B Cell Lymphoma

The Food and Drug Administration has approved acalabrutinib (Calquence) as initial or subsequent treatment for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).

Olivier Le Moal/Getty Images

The approval came as part of Project Orbis, a collaboration among the FDA, the Australian Therapeutic Goods Administration, and Health Canada. The program allows for the concurrent submission of review of oncology drug applications among the various agencies.

Acalabrutinib, a bruton tyrosin kinase inhibitor, is already approved in the United States for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy. The FDA granted breakthrough therapy designation to acalabrutinib as a monotherapy for adults with CLL in August 2019, allowing for an expedited review.

The approval in CLL/SLL was based on results from two randomized clinical trials comparing acalabrutinib with other standard treatments. In the first trial, patients with previously untreated CLL who received acalabrutinib had a longer progression-free survival time, compared with patients who received standard treatment. A similar result was seen in the second trial among patients with previously treated CLL.

The most common adverse events associated with acalabrutinib include anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. Patients receiving the drug should be monitored for symptoms of arrhythmia, serious infection, bleeding, and low blood count. Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved acalabrutinib (Calquence) as initial or subsequent treatment for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).

Olivier Le Moal/Getty Images

The approval came as part of Project Orbis, a collaboration among the FDA, the Australian Therapeutic Goods Administration, and Health Canada. The program allows for the concurrent submission of review of oncology drug applications among the various agencies.

Acalabrutinib, a bruton tyrosin kinase inhibitor, is already approved in the United States for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy. The FDA granted breakthrough therapy designation to acalabrutinib as a monotherapy for adults with CLL in August 2019, allowing for an expedited review.

The approval in CLL/SLL was based on results from two randomized clinical trials comparing acalabrutinib with other standard treatments. In the first trial, patients with previously untreated CLL who received acalabrutinib had a longer progression-free survival time, compared with patients who received standard treatment. A similar result was seen in the second trial among patients with previously treated CLL.

The most common adverse events associated with acalabrutinib include anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. Patients receiving the drug should be monitored for symptoms of arrhythmia, serious infection, bleeding, and low blood count. Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved acalabrutinib (Calquence) as initial or subsequent treatment for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).

Olivier Le Moal/Getty Images

The approval came as part of Project Orbis, a collaboration among the FDA, the Australian Therapeutic Goods Administration, and Health Canada. The program allows for the concurrent submission of review of oncology drug applications among the various agencies.

Acalabrutinib, a bruton tyrosin kinase inhibitor, is already approved in the United States for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy. The FDA granted breakthrough therapy designation to acalabrutinib as a monotherapy for adults with CLL in August 2019, allowing for an expedited review.

The approval in CLL/SLL was based on results from two randomized clinical trials comparing acalabrutinib with other standard treatments. In the first trial, patients with previously untreated CLL who received acalabrutinib had a longer progression-free survival time, compared with patients who received standard treatment. A similar result was seen in the second trial among patients with previously treated CLL.

The most common adverse events associated with acalabrutinib include anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain. Patients receiving the drug should be monitored for symptoms of arrhythmia, serious infection, bleeding, and low blood count. Full prescribing information can be found on the FDA website.

[email protected]

Ibrutinib monotherapy was associated with lower total health care costs compared with chemoimmunotherapy in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to a retrospective study.

©Mathier/thinkstockphotos.com

“This study compared time to next treatment, health care resource utilization, and total direct costs among patients with CLL initiating front-line ibrutinib single agent or chemoimmunotherapy,” wrote Bruno Emond, of Analysis Group, Montreal, and colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.

The researchers retrospectively analyzed data from 1,161 patients with CLL who were started on ibrutinib monotherapy or chemoimmunotherapy from 2014 to 2017. Data were collected from the Optum Clinformatics Extended DataMart De-Identified Databases.

Between the two groups, differences in baseline characteristics were controlled for by way of inverse probability of treatment weighting. Two treatment periods were included in the study: the initial 6 months of treatment and entire duration of frontline therapy.

The team also conducted a subgroup analysis of patients treated with bendamustine and rituximab. This cohort was analyzed independently since the regimen is commonly used in clinical practice.

After analysis, the researchers found that ibrutinib monotherapy was associated with net monthly cost savings of $3,766 (P less than .0001), compared with chemoimmunotherapy and bendamustine/rituximab over the frontline therapy period.

Ibrutinib patients had fewer monthly days with outpatient services (rate ratio, 0.75; 95% confidence interval, 0.60-0.94; P = .0200), compared with those on chemoimmunotherapy; and were less likely to initiate a next line of treatment, compared with chemoimmunotherapy patients (hazard ratio, 0.54; 95% CI, 0.33-0.90; P = .0163).

