Aggressive Lymphomas

Bortezomib added to an alternating chemoimmunotherapy regimen did not improve time to treatment failure in patients with newly diagnosed mantle cell lymphoma (MCL), results of a phase 2 study have suggested.

Response rates and time to treatment failure were similar to what has been seen historically without the addition of bortezomib, according to study investigator Jorge E. Romaguera, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The phase 2 study included 95 patients with newly diagnosed MCL treated with alternating cycles of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD) and bortezomib added to rituximab plus high-dose methotrexate and high-dose cytarabine (BzR-MA).

Of 87 patients evaluable for response, alternating BzR-hyperCVAD/BzR-MA resulted in an overall response rate of 100% and a complete response rate of 82%, Dr. Romaguera and his colleagues reported in the journal Cancer. At a median follow-up of 44 months, median time to treatment failure was 55 months, and median overall survival had not yet been reached, according to the report.

Dr. Romaguera and his coauthors compared these results with those from a previous study of alternating R-hyperCVAD/R-MA, in which the median time to treatment failure was 56.4 months. “This suggests that the addition of bortezomib does not improve the outcome,” they wrote in the current report.

Although more follow-up is needed, the landscape of MCL treatment is changing quickly, they added. In particular, lenalidomide and ibrutinib, already approved for relapsed/refractory MCL, are now being evaluated as part of first-line MCL regimens. “These drugs will offer strategies of either consolidation or maintenance after induction and will hopefully help continue to improve the duration of the initial response and the overall outcome,” the researchers wrote.

In the current phase 2 study, the fact that 100% of patients achieved complete response suggested that relapses come from minimal residual disease, which “has clearly become a clinical factor for the outcomes of patients with MCL and will likely become the next endpoint,” they wrote.

The researchers reported having no financial disclosures related to the study, which was supported by Takeda Oncology.

SOURCE: Romaguera JE et al. Cancer. 2018 May 3. doi: 10.1002/cncr.31361.

Bortezomib added to an alternating chemoimmunotherapy regimen did not improve time to treatment failure in patients with newly diagnosed mantle cell lymphoma (MCL), results of a phase 2 study have suggested.

Response rates and time to treatment failure were similar to what has been seen historically without the addition of bortezomib, according to study investigator Jorge E. Romaguera, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The phase 2 study included 95 patients with newly diagnosed MCL treated with alternating cycles of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD) and bortezomib added to rituximab plus high-dose methotrexate and high-dose cytarabine (BzR-MA).

Of 87 patients evaluable for response, alternating BzR-hyperCVAD/BzR-MA resulted in an overall response rate of 100% and a complete response rate of 82%, Dr. Romaguera and his colleagues reported in the journal Cancer. At a median follow-up of 44 months, median time to treatment failure was 55 months, and median overall survival had not yet been reached, according to the report.

Dr. Romaguera and his coauthors compared these results with those from a previous study of alternating R-hyperCVAD/R-MA, in which the median time to treatment failure was 56.4 months. “This suggests that the addition of bortezomib does not improve the outcome,” they wrote in the current report.

Although more follow-up is needed, the landscape of MCL treatment is changing quickly, they added. In particular, lenalidomide and ibrutinib, already approved for relapsed/refractory MCL, are now being evaluated as part of first-line MCL regimens. “These drugs will offer strategies of either consolidation or maintenance after induction and will hopefully help continue to improve the duration of the initial response and the overall outcome,” the researchers wrote.

In the current phase 2 study, the fact that 100% of patients achieved complete response suggested that relapses come from minimal residual disease, which “has clearly become a clinical factor for the outcomes of patients with MCL and will likely become the next endpoint,” they wrote.

The researchers reported having no financial disclosures related to the study, which was supported by Takeda Oncology.

SOURCE: Romaguera JE et al. Cancer. 2018 May 3. doi: 10.1002/cncr.31361.

Bortezomib added to an alternating chemoimmunotherapy regimen did not improve time to treatment failure in patients with newly diagnosed mantle cell lymphoma (MCL), results of a phase 2 study have suggested.

Response rates and time to treatment failure were similar to what has been seen historically without the addition of bortezomib, according to study investigator Jorge E. Romaguera, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The phase 2 study included 95 patients with newly diagnosed MCL treated with alternating cycles of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD) and bortezomib added to rituximab plus high-dose methotrexate and high-dose cytarabine (BzR-MA).

Of 87 patients evaluable for response, alternating BzR-hyperCVAD/BzR-MA resulted in an overall response rate of 100% and a complete response rate of 82%, Dr. Romaguera and his colleagues reported in the journal Cancer. At a median follow-up of 44 months, median time to treatment failure was 55 months, and median overall survival had not yet been reached, according to the report.

