early-stage disease.

The researchers also documented 13 cases (9%) of secondary malignancy diagnosed at least 3 months after the diagnosis of CTCL. The cancers included bladder cancer, nasopharynx cancer, renal cell carcinoma, lung cancer, and superficial spreading malignant melanoma.

Older age, stage IV disease, lymphomatoid papulosis, and having CTCL for > 10 years raised the chances of developing secondary solid tumors. In 60% of patients, the secondary malignancies occurred during the first year of diagnosis.

Research has suggested that antilymphoma drugs, particularly alkylating agents, may lead to leukemia, the researchers note. In this study, 6 patients with secondary cancers were getting systemic treatment with interferon or acitretin; 7 were getting no systemic treatment.

The researchers add that MF and hematologic malignancies may share genetic origin, carcinogens, or viruses that affect lymphocyte precursors. They also note that the first neoplasm may produce cytokines that induce development of the secondary neoplasm. The researchers cite research that found MF is a T helper cell 2–mediated disease associated with human leukocyte antigen 2 alleles. Viruses such as Epstein-Barr and herpes simplex also have been implicated.

“Extensive evaluation” for secondary malignancies in adult patients with MF is wise, the researchers advise, particularly if the patient has lymphomatoid papulosis.

Source:

Cengiz FP, Emiroğlu N, Onsun N. Turk J Haematol. 2017;34(4):378-379.

doi: 10.4274/tjh.2017.0234.

Adult patients with mycosis fungoides (MF) have a higher risk of secondary malignancies, according to a 20-year population-based cohort study. The researchers, from Bezmialem Vakif University in Istanbul, Turkey, say their findings support earlier research about a higher risk of, for instance, Hodgkin lymphoma, chronic leukemia, and lung cancer.

Between 1998 and 2015, the researchers documented 143 cases of cutaneous T-cell lymphoma (CTCL). The majority of patients had early-stage disease.

The researchers also documented 13 cases (9%) of secondary malignancy diagnosed at least 3 months after the diagnosis of CTCL. The cancers included bladder cancer, nasopharynx cancer, renal cell carcinoma, lung cancer, and superficial spreading malignant melanoma.

Older age, stage IV disease, lymphomatoid papulosis, and having CTCL for > 10 years raised the chances of developing secondary solid tumors. In 60% of patients, the secondary malignancies occurred during the first year of diagnosis.

Research has suggested that antilymphoma drugs, particularly alkylating agents, may lead to leukemia, the researchers note. In this study, 6 patients with secondary cancers were getting systemic treatment with interferon or acitretin; 7 were getting no systemic treatment.

The researchers add that MF and hematologic malignancies may share genetic origin, carcinogens, or viruses that affect lymphocyte precursors. They also note that the first neoplasm may produce cytokines that induce development of the secondary neoplasm. The researchers cite research that found MF is a T helper cell 2–mediated disease associated with human leukocyte antigen 2 alleles. Viruses such as Epstein-Barr and herpes simplex also have been implicated.

“Extensive evaluation” for secondary malignancies in adult patients with MF is wise, the researchers advise, particularly if the patient has lymphomatoid papulosis.

Source:

Cengiz FP, Emiroğlu N, Onsun N. Turk J Haematol. 2017;34(4):378-379.

doi: 10.4274/tjh.2017.0234.

Adult patients with mycosis fungoides (MF) have a higher risk of secondary malignancies, according to a 20-year population-based cohort study. The researchers, from Bezmialem Vakif University in Istanbul, Turkey, say their findings support earlier research about a higher risk of, for instance, Hodgkin lymphoma, chronic leukemia, and lung cancer.

Between 1998 and 2015, the researchers documented 143 cases of cutaneous T-cell lymphoma (CTCL). The majority of patients had early-stage disease.

The researchers also documented 13 cases (9%) of secondary malignancy diagnosed at least 3 months after the diagnosis of CTCL. The cancers included bladder cancer, nasopharynx cancer, renal cell carcinoma, lung cancer, and superficial spreading malignant melanoma.