“Cost savings and reductions in health care resource utilization were even more pronounced when considering only the first 6 months of front-line treatment,” the researchers wrote.

The researchers acknowledged that two key limitations of the study were the potential influence of unobserved confounding factors and the use of claims data, which could include errors and omissions.

“These results suggest that ibrutinib single-agent is associated with lower total costs driven by lower medical costs, despite higher pharmacy costs, compared with chemoimmunotherapy and bendamustine/rituximab,” they concluded.

The authors reported financial affiliations with Janssen Scientific Affairs, which funded the study, and other companies.

SOURCE: Emond B et al. Clin Lymphoma Myeloma Leuk. 2019 Aug 26. doi: 10.1016/j.clml.2019.08.004.

Ibrutinib monotherapy was associated with lower total health care costs compared with chemoimmunotherapy in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to a retrospective study.

©Mathier/thinkstockphotos.com

“This study compared time to next treatment, health care resource utilization, and total direct costs among patients with CLL initiating front-line ibrutinib single agent or chemoimmunotherapy,” wrote Bruno Emond, of Analysis Group, Montreal, and colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.

The researchers retrospectively analyzed data from 1,161 patients with CLL who were started on ibrutinib monotherapy or chemoimmunotherapy from 2014 to 2017. Data were collected from the Optum Clinformatics Extended DataMart De-Identified Databases.

Between the two groups, differences in baseline characteristics were controlled for by way of inverse probability of treatment weighting. Two treatment periods were included in the study: the initial 6 months of treatment and entire duration of frontline therapy.

The team also conducted a subgroup analysis of patients treated with bendamustine and rituximab. This cohort was analyzed independently since the regimen is commonly used in clinical practice.

After analysis, the researchers found that ibrutinib monotherapy was associated with net monthly cost savings of $3,766 (P less than .0001), compared with chemoimmunotherapy and bendamustine/rituximab over the frontline therapy period.

Ibrutinib patients had fewer monthly days with outpatient services (rate ratio, 0.75; 95% confidence interval, 0.60-0.94; P = .0200), compared with those on chemoimmunotherapy; and were less likely to initiate a next line of treatment, compared with chemoimmunotherapy patients (hazard ratio, 0.54; 95% CI, 0.33-0.90; P = .0163).

“Cost savings and reductions in health care resource utilization were even more pronounced when considering only the first 6 months of front-line treatment,” the researchers wrote.

The researchers acknowledged that two key limitations of the study were the potential influence of unobserved confounding factors and the use of claims data, which could include errors and omissions.

“These results suggest that ibrutinib single-agent is associated with lower total costs driven by lower medical costs, despite higher pharmacy costs, compared with chemoimmunotherapy and bendamustine/rituximab,” they concluded.

The authors reported financial affiliations with Janssen Scientific Affairs, which funded the study, and other companies.

SOURCE: Emond B et al. Clin Lymphoma Myeloma Leuk. 2019 Aug 26. doi: 10.1016/j.clml.2019.08.004.

Ibrutinib monotherapy was associated with lower total health care costs compared with chemoimmunotherapy in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to a retrospective study.

©Mathier/thinkstockphotos.com

“This study compared time to next treatment, health care resource utilization, and total direct costs among patients with CLL initiating front-line ibrutinib single agent or chemoimmunotherapy,” wrote Bruno Emond, of Analysis Group, Montreal, and colleagues. Their report is in Clinical Lymphoma, Myeloma & Leukemia.

The researchers retrospectively analyzed data from 1,161 patients with CLL who were started on ibrutinib monotherapy or chemoimmunotherapy from 2014 to 2017. Data were collected from the Optum Clinformatics Extended DataMart De-Identified Databases.

Between the two groups, differences in baseline characteristics were controlled for by way of inverse probability of treatment weighting. Two treatment periods were included in the study: the initial 6 months of treatment and entire duration of frontline therapy.

The team also conducted a subgroup analysis of patients treated with bendamustine and rituximab. This cohort was analyzed independently since the regimen is commonly used in clinical practice.

After analysis, the researchers found that ibrutinib monotherapy was associated with net monthly cost savings of $3,766 (P less than .0001), compared with chemoimmunotherapy and bendamustine/rituximab over the frontline therapy period.

Ibrutinib patients had fewer monthly days with outpatient services (rate ratio, 0.75; 95% confidence interval, 0.60-0.94; P = .0200), compared with those on chemoimmunotherapy; and were less likely to initiate a next line of treatment, compared with chemoimmunotherapy patients (hazard ratio, 0.54; 95% CI, 0.33-0.90; P = .0163).