Dr. Romaguera and his coauthors compared these results with those from a previous study of alternating R-hyperCVAD/R-MA, in which the median time to treatment failure was 56.4 months. “This suggests that the addition of bortezomib does not improve the outcome,” they wrote in the current report.

Although more follow-up is needed, the landscape of MCL treatment is changing quickly, they added. In particular, lenalidomide and ibrutinib, already approved for relapsed/refractory MCL, are now being evaluated as part of first-line MCL regimens. “These drugs will offer strategies of either consolidation or maintenance after induction and will hopefully help continue to improve the duration of the initial response and the overall outcome,” the researchers wrote.

In the current phase 2 study, the fact that 100% of patients achieved complete response suggested that relapses come from minimal residual disease, which “has clearly become a clinical factor for the outcomes of patients with MCL and will likely become the next endpoint,” they wrote.

The researchers reported having no financial disclosures related to the study, which was supported by Takeda Oncology.

SOURCE: Romaguera JE et al. Cancer. 2018 May 3. doi: 10.1002/cncr.31361.

Micrograph showing CLL

Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.

Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).

Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).

These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.

The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.

There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.

The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.

Treatment

Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.

Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.

In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.

In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.

At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.

Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).

“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”

Safety

Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.

Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.

Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.

The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).

Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).

Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.

There were no treatment-related deaths.

The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.

“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.

“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”

Response

The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).

Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.

The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.

One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.

The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.

Micrograph showing CLL

Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.

Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).

Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).

These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.

The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.

There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.

The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.

Treatment

Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.

Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.

In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.

In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.

At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.

Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).

“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”

Safety

Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.

Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.

Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.

The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).

Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).

Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.

There were no treatment-related deaths.

The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.

“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.

“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”

Response

The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).

Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.

The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.

One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.

The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.

Micrograph showing CLL

Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.

Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).

Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).

These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.

The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.

There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.

The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.

Treatment

Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.

Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.

In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.

In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.

At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.

Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).

“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”

Safety

Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.

Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.

Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.

The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).

Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).

Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.

There were no treatment-related deaths.

The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.

“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.

“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”

Response

The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).

Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.

The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.

One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.

The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.

There appears to be no causal link between acute Q fever and the development of non-Hodgkin lymphoma, according to findings from a retrospective analysis of 12 years of Dutch data.

Sonja E. van Roeden, MD, and colleagues from Utrecht University, the Netherlands, performed a retrospective, population-based analysis of the entire general population of the Netherlands from 2002 to 2013, encompassing the 3-year period of a large Q fever epidemic in the country.

National Institutes of Health (NIH)/Wikimedia Commons

[email protected]

SOURCE: van Roeden SE et al. Lancet Haematol. 2018 May;5:e211-9.

There appears to be no causal link between acute Q fever and the development of non-Hodgkin lymphoma, according to findings from a retrospective analysis of 12 years of Dutch data.

Sonja E. van Roeden, MD, and colleagues from Utrecht University, the Netherlands, performed a retrospective, population-based analysis of the entire general population of the Netherlands from 2002 to 2013, encompassing the 3-year period of a large Q fever epidemic in the country.

National Institutes of Health (NIH)/Wikimedia Commons

[email protected]

SOURCE: van Roeden SE et al. Lancet Haematol. 2018 May;5:e211-9.

There appears to be no causal link between acute Q fever and the development of non-Hodgkin lymphoma, according to findings from a retrospective analysis of 12 years of Dutch data.

Sonja E. van Roeden, MD, and colleagues from Utrecht University, the Netherlands, performed a retrospective, population-based analysis of the entire general population of the Netherlands from 2002 to 2013, encompassing the 3-year period of a large Q fever epidemic in the country.

National Institutes of Health (NIH)/Wikimedia Commons

[email protected]

SOURCE: van Roeden SE et al. Lancet Haematol. 2018 May;5:e211-9.

Micrograph showing Hodgkin lymphoma

Nivolumab can provide “long-term benefits” in patients with relapsed or refractory classical Hodgkin lymphoma (cHL), according to researchers.

Extended follow-up of the CheckMate-205 study showed that nearly 70% of patients responded to nivolumab.

The median duration of response was 17 months, and the median progression-free survival (PFS) was 15 months.

The most common drug-related AEs were fatigue, diarrhea, infusion-related reactions, rash, nausea, and pruritus.

Philippe Armand, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in the Journal of Clinical Oncology.

The study was sponsored by Bristol-Myers Squibb Company.