Older age, stage IV disease, lymphomatoid papulosis, and having CTCL for > 10 years raised the chances of developing secondary solid tumors. In 60% of patients, the secondary malignancies occurred during the first year of diagnosis.

Research has suggested that antilymphoma drugs, particularly alkylating agents, may lead to leukemia, the researchers note. In this study, 6 patients with secondary cancers were getting systemic treatment with interferon or acitretin; 7 were getting no systemic treatment.

The researchers add that MF and hematologic malignancies may share genetic origin, carcinogens, or viruses that affect lymphocyte precursors. They also note that the first neoplasm may produce cytokines that induce development of the secondary neoplasm. The researchers cite research that found MF is a T helper cell 2–mediated disease associated with human leukocyte antigen 2 alleles. Viruses such as Epstein-Barr and herpes simplex also have been implicated.

“Extensive evaluation” for secondary malignancies in adult patients with MF is wise, the researchers advise, particularly if the patient has lymphomatoid papulosis.

Source:

Cengiz FP, Emiroğlu N, Onsun N. Turk J Haematol. 2017;34(4):378-379.

doi: 10.4274/tjh.2017.0234.

Photo courtesy of ASH

ATLANTA—Phase 3 trial results suggest one 4-drug combination may be more effective than another as frontline treatment for advanced Hodgkin lymphoma (HL).

In the ECHELON-1 trial, treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) staved off progression, death, and the need for subsequent therapy more effectively than treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

However, there was no significant difference between the treatment arms when it came to response rates or overall survival.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.

These data were presented at the 2017 ASH Annual Meeting (abstract 6) and simultaneously published in The New England Journal of Medicine. The trial was funded by Millennium Pharmaceuticals and Seattle Genetics, Inc.

“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades, and there remains an unmet need for additional regimens in frontline treatment,” said Joseph M. Connors, MD, of BC Cancer in Vancouver, British Columbia, Canada.

With this in mind, he and his colleagues conducted ECHELON-1. The study enrolled 1334 patients who had stage III or IV HL and had not previously received systemic chemotherapy or radiotherapy.

Fifty-eight percent of patients were male, and the median age was 36 (range, 18-83). Sixty-four percent of patients had stage IV disease, 62% had extranodal involvement at diagnosis, and 58% had B symptoms.

The patients were randomized to receive A+AVD (n=664) or ABVD (n=670) on days 1 and 15 of each 28-day cycle for up to 6 cycles. Baseline characteristics were well-balanced between the treatment arms.

The median follow-up was 24.9 months (range, 0-49.3).

Primary endpoint

The study’s primary endpoint is modified progression-free survival (PFS), which is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

“Reducing the risk of relapse is an important concern for patients and their physicians,” Dr Connors noted. “In the trial, 33% fewer patients [in the A+AVD arm] required subsequent salvage chemotherapy or high-dose chemotherapy and transplant compared to the patients treated with ABVD.”

According to the independent review facility, the 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

Certain pre-specified subgroups of patients appeared to benefit more with A+AVD than with ABVD, including:

• Males
• Patients treated in North America
• Patients with involvement of more than 1 extranodal site
• Patients with International Prognostic Scores of 4 to 7
• Patients with stage IV disease
• Patients younger than 60.

Secondary endpoints

Secondary endpoints trended in favor of the A+AVD arm, although there were no significant differences between the treatment arms.

The objective response rate at the end of the randomized regimen was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The proportion of patients with a Deauville score ≤2 after the completion of frontline therapy was 85% in the A+AVD arm and 80% in the ABVD arm (P=0.03).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

Safety

“[T]he safety profile [of A+AVD] was generally consistent with that known for the single-agent components of the regimen,” Dr Connors said.

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Common AEs (in the A+AVD and ABVD arms, respectively) included neutropenia (58% and 45%), constipation (42% and 37%), vomiting (33% and 28%), fatigue (both 32%), diarrhea (27% and 18%), pyrexia (27% and 22%), abdominal pain (21% and 10%), and stomatitis (21% and 16%).