Patients

This phase 2 trial enrolled 243 adults with relapsed or refractory cHL who had undergone autologous hematopoietic stem cell transplant (auto-HSCT).

Their median age was 34 (range, 26-46), and 58% were male. Fifty-seven percent had stage IV disease, 20% had stage III, 21% had stage II, and 2% had stage I.

Patients had received a median of 4 prior therapies (range, 3-5). The median time from diagnosis to first nivolumab dose was 4.5 years (range, 2.4-7.6), and the median time from most recent auto-HSCT to first nivolumab dose was 2.0 years (range, 0.9-4.9).

The researchers divided patients into 3 cohorts according to exposure to brentuximab vedotin (BV):

• Cohort A was BV-naïve (n=63)
• Cohort B received BV only after auto-HSCT (n=80)
• Cohort C received BV before and/or after auto-HSCT (n=100).

Baseline characteristics were generally similar across the cohorts. However, cohort A had fewer prior treatments (median of 2 vs 4 in cohorts B and C).

Cohort B had the longest interval between diagnosis and first nivolumab dose (6.2 years vs 3.1 in cohort A and 3.5 in C) and between most recent auto-HSCT and first nivolumab dose (3.4 years vs 1 in cohort A and 1.7 in C).

Treatment

All patients received nivolumab at 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

In cohort C, patients who were in complete response (CR) for 1 year had to discontinue nivolumab, but they could resume treatment if they relapsed within 2 years.

A protocol amendment allowed patients to continue treatment despite progression if they had stable performance status and were deriving “perceived clinical benefit.”

At a median follow-up of 18 months, 40% percent of all patients were still on treatment, including 48% of patients in cohort A, 40% in cohort B, and 35% in cohort C.

Safety

The most common drug-related AEs were fatigue (23%), diarrhea (15%), infusion-related reactions (14%), rash (12%), nausea (10%), and pruritus (10%).

The most common grade 3/4 drug-related AEs were lipase increase (5%), neutropenia (3%), ALT increase (2%), AST increase (2%), and amylase increase (2%).

The most common serious drug-related AEs were infusion-related reactions (2%), pneumonitis (1%), pneumonia (1%), pleural effusion (1%), and pyrexia (1%).

Seven percent of patients discontinued treatment due to AEs. The most common of these were pneumonitis (2%) and autoimmune hepatitis (1%).

There were no deaths due to drug-related AEs.

Efficacy

The objective response rate was 69% overall, 65% in cohort A, 68% in cohort B, and 73% in cohort C.

CR was the best response for 16% of all patients, 29% of cohort A, 13% of cohort B, and 12% of cohort C.

The median duration of response was 17 months overall, 20 months for cohort A, 16 months for cohort B, 15 months for cohort C, and 20 months for patients who achieved a CR.

The researchers said responses were similar irrespective of BV treatment sequence.

The median PFS was 15 months for all patients, 18 months for cohort A, 15 months for cohort B, 12 months for cohort C, and 22 months for patients who achieved a CR.

The median overall survival was not reached in any of the cohorts.

The 12-month overall survival was 92% overall, 93% in cohort A, 95% in cohort B, 90% in cohort C, and 100% in patients who achieved a CR.

Subsequent HSCT

Forty-four patients proceeded to allogeneic HSCT after nivolumab, and the median post-HSCT follow-up was 5.5 months (range, 2.9-11.8).

At 6 months, the rate of transplant-related mortality was 13%, and the rate of disease progression was 7%.

The rate of grade 2-4 acute graft-vs-host disease (GVHD) was 30%, the rate of grade 3-4 acute GVHD was 20%, and the rate of chronic GVHD was 15%.

Micrograph showing Hodgkin lymphoma

Nivolumab can provide “long-term benefits” in patients with relapsed or refractory classical Hodgkin lymphoma (cHL), according to researchers.

Extended follow-up of the CheckMate-205 study showed that nearly 70% of patients responded to nivolumab.

The median duration of response was 17 months, and the median progression-free survival (PFS) was 15 months.

The most common drug-related AEs were fatigue, diarrhea, infusion-related reactions, rash, nausea, and pruritus.

Philippe Armand, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in the Journal of Clinical Oncology.

The study was sponsored by Bristol-Myers Squibb Company.

Patients

This phase 2 trial enrolled 243 adults with relapsed or refractory cHL who had undergone autologous hematopoietic stem cell transplant (auto-HSCT).

Their median age was 34 (range, 26-46), and 58% were male. Fifty-seven percent had stage IV disease, 20% had stage III, 21% had stage II, and 2% had stage I.

Patients had received a median of 4 prior therapies (range, 3-5). The median time from diagnosis to first nivolumab dose was 4.5 years (range, 2.4-7.6), and the median time from most recent auto-HSCT to first nivolumab dose was 2.0 years (range, 0.9-4.9).

The researchers divided patients into 3 cohorts according to exposure to brentuximab vedotin (BV):

• Cohort A was BV-naïve (n=63)
• Cohort B received BV only after auto-HSCT (n=80)
• Cohort C received BV before and/or after auto-HSCT (n=100).

Baseline characteristics were generally similar across the cohorts. However, cohort A had fewer prior treatments (median of 2 vs 4 in cohorts B and C).

Cohort B had the longest interval between diagnosis and first nivolumab dose (6.2 years vs 3.1 in cohort A and 3.5 in C) and between most recent auto-HSCT and first nivolumab dose (3.4 years vs 1 in cohort A and 1.7 in C).

Treatment

All patients received nivolumab at 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

In cohort C, patients who were in complete response (CR) for 1 year had to discontinue nivolumab, but they could resume treatment if they relapsed within 2 years.

A protocol amendment allowed patients to continue treatment despite progression if they had stable performance status and were deriving “perceived clinical benefit.”

At a median follow-up of 18 months, 40% percent of all patients were still on treatment, including 48% of patients in cohort A, 40% in cohort B, and 35% in cohort C.

Safety

The most common drug-related AEs were fatigue (23%), diarrhea (15%), infusion-related reactions (14%), rash (12%), nausea (10%), and pruritus (10%).

The most common grade 3/4 drug-related AEs were lipase increase (5%), neutropenia (3%), ALT increase (2%), AST increase (2%), and amylase increase (2%).

The most common serious drug-related AEs were infusion-related reactions (2%), pneumonitis (1%), pneumonia (1%), pleural effusion (1%), and pyrexia (1%).

Seven percent of patients discontinued treatment due to AEs. The most common of these were pneumonitis (2%) and autoimmune hepatitis (1%).

There were no deaths due to drug-related AEs.

Efficacy

The objective response rate was 69% overall, 65% in cohort A, 68% in cohort B, and 73% in cohort C.

CR was the best response for 16% of all patients, 29% of cohort A, 13% of cohort B, and 12% of cohort C.

The median duration of response was 17 months overall, 20 months for cohort A, 16 months for cohort B, 15 months for cohort C, and 20 months for patients who achieved a CR.

The researchers said responses were similar irrespective of BV treatment sequence.

The median PFS was 15 months for all patients, 18 months for cohort A, 15 months for cohort B, 12 months for cohort C, and 22 months for patients who achieved a CR.

The median overall survival was not reached in any of the cohorts.

The 12-month overall survival was 92% overall, 93% in cohort A, 95% in cohort B, 90% in cohort C, and 100% in patients who achieved a CR.

Subsequent HSCT

Forty-four patients proceeded to allogeneic HSCT after nivolumab, and the median post-HSCT follow-up was 5.5 months (range, 2.9-11.8).

At 6 months, the rate of transplant-related mortality was 13%, and the rate of disease progression was 7%.

The rate of grade 2-4 acute graft-vs-host disease (GVHD) was 30%, the rate of grade 3-4 acute GVHD was 20%, and the rate of chronic GVHD was 15%.

Micrograph showing Hodgkin lymphoma

Nivolumab can provide “long-term benefits” in patients with relapsed or refractory classical Hodgkin lymphoma (cHL), according to researchers.

Extended follow-up of the CheckMate-205 study showed that nearly 70% of patients responded to nivolumab.

The median duration of response was 17 months, and the median progression-free survival (PFS) was 15 months.

The most common drug-related AEs were fatigue, diarrhea, infusion-related reactions, rash, nausea, and pruritus.

Philippe Armand, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in the Journal of Clinical Oncology.

The study was sponsored by Bristol-Myers Squibb Company.

Patients

This phase 2 trial enrolled 243 adults with relapsed or refractory cHL who had undergone autologous hematopoietic stem cell transplant (auto-HSCT).

Their median age was 34 (range, 26-46), and 58% were male. Fifty-seven percent had stage IV disease, 20% had stage III, 21% had stage II, and 2% had stage I.

Patients had received a median of 4 prior therapies (range, 3-5). The median time from diagnosis to first nivolumab dose was 4.5 years (range, 2.4-7.6), and the median time from most recent auto-HSCT to first nivolumab dose was 2.0 years (range, 0.9-4.9).

The researchers divided patients into 3 cohorts according to exposure to brentuximab vedotin (BV):

• Cohort A was BV-naïve (n=63)
• Cohort B received BV only after auto-HSCT (n=80)
• Cohort C received BV before and/or after auto-HSCT (n=100).