Peripheral neuropathy events were observed in 67% of patients in the A+AVD arm and 43% in the ABVD arm. Grade 3 or higher peripheral neuropathy was reported in 11% and 2%, respectively.

Febrile neutropenia occurred in 19% of patients in the A+AVD arm and 8% of those in the ABVD arm. However, prophylaxis with granulocyte colony-stimulating factor (G-CSF) was able to reduce the incidence of febrile neutropenia. In the A+AVD arm, the rate of febrile neutropenia was 11% among patients who received G-CSF and 21% among patients who did not.

Pulmonary toxicity occurred in 2% of patients in the A+AVD arm and 7% of those in the ABVD arm. Grade 3 or higher pulmonary toxicity was reported in 0.76% and 3%, respectively.

There were 9 deaths during treatment in the A+AVD arm. Seven were due to neutropenia or associated complications, and 2 were due to myocardial infarction. One of the patients who died of neutropenia had the condition prior to trial enrollment. The remaining 6 patients did not receive G-CSF prophylaxis.

In the ABVD arm, there were 13 deaths during treatment. Eleven were due to or associated with pulmonary-related toxicity, 1 was due to cardiopulmonary failure, and 1 death had an unknown cause.

Photo courtesy of ASH

ATLANTA—Phase 3 trial results suggest one 4-drug combination may be more effective than another as frontline treatment for advanced Hodgkin lymphoma (HL).

In the ECHELON-1 trial, treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) staved off progression, death, and the need for subsequent therapy more effectively than treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

However, there was no significant difference between the treatment arms when it came to response rates or overall survival.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.

These data were presented at the 2017 ASH Annual Meeting (abstract 6) and simultaneously published in The New England Journal of Medicine. The trial was funded by Millennium Pharmaceuticals and Seattle Genetics, Inc.

“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades, and there remains an unmet need for additional regimens in frontline treatment,” said Joseph M. Connors, MD, of BC Cancer in Vancouver, British Columbia, Canada.

With this in mind, he and his colleagues conducted ECHELON-1. The study enrolled 1334 patients who had stage III or IV HL and had not previously received systemic chemotherapy or radiotherapy.

Fifty-eight percent of patients were male, and the median age was 36 (range, 18-83). Sixty-four percent of patients had stage IV disease, 62% had extranodal involvement at diagnosis, and 58% had B symptoms.

The patients were randomized to receive A+AVD (n=664) or ABVD (n=670) on days 1 and 15 of each 28-day cycle for up to 6 cycles. Baseline characteristics were well-balanced between the treatment arms.

The median follow-up was 24.9 months (range, 0-49.3).

Primary endpoint

The study’s primary endpoint is modified progression-free survival (PFS), which is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

“Reducing the risk of relapse is an important concern for patients and their physicians,” Dr Connors noted. “In the trial, 33% fewer patients [in the A+AVD arm] required subsequent salvage chemotherapy or high-dose chemotherapy and transplant compared to the patients treated with ABVD.”

According to the independent review facility, the 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

Certain pre-specified subgroups of patients appeared to benefit more with A+AVD than with ABVD, including:

• Males
• Patients treated in North America
• Patients with involvement of more than 1 extranodal site
• Patients with International Prognostic Scores of 4 to 7
• Patients with stage IV disease
• Patients younger than 60.

Secondary endpoints

Secondary endpoints trended in favor of the A+AVD arm, although there were no significant differences between the treatment arms.

The objective response rate at the end of the randomized regimen was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The proportion of patients with a Deauville score ≤2 after the completion of frontline therapy was 85% in the A+AVD arm and 80% in the ABVD arm (P=0.03).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

Safety

“[T]he safety profile [of A+AVD] was generally consistent with that known for the single-agent components of the regimen,” Dr Connors said.

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Common AEs (in the A+AVD and ABVD arms, respectively) included neutropenia (58% and 45%), constipation (42% and 37%), vomiting (33% and 28%), fatigue (both 32%), diarrhea (27% and 18%), pyrexia (27% and 22%), abdominal pain (21% and 10%), and stomatitis (21% and 16%).

Peripheral neuropathy events were observed in 67% of patients in the A+AVD arm and 43% in the ABVD arm. Grade 3 or higher peripheral neuropathy was reported in 11% and 2%, respectively.

Febrile neutropenia occurred in 19% of patients in the A+AVD arm and 8% of those in the ABVD arm. However, prophylaxis with granulocyte colony-stimulating factor (G-CSF) was able to reduce the incidence of febrile neutropenia. In the A+AVD arm, the rate of febrile neutropenia was 11% among patients who received G-CSF and 21% among patients who did not.

Pulmonary toxicity occurred in 2% of patients in the A+AVD arm and 7% of those in the ABVD arm. Grade 3 or higher pulmonary toxicity was reported in 0.76% and 3%, respectively.

There were 9 deaths during treatment in the A+AVD arm. Seven were due to neutropenia or associated complications, and 2 were due to myocardial infarction. One of the patients who died of neutropenia had the condition prior to trial enrollment. The remaining 6 patients did not receive G-CSF prophylaxis.

In the ABVD arm, there were 13 deaths during treatment. Eleven were due to or associated with pulmonary-related toxicity, 1 was due to cardiopulmonary failure, and 1 death had an unknown cause.

Photo courtesy of ASH

ATLANTA—Phase 3 trial results suggest one 4-drug combination may be more effective than another as frontline treatment for advanced Hodgkin lymphoma (HL).

In the ECHELON-1 trial, treatment with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) staved off progression, death, and the need for subsequent therapy more effectively than treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

However, there was no significant difference between the treatment arms when it came to response rates or overall survival.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.

These data were presented at the 2017 ASH Annual Meeting (abstract 6) and simultaneously published in The New England Journal of Medicine. The trial was funded by Millennium Pharmaceuticals and Seattle Genetics, Inc.

“The standard of care in the treatment of Hodgkin lymphoma has not changed over the last several decades, and there remains an unmet need for additional regimens in frontline treatment,” said Joseph M. Connors, MD, of BC Cancer in Vancouver, British Columbia, Canada.

With this in mind, he and his colleagues conducted ECHELON-1. The study enrolled 1334 patients who had stage III or IV HL and had not previously received systemic chemotherapy or radiotherapy.

Fifty-eight percent of patients were male, and the median age was 36 (range, 18-83). Sixty-four percent of patients had stage IV disease, 62% had extranodal involvement at diagnosis, and 58% had B symptoms.

The patients were randomized to receive A+AVD (n=664) or ABVD (n=670) on days 1 and 15 of each 28-day cycle for up to 6 cycles. Baseline characteristics were well-balanced between the treatment arms.

The median follow-up was 24.9 months (range, 0-49.3).

Primary endpoint

The study’s primary endpoint is modified progression-free survival (PFS), which is defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

“Reducing the risk of relapse is an important concern for patients and their physicians,” Dr Connors noted. “In the trial, 33% fewer patients [in the A+AVD arm] required subsequent salvage chemotherapy or high-dose chemotherapy and transplant compared to the patients treated with ABVD.”

According to the independent review facility, the 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

Certain pre-specified subgroups of patients appeared to benefit more with A+AVD than with ABVD, including:

• Males
• Patients treated in North America
• Patients with involvement of more than 1 extranodal site
• Patients with International Prognostic Scores of 4 to 7
• Patients with stage IV disease
• Patients younger than 60.

Secondary endpoints

Secondary endpoints trended in favor of the A+AVD arm, although there were no significant differences between the treatment arms.

The objective response rate at the end of the randomized regimen was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The proportion of patients with a Deauville score ≤2 after the completion of frontline therapy was 85% in the A+AVD arm and 80% in the ABVD arm (P=0.03).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

Safety

“[T]he safety profile [of A+AVD] was generally consistent with that known for the single-agent components of the regimen,” Dr Connors said.

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Common AEs (in the A+AVD and ABVD arms, respectively) included neutropenia (58% and 45%), constipation (42% and 37%), vomiting (33% and 28%), fatigue (both 32%), diarrhea (27% and 18%), pyrexia (27% and 22%), abdominal pain (21% and 10%), and stomatitis (21% and 16%).