Baseline characteristics were generally similar across the cohorts. However, cohort A had fewer prior treatments (median of 2 vs 4 in cohorts B and C).

Cohort B had the longest interval between diagnosis and first nivolumab dose (6.2 years vs 3.1 in cohort A and 3.5 in C) and between most recent auto-HSCT and first nivolumab dose (3.4 years vs 1 in cohort A and 1.7 in C).

Treatment

All patients received nivolumab at 3 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

In cohort C, patients who were in complete response (CR) for 1 year had to discontinue nivolumab, but they could resume treatment if they relapsed within 2 years.

A protocol amendment allowed patients to continue treatment despite progression if they had stable performance status and were deriving “perceived clinical benefit.”

At a median follow-up of 18 months, 40% percent of all patients were still on treatment, including 48% of patients in cohort A, 40% in cohort B, and 35% in cohort C.

Safety

The most common drug-related AEs were fatigue (23%), diarrhea (15%), infusion-related reactions (14%), rash (12%), nausea (10%), and pruritus (10%).

The most common grade 3/4 drug-related AEs were lipase increase (5%), neutropenia (3%), ALT increase (2%), AST increase (2%), and amylase increase (2%).

The most common serious drug-related AEs were infusion-related reactions (2%), pneumonitis (1%), pneumonia (1%), pleural effusion (1%), and pyrexia (1%).

Seven percent of patients discontinued treatment due to AEs. The most common of these were pneumonitis (2%) and autoimmune hepatitis (1%).

There were no deaths due to drug-related AEs.

Efficacy

The objective response rate was 69% overall, 65% in cohort A, 68% in cohort B, and 73% in cohort C.

CR was the best response for 16% of all patients, 29% of cohort A, 13% of cohort B, and 12% of cohort C.

The median duration of response was 17 months overall, 20 months for cohort A, 16 months for cohort B, 15 months for cohort C, and 20 months for patients who achieved a CR.

The researchers said responses were similar irrespective of BV treatment sequence.

The median PFS was 15 months for all patients, 18 months for cohort A, 15 months for cohort B, 12 months for cohort C, and 22 months for patients who achieved a CR.

The median overall survival was not reached in any of the cohorts.

The 12-month overall survival was 92% overall, 93% in cohort A, 95% in cohort B, 90% in cohort C, and 100% in patients who achieved a CR.

Subsequent HSCT

Forty-four patients proceeded to allogeneic HSCT after nivolumab, and the median post-HSCT follow-up was 5.5 months (range, 2.9-11.8).

At 6 months, the rate of transplant-related mortality was 13%, and the rate of disease progression was 7%.

The rate of grade 2-4 acute graft-vs-host disease (GVHD) was 30%, the rate of grade 3-4 acute GVHD was 20%, and the rate of chronic GVHD was 15%.

Follicular lymphoma

The US Food and Drug Administration (FDA) has granted 2 fast track designations to 5F9, an anti-CD47 antibody.

The designations are for 5F9 as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).

Data supporting the fast track designations were derived from a phase 1b/2 trial of 5F9 in combination with rituximab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including DLBCL and FL.

Forty Seven, Inc., the company developing 5F9, expects to announce initial safety and efficacy data from the phase 1b portion of the trial in the second quarter of 2018.

About fast track designation

The FDA’s fast track drug development program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers.

Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met.

Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

Follicular lymphoma

The US Food and Drug Administration (FDA) has granted 2 fast track designations to 5F9, an anti-CD47 antibody.

The designations are for 5F9 as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).

Data supporting the fast track designations were derived from a phase 1b/2 trial of 5F9 in combination with rituximab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including DLBCL and FL.

Forty Seven, Inc., the company developing 5F9, expects to announce initial safety and efficacy data from the phase 1b portion of the trial in the second quarter of 2018.

About fast track designation

The FDA’s fast track drug development program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers.

Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met.

Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

Follicular lymphoma

The US Food and Drug Administration (FDA) has granted 2 fast track designations to 5F9, an anti-CD47 antibody.

The designations are for 5F9 as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).

Data supporting the fast track designations were derived from a phase 1b/2 trial of 5F9 in combination with rituximab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including DLBCL and FL.

Forty Seven, Inc., the company developing 5F9, expects to announce initial safety and efficacy data from the phase 1b portion of the trial in the second quarter of 2018.

About fast track designation

The FDA’s fast track drug development program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers.

Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met.

Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

Novartis’s tisagenlecleucel (Kymriah) is now approved for adults with relapsed or refractory large B-cell lymphoma after failure of two or more lines of systemic therapy.

The Food and Drug Administration approved the expanded indication on May 1. The chimeric antigen receptor (CAR) T-cell therapy was initially approved in Aug. 2017 for refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years old. The new approval brings tisagenlecleucel into direct competition with Gilead Science’s CAR T-cell therapy axicabtagene ciloleucel (Yescarta), which was approved in Oct. 2017 for B-cell lymphoma.

Courtesy Novartis

[email protected]

Novartis’s tisagenlecleucel (Kymriah) is now approved for adults with relapsed or refractory large B-cell lymphoma after failure of two or more lines of systemic therapy.

The Food and Drug Administration approved the expanded indication on May 1. The chimeric antigen receptor (CAR) T-cell therapy was initially approved in Aug. 2017 for refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years old. The new approval brings tisagenlecleucel into direct competition with Gilead Science’s CAR T-cell therapy axicabtagene ciloleucel (Yescarta), which was approved in Oct. 2017 for B-cell lymphoma.

Courtesy Novartis

[email protected]

Novartis’s tisagenlecleucel (Kymriah) is now approved for adults with relapsed or refractory large B-cell lymphoma after failure of two or more lines of systemic therapy.

The Food and Drug Administration approved the expanded indication on May 1. The chimeric antigen receptor (CAR) T-cell therapy was initially approved in Aug. 2017 for refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years old. The new approval brings tisagenlecleucel into direct competition with Gilead Science’s CAR T-cell therapy axicabtagene ciloleucel (Yescarta), which was approved in Oct. 2017 for B-cell lymphoma.

Courtesy Novartis

[email protected]

follicular lymphoma

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.

Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.

The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.

As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”

The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.

Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.

This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.

Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.

The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.

follicular lymphoma

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.

Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.

The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.

As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”

The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.

Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.

This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.

Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.

The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.

follicular lymphoma

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.

Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.

The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.

As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”

The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.

Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.

This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.

At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.

Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.

The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.

The overall 5-year survival rate for non-Hodgkin lymphoma (NHL) is 71.4%, according to the National Cancer Institute.

That number falls neatly into the middle of the range for survival by stage at diagnosis, with stage I (81.8%) and stage II (75.3%) disease on the high side and stage III (69.1%) and stage IV (61.7%) on the low side, the most recent data from the Surveillance, Epidemiology, and End Results (SEER) Program show. Five-year survival for NHL of unknown stage at diagnosis is 76.4%.

[email protected]

The overall 5-year survival rate for non-Hodgkin lymphoma (NHL) is 71.4%, according to the National Cancer Institute.

That number falls neatly into the middle of the range for survival by stage at diagnosis, with stage I (81.8%) and stage II (75.3%) disease on the high side and stage III (69.1%) and stage IV (61.7%) on the low side, the most recent data from the Surveillance, Epidemiology, and End Results (SEER) Program show. Five-year survival for NHL of unknown stage at diagnosis is 76.4%.

[email protected]

The overall 5-year survival rate for non-Hodgkin lymphoma (NHL) is 71.4%, according to the National Cancer Institute.

That number falls neatly into the middle of the range for survival by stage at diagnosis, with stage I (81.8%) and stage II (75.3%) disease on the high side and stage III (69.1%) and stage IV (61.7%) on the low side, the most recent data from the Surveillance, Epidemiology, and End Results (SEER) Program show. Five-year survival for NHL of unknown stage at diagnosis is 76.4%.

[email protected]

Photo from Novartis

The US Food and Drug Administration (FDA) has approved tisagenlecleucel (Kymriah®) for its second indication.

The chimeric antigen receptor (CAR) T-cell therapy is now approved to treat adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy.

This includes patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

The application for tisagenlecleucel in B-cell lymphoma was granted priority review. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

Tisagenlecleucel is also FDA-approved to treat patients age 25 and younger who have B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Access to tisagenlecleucel

The prescribing information for tisagenlecleucel includes a boxed warning detailing the risk of cytokine release syndrome (CRS) and neurological toxicities for patients receiving tisagenlecleucel.

Because of these risks, tisagenlecleucel is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program serves to inform and educate healthcare professionals about the risks associated with tisagenlecleucel treatment.

Novartis, the company marketing tisagenlecleucel, has established a network of certified treatment centers throughout the US. Staff at these centers are trained on the use of tisagenlecleucel and appropriate patient care.

Tisagenlecleucel is manufactured at a Novartis facility in Morris Plains, New Jersey. In the US, the target turnaround time for manufacturing tisagenlecleucel is 22 days.