Peripheral neuropathy events were observed in 67% of patients in the A+AVD arm and 43% in the ABVD arm. Grade 3 or higher peripheral neuropathy was reported in 11% and 2%, respectively.

Febrile neutropenia occurred in 19% of patients in the A+AVD arm and 8% of those in the ABVD arm. However, prophylaxis with granulocyte colony-stimulating factor (G-CSF) was able to reduce the incidence of febrile neutropenia. In the A+AVD arm, the rate of febrile neutropenia was 11% among patients who received G-CSF and 21% among patients who did not.

Pulmonary toxicity occurred in 2% of patients in the A+AVD arm and 7% of those in the ABVD arm. Grade 3 or higher pulmonary toxicity was reported in 0.76% and 3%, respectively.

There were 9 deaths during treatment in the A+AVD arm. Seven were due to neutropenia or associated complications, and 2 were due to myocardial infarction. One of the patients who died of neutropenia had the condition prior to trial enrollment. The remaining 6 patients did not receive G-CSF prophylaxis.

In the ABVD arm, there were 13 deaths during treatment. Eleven were due to or associated with pulmonary-related toxicity, 1 was due to cardiopulmonary failure, and 1 death had an unknown cause.

Photo from Georgia State University

Preclinical research suggests infrared spectroscopy could be used to diagnose non-Hodgkin lymphoma (NHL).

Researchers used mid-infrared spectroscopy to analyze blood serum derived from mice and differentiate mice with NHL and subcutaneous melanoma from each other and from healthy control mice.

The findings suggest infrared spectroscopy can detect biochemical changes induced by NHL and melanoma and therefore has diagnostic potential as a screening technique for these cancers.

A.G. Unil Perera, PhD, of Georgia State University in Atlanta, and his colleagues detailed these findings in Scientific Reports.

The researchers said that Fourier Transform Infrared (FTIR) spectroscopy in Attenuated Total Reflection (ATR) sampling mode provides high-quality results with better reproducibility compared to other vibrational spectroscopy.

With previous work, Dr Perera and his colleagues discovered that a blood test for ulcerative colitis using ATR-FTIR spectroscopy could provide a cheaper, less invasive alternative for screening compared to colonoscopy.

In the current study, the researchers tested ATR-FTIR spectroscopy in mouse models of malignancy—EL4 NHL and B16 subcutaneous melanoma.

The team extracted blood serum from these mice and control mice. Droplets of serum were placed on an ATR crystal of the FTIR instrument.

Incident infrared beams were absorbed and reflected by the serum, creating a wave that was recorded and used to produce an absorbance curve with peaks that identified the presence of certain biomarkers in the sample.

The researchers compared the absorbance curves from the control and cancer mice and assessed biochemical changes induced by NHL and melanoma.

The team found “remarkable” differences between the ATR-FTIR spectra of serum samples from tumor-bearing mice and control mice.

Dr Perera said these findings are applicable to humans because mice and humans have some biomarkers and chemicals in common.

Using the data collected on the biomarkers for NHL and melanoma, the researchers could develop detectors for these particular absorbance peaks, which doctors could use to test patients’ blood samples for these cancers.

“Our final goal is to say we can use this infrared technique to identify various diseases,” Dr Perera said. “This study shows infrared spectroscopy can identify cancer. Right now, when you go to the doctor, they do blood tests for sugar and several other things but not for serious diseases like cancer and colitis.”

“One day, we hope that even these serious diseases can be rapidly screened. Your primary doctor could keep a record of your number and check that every time you come back. Then, if there is some indication of cancer or colitis, they can do biopsies, colonoscopies, etc.”

Photo from Georgia State University

Preclinical research suggests infrared spectroscopy could be used to diagnose non-Hodgkin lymphoma (NHL).

Researchers used mid-infrared spectroscopy to analyze blood serum derived from mice and differentiate mice with NHL and subcutaneous melanoma from each other and from healthy control mice.