Tisagenlecleucel costs $475,000 for a single course of treatment. However, Novartis said it is collaborating with the US Centers for Medicare and Medicaid Services on the creation of an appropriate value-based pricing approach.

The company also has a program called KYMRIAH CARES™, which offers financial assistance to eligible patients to help them gain access to tisagenlecleucel.

Phase 2 trial

The FDA approval of tisagenlecleucel for adults with relapsed/refractory B-cell lymphoma is based on results of the phase 2 JULIET trial.

The prescribing information for tisagenlecleucel includes data on 106 patients treated on this trial.

Only 68 of these patients were evaluable for efficacy. They had a median age of 56 (range, 22 to 74), and 71% were male.

Seventy-eight percent of patients had primary DLBCL not otherwise specified, and 22% had DLBCL following transformation from follicular lymphoma. Seventeen percent had high grade DLBCL.

Fifty-six percent of patients had refractory disease, and 44% had relapsed after their last therapy. The median number of prior therapies was 3 (range, 1 to 6), and 44% of patients had undergone autologous transplant.

Ninety percent of patients received lymphodepleting chemotherapy (66% fludarabine and 24% bendamustine) prior to tisagenlecleucel, and 10% did not. The median dose of tisagenlecleucel was 3.5 × 10⁸ CAR+ T cells (range, 1.0 to 5.2 × 10⁸).

The overall response rate was 50%, with 32% of patients achieving a complete response and 18% achieving a partial response. The median duration of response was not reached with a median follow-up of 9.4 months.

In all 106 patients infused with tisagenlecleucel, the most common grade 3/4 adverse events were infections (25%), CRS (23%), neurologic events (18%), febrile neutropenia (17%), encephalopathy (11%), lymphopenia (94%), neutropenia (81%), leukopenia (77%), anemia (58%), thrombocytopenia (54%), hypophosphatemia (24%), hypokalemia (12%), and hyponatremia (11%).

Three patients died within 30 days of tisagenlecleucel infusion. All of them had CRS and either stable or progressive disease. One of these patients developed bowel necrosis.

One patient died of infection. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema.

Photo from Novartis

The US Food and Drug Administration (FDA) has approved tisagenlecleucel (Kymriah®) for its second indication.

The chimeric antigen receptor (CAR) T-cell therapy is now approved to treat adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy.

This includes patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

The application for tisagenlecleucel in B-cell lymphoma was granted priority review. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

Tisagenlecleucel is also FDA-approved to treat patients age 25 and younger who have B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Access to tisagenlecleucel

The prescribing information for tisagenlecleucel includes a boxed warning detailing the risk of cytokine release syndrome (CRS) and neurological toxicities for patients receiving tisagenlecleucel.

Because of these risks, tisagenlecleucel is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program serves to inform and educate healthcare professionals about the risks associated with tisagenlecleucel treatment.

Novartis, the company marketing tisagenlecleucel, has established a network of certified treatment centers throughout the US. Staff at these centers are trained on the use of tisagenlecleucel and appropriate patient care.

Tisagenlecleucel is manufactured at a Novartis facility in Morris Plains, New Jersey. In the US, the target turnaround time for manufacturing tisagenlecleucel is 22 days.

Tisagenlecleucel costs $475,000 for a single course of treatment. However, Novartis said it is collaborating with the US Centers for Medicare and Medicaid Services on the creation of an appropriate value-based pricing approach.

The company also has a program called KYMRIAH CARES™, which offers financial assistance to eligible patients to help them gain access to tisagenlecleucel.

Phase 2 trial

The FDA approval of tisagenlecleucel for adults with relapsed/refractory B-cell lymphoma is based on results of the phase 2 JULIET trial.

The prescribing information for tisagenlecleucel includes data on 106 patients treated on this trial.

Only 68 of these patients were evaluable for efficacy. They had a median age of 56 (range, 22 to 74), and 71% were male.

Seventy-eight percent of patients had primary DLBCL not otherwise specified, and 22% had DLBCL following transformation from follicular lymphoma. Seventeen percent had high grade DLBCL.

Fifty-six percent of patients had refractory disease, and 44% had relapsed after their last therapy. The median number of prior therapies was 3 (range, 1 to 6), and 44% of patients had undergone autologous transplant.

Ninety percent of patients received lymphodepleting chemotherapy (66% fludarabine and 24% bendamustine) prior to tisagenlecleucel, and 10% did not. The median dose of tisagenlecleucel was 3.5 × 10⁸ CAR+ T cells (range, 1.0 to 5.2 × 10⁸).

The overall response rate was 50%, with 32% of patients achieving a complete response and 18% achieving a partial response. The median duration of response was not reached with a median follow-up of 9.4 months.

In all 106 patients infused with tisagenlecleucel, the most common grade 3/4 adverse events were infections (25%), CRS (23%), neurologic events (18%), febrile neutropenia (17%), encephalopathy (11%), lymphopenia (94%), neutropenia (81%), leukopenia (77%), anemia (58%), thrombocytopenia (54%), hypophosphatemia (24%), hypokalemia (12%), and hyponatremia (11%).

Three patients died within 30 days of tisagenlecleucel infusion. All of them had CRS and either stable or progressive disease. One of these patients developed bowel necrosis.

One patient died of infection. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema.

Photo from Novartis

The US Food and Drug Administration (FDA) has approved tisagenlecleucel (Kymriah®) for its second indication.

The chimeric antigen receptor (CAR) T-cell therapy is now approved to treat adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy.

This includes patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

The application for tisagenlecleucel in B-cell lymphoma was granted priority review. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

Tisagenlecleucel is also FDA-approved to treat patients age 25 and younger who have B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

Access to tisagenlecleucel

The prescribing information for tisagenlecleucel includes a boxed warning detailing the risk of cytokine release syndrome (CRS) and neurological toxicities for patients receiving tisagenlecleucel.

Because of these risks, tisagenlecleucel is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program serves to inform and educate healthcare professionals about the risks associated with tisagenlecleucel treatment.

Novartis, the company marketing tisagenlecleucel, has established a network of certified treatment centers throughout the US. Staff at these centers are trained on the use of tisagenlecleucel and appropriate patient care.

Tisagenlecleucel is manufactured at a Novartis facility in Morris Plains, New Jersey. In the US, the target turnaround time for manufacturing tisagenlecleucel is 22 days.

Tisagenlecleucel costs $475,000 for a single course of treatment. However, Novartis said it is collaborating with the US Centers for Medicare and Medicaid Services on the creation of an appropriate value-based pricing approach.

The company also has a program called KYMRIAH CARES™, which offers financial assistance to eligible patients to help them gain access to tisagenlecleucel.

Phase 2 trial

The FDA approval of tisagenlecleucel for adults with relapsed/refractory B-cell lymphoma is based on results of the phase 2 JULIET trial.

The prescribing information for tisagenlecleucel includes data on 106 patients treated on this trial.

Only 68 of these patients were evaluable for efficacy. They had a median age of 56 (range, 22 to 74), and 71% were male.

Seventy-eight percent of patients had primary DLBCL not otherwise specified, and 22% had DLBCL following transformation from follicular lymphoma. Seventeen percent had high grade DLBCL.

Fifty-six percent of patients had refractory disease, and 44% had relapsed after their last therapy. The median number of prior therapies was 3 (range, 1 to 6), and 44% of patients had undergone autologous transplant.

Ninety percent of patients received lymphodepleting chemotherapy (66% fludarabine and 24% bendamustine) prior to tisagenlecleucel, and 10% did not. The median dose of tisagenlecleucel was 3.5 × 10⁸ CAR+ T cells (range, 1.0 to 5.2 × 10⁸).

The overall response rate was 50%, with 32% of patients achieving a complete response and 18% achieving a partial response. The median duration of response was not reached with a median follow-up of 9.4 months.

In all 106 patients infused with tisagenlecleucel, the most common grade 3/4 adverse events were infections (25%), CRS (23%), neurologic events (18%), febrile neutropenia (17%), encephalopathy (11%), lymphopenia (94%), neutropenia (81%), leukopenia (77%), anemia (58%), thrombocytopenia (54%), hypophosphatemia (24%), hypokalemia (12%), and hyponatremia (11%).

Three patients died within 30 days of tisagenlecleucel infusion. All of them had CRS and either stable or progressive disease. One of these patients developed bowel necrosis.

One patient died of infection. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema.

Photo from Penn Medicine

Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.

The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.

The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.

The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.

Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.

For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.

Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.

Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.

The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.

Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.

“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”

Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.

To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.

“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.

“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”

These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.

“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.

“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”

The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.

Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.

Photo from Penn Medicine

Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.

The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.

The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.

The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.

Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.

For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.

Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.

Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.

The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.

Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.

“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”

Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.

To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.

“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.

“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”

These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.

“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.

“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”

The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.

Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.

Photo from Penn Medicine

Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.

The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.

The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.

The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.

Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.

For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.

Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.

Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.

The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.

Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.

“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”

Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.

To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.

“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.

“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”

These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.

“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.

“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”

The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.

Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.