The findings suggest infrared spectroscopy can detect biochemical changes induced by NHL and melanoma and therefore has diagnostic potential as a screening technique for these cancers.

A.G. Unil Perera, PhD, of Georgia State University in Atlanta, and his colleagues detailed these findings in Scientific Reports.

The researchers said that Fourier Transform Infrared (FTIR) spectroscopy in Attenuated Total Reflection (ATR) sampling mode provides high-quality results with better reproducibility compared to other vibrational spectroscopy.

With previous work, Dr Perera and his colleagues discovered that a blood test for ulcerative colitis using ATR-FTIR spectroscopy could provide a cheaper, less invasive alternative for screening compared to colonoscopy.

In the current study, the researchers tested ATR-FTIR spectroscopy in mouse models of malignancy—EL4 NHL and B16 subcutaneous melanoma.

The team extracted blood serum from these mice and control mice. Droplets of serum were placed on an ATR crystal of the FTIR instrument.

Incident infrared beams were absorbed and reflected by the serum, creating a wave that was recorded and used to produce an absorbance curve with peaks that identified the presence of certain biomarkers in the sample.

The researchers compared the absorbance curves from the control and cancer mice and assessed biochemical changes induced by NHL and melanoma.

The team found “remarkable” differences between the ATR-FTIR spectra of serum samples from tumor-bearing mice and control mice.

Dr Perera said these findings are applicable to humans because mice and humans have some biomarkers and chemicals in common.

Using the data collected on the biomarkers for NHL and melanoma, the researchers could develop detectors for these particular absorbance peaks, which doctors could use to test patients’ blood samples for these cancers.

“Our final goal is to say we can use this infrared technique to identify various diseases,” Dr Perera said. “This study shows infrared spectroscopy can identify cancer. Right now, when you go to the doctor, they do blood tests for sugar and several other things but not for serious diseases like cancer and colitis.”

“One day, we hope that even these serious diseases can be rapidly screened. Your primary doctor could keep a record of your number and check that every time you come back. Then, if there is some indication of cancer or colitis, they can do biopsies, colonoscopies, etc.”

Photo from Georgia State University

Preclinical research suggests infrared spectroscopy could be used to diagnose non-Hodgkin lymphoma (NHL).

Researchers used mid-infrared spectroscopy to analyze blood serum derived from mice and differentiate mice with NHL and subcutaneous melanoma from each other and from healthy control mice.

The findings suggest infrared spectroscopy can detect biochemical changes induced by NHL and melanoma and therefore has diagnostic potential as a screening technique for these cancers.

A.G. Unil Perera, PhD, of Georgia State University in Atlanta, and his colleagues detailed these findings in Scientific Reports.

The researchers said that Fourier Transform Infrared (FTIR) spectroscopy in Attenuated Total Reflection (ATR) sampling mode provides high-quality results with better reproducibility compared to other vibrational spectroscopy.

With previous work, Dr Perera and his colleagues discovered that a blood test for ulcerative colitis using ATR-FTIR spectroscopy could provide a cheaper, less invasive alternative for screening compared to colonoscopy.

In the current study, the researchers tested ATR-FTIR spectroscopy in mouse models of malignancy—EL4 NHL and B16 subcutaneous melanoma.

The team extracted blood serum from these mice and control mice. Droplets of serum were placed on an ATR crystal of the FTIR instrument.

Incident infrared beams were absorbed and reflected by the serum, creating a wave that was recorded and used to produce an absorbance curve with peaks that identified the presence of certain biomarkers in the sample.

The researchers compared the absorbance curves from the control and cancer mice and assessed biochemical changes induced by NHL and melanoma.

The team found “remarkable” differences between the ATR-FTIR spectra of serum samples from tumor-bearing mice and control mice.

Dr Perera said these findings are applicable to humans because mice and humans have some biomarkers and chemicals in common.

Using the data collected on the biomarkers for NHL and melanoma, the researchers could develop detectors for these particular absorbance peaks, which doctors could use to test patients’ blood samples for these cancers.

“Our final goal is to say we can use this infrared technique to identify various diseases,” Dr Perera said. “This study shows infrared spectroscopy can identify cancer. Right now, when you go to the doctor, they do blood tests for sugar and several other things but not for serious diseases like cancer and colitis.”

“One day, we hope that even these serious diseases can be rapidly screened. Your primary doctor could keep a record of your number and check that every time you come back. Then, if there is some indication of cancer or colitis, they can do biopsies, colonoscopies, etc.”

ATLANTA – Ibrutinib yielded a median progression-free survival (PFS) of nearly 3 years for patients with relapsed or refractory mantle cell lymphoma (MCL) treated with the agent after just one prior line of therapy, according to pooled long-term follow-up data presented at the annual meeting of the American Society of Hematology.

With a 3.5-year median follow-up, a median PFS of 33.6 months was reported for MCL patients with one prior line of therapy, compared to 8.4 months for patients who had two or more prior lines of therapy, reported lead study author Simon Rule, MD, of Plymouth (England) University Medical School.

“I think the take-home message from the ibrutinib data is the earlier you use the drug in the relapse setting, the better the outcomes you’re going to get,” Dr. Rule said in an interview. “It is quite dramatic, the difference between one prior line of therapy and subsequent lines of therapy.”

Response rates were also higher in MCL patients who had only one prior line of therapy, Dr. Rule said.

The overall and complete response rates for that group were 77.8% and 36.4%, respectively, according to data Dr. Rule presented in an oral presentation. For patients receiving more than one line of therapy prior to ibrutinib, overall and complete response rates were 66.8% and 22.9%.

The pooled analysis presented by Dr. Rule included 370 patients enrolled in ibrutinib trials between 2011 and 2013. Patients in those trials received oral ibrutinib 560 mg daily until progressive disease or unacceptable toxicity.

Patients achieving a CR had an “extraordinary” PFS of nearly 4 years and a median duration of response of 55 months, Dr. Rule said.

Atrial fibrillation (AF) rates were reported to be 5.7% (21/370 patients). A total of 53 patients in the analysis had ongoing controlled AF/arrhythmia or had a history of it. Over the course of follow-up, 70% of them (37 patients) had no recurrences, according to Dr. Rule and his colleagues.

No patients discontinued ibrutinib because of grade 3-4 AF, they reported. Moreover, less than 2% of the 370 patients discontinued or reduced dose of ibrutinib because of grade 3-4 bleeding or AF.

New onset grade 3-4 adverse events were more common in the first year of treatment and generally were less frequent over time, Dr. Rule said.

Patients with only one prior line of therapy were less likely to have grade 3-4 adverse events, suggesting again that “the earlier you use [ibrutinib], the fewer side effects you get, particularly with hematologic toxicity,” Dr. Rule said.

Sponsorship for the research came from Janssen, and funding for writing assistance came from Janssen Global Services. Dr. Rule reported financial relationships with Janssen and several other companies.

SOURCE: Rule S et al. ASH 2017 Abstract 151.

ATLANTA – Ibrutinib yielded a median progression-free survival (PFS) of nearly 3 years for patients with relapsed or refractory mantle cell lymphoma (MCL) treated with the agent after just one prior line of therapy, according to pooled long-term follow-up data presented at the annual meeting of the American Society of Hematology.

With a 3.5-year median follow-up, a median PFS of 33.6 months was reported for MCL patients with one prior line of therapy, compared to 8.4 months for patients who had two or more prior lines of therapy, reported lead study author Simon Rule, MD, of Plymouth (England) University Medical School.

“I think the take-home message from the ibrutinib data is the earlier you use the drug in the relapse setting, the better the outcomes you’re going to get,” Dr. Rule said in an interview. “It is quite dramatic, the difference between one prior line of therapy and subsequent lines of therapy.”

Response rates were also higher in MCL patients who had only one prior line of therapy, Dr. Rule said.

The overall and complete response rates for that group were 77.8% and 36.4%, respectively, according to data Dr. Rule presented in an oral presentation. For patients receiving more than one line of therapy prior to ibrutinib, overall and complete response rates were 66.8% and 22.9%.

The pooled analysis presented by Dr. Rule included 370 patients enrolled in ibrutinib trials between 2011 and 2013. Patients in those trials received oral ibrutinib 560 mg daily until progressive disease or unacceptable toxicity.

Patients achieving a CR had an “extraordinary” PFS of nearly 4 years and a median duration of response of 55 months, Dr. Rule said.

Atrial fibrillation (AF) rates were reported to be 5.7% (21/370 patients). A total of 53 patients in the analysis had ongoing controlled AF/arrhythmia or had a history of it. Over the course of follow-up, 70% of them (37 patients) had no recurrences, according to Dr. Rule and his colleagues.

No patients discontinued ibrutinib because of grade 3-4 AF, they reported. Moreover, less than 2% of the 370 patients discontinued or reduced dose of ibrutinib because of grade 3-4 bleeding or AF.

New onset grade 3-4 adverse events were more common in the first year of treatment and generally were less frequent over time, Dr. Rule said.

Patients with only one prior line of therapy were less likely to have grade 3-4 adverse events, suggesting again that “the earlier you use [ibrutinib], the fewer side effects you get, particularly with hematologic toxicity,” Dr. Rule said.

Sponsorship for the research came from Janssen, and funding for writing assistance came from Janssen Global Services. Dr. Rule reported financial relationships with Janssen and several other companies.

SOURCE: Rule S et al. ASH 2017 Abstract 151.

ATLANTA – Ibrutinib yielded a median progression-free survival (PFS) of nearly 3 years for patients with relapsed or refractory mantle cell lymphoma (MCL) treated with the agent after just one prior line of therapy, according to pooled long-term follow-up data presented at the annual meeting of the American Society of Hematology.

With a 3.5-year median follow-up, a median PFS of 33.6 months was reported for MCL patients with one prior line of therapy, compared to 8.4 months for patients who had two or more prior lines of therapy, reported lead study author Simon Rule, MD, of Plymouth (England) University Medical School.

“I think the take-home message from the ibrutinib data is the earlier you use the drug in the relapse setting, the better the outcomes you’re going to get,” Dr. Rule said in an interview. “It is quite dramatic, the difference between one prior line of therapy and subsequent lines of therapy.”

Response rates were also higher in MCL patients who had only one prior line of therapy, Dr. Rule said.

The overall and complete response rates for that group were 77.8% and 36.4%, respectively, according to data Dr. Rule presented in an oral presentation. For patients receiving more than one line of therapy prior to ibrutinib, overall and complete response rates were 66.8% and 22.9%.

The pooled analysis presented by Dr. Rule included 370 patients enrolled in ibrutinib trials between 2011 and 2013. Patients in those trials received oral ibrutinib 560 mg daily until progressive disease or unacceptable toxicity.

Patients achieving a CR had an “extraordinary” PFS of nearly 4 years and a median duration of response of 55 months, Dr. Rule said.

Atrial fibrillation (AF) rates were reported to be 5.7% (21/370 patients). A total of 53 patients in the analysis had ongoing controlled AF/arrhythmia or had a history of it. Over the course of follow-up, 70% of them (37 patients) had no recurrences, according to Dr. Rule and his colleagues.

No patients discontinued ibrutinib because of grade 3-4 AF, they reported. Moreover, less than 2% of the 370 patients discontinued or reduced dose of ibrutinib because of grade 3-4 bleeding or AF.

New onset grade 3-4 adverse events were more common in the first year of treatment and generally were less frequent over time, Dr. Rule said.

Patients with only one prior line of therapy were less likely to have grade 3-4 adverse events, suggesting again that “the earlier you use [ibrutinib], the fewer side effects you get, particularly with hematologic toxicity,” Dr. Rule said.

Sponsorship for the research came from Janssen, and funding for writing assistance came from Janssen Global Services. Dr. Rule reported financial relationships with Janssen and several other companies.

SOURCE: Rule S et al. ASH 2017 Abstract 151.