“Cost savings and reductions in health care resource utilization were even more pronounced when considering only the first 6 months of front-line treatment,” the researchers wrote.

The researchers acknowledged that two key limitations of the study were the potential influence of unobserved confounding factors and the use of claims data, which could include errors and omissions.

“These results suggest that ibrutinib single-agent is associated with lower total costs driven by lower medical costs, despite higher pharmacy costs, compared with chemoimmunotherapy and bendamustine/rituximab,” they concluded.

The authors reported financial affiliations with Janssen Scientific Affairs, which funded the study, and other companies.

SOURCE: Emond B et al. Clin Lymphoma Myeloma Leuk. 2019 Aug 26. doi: 10.1016/j.clml.2019.08.004.

The benefit of rituximab maintenance therapy in follicular lymphoma is long lasting and evident out to at least 9 years, according to the final efficacy analysis of the PRIMA phase 3, randomized, controlled trial.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Previously reported results of this pivotal trial showed prolongation of progression-free survival and time to next treatment with rituximab maintenance at a follow-up of 3 years and 6 years.

“Rituximab maintenance is now widely recommended for patients with follicular lymphoma responding to first-line rituximab-based immunochemotherapy,” Emmanuel Bachy, MD, PhD, of Institut National de la Santé et de la Recherche Médicale in Pierre-Bénite, France, and colleagues reported in the Journal of Clinical Oncology.

In PRIMA, patients with previously untreated high–tumor burden follicular lymphoma received any of three immunochemotherapy induction regimens. The 1,018 patients having a response were then randomly assigned to receive 2 years of rituximab (Rituxan) maintenance or observation only.

Dr. Bachy and colleagues performed the trial’s final efficacy analyses, now at a median follow-up of 9 years.

Among the 607 patients consenting to the extended follow-up, median progression-free survival was 10.5 years in the rituximab-maintenance group, compared with 4.1 years in the observation group (hazard ratio, 0.61; P less than .001).

“Subgroup analyses showed the substantial progression-free survival improvement associated with rituximab maintenance was independent of age, sex, induction immunochemotherapy regimen, response to induction, or [Follicular Lymphoma International Prognostic Index] risk score,” the investigators wrote.

Rituximab maintenance also prolonged the median time to next antilymphoma treatment (not reached vs. 6.1 years; hazard ratio, 0.66; P less than .001) and time to next chemotherapy treatment (not reached vs. 9.3 years; hazard ratio, 0.71; P less than .001).

But there was no significant difference in overall survival. Median overall survival was not reached in either group (hazard ratio, 1.04; P = .7948). The estimated 10-year overall survival rate was about 80% in both groups.

“This 9-year follow-up of the PRIMA study demonstrates that rituximab maintenance after induction immunochemotherapy provides a significant long-term [progression-free survival] benefit over observation,” the investigators wrote. “Despite the lack of [overall survival] advantage, it is noteworthy that more than half of the patients in the rituximab maintenance arm remain free of disease progression and have not required new antilymphoma treatment beyond 10 years.”

The trial was sponsored by the Lymphoma Study Association and supported by F. Hoffmann–La Roche and Biogen. Dr. Bachy reported financial disclosures related to Roche and other companies.

SOURCE: Bachy E et al. J Clin Oncol. 2019 Nov 1;37(31):2815-24.

The benefit of rituximab maintenance therapy in follicular lymphoma is long lasting and evident out to at least 9 years, according to the final efficacy analysis of the PRIMA phase 3, randomized, controlled trial.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Previously reported results of this pivotal trial showed prolongation of progression-free survival and time to next treatment with rituximab maintenance at a follow-up of 3 years and 6 years.

“Rituximab maintenance is now widely recommended for patients with follicular lymphoma responding to first-line rituximab-based immunochemotherapy,” Emmanuel Bachy, MD, PhD, of Institut National de la Santé et de la Recherche Médicale in Pierre-Bénite, France, and colleagues reported in the Journal of Clinical Oncology.

In PRIMA, patients with previously untreated high–tumor burden follicular lymphoma received any of three immunochemotherapy induction regimens. The 1,018 patients having a response were then randomly assigned to receive 2 years of rituximab (Rituxan) maintenance or observation only.

Dr. Bachy and colleagues performed the trial’s final efficacy analyses, now at a median follow-up of 9 years.

Among the 607 patients consenting to the extended follow-up, median progression-free survival was 10.5 years in the rituximab-maintenance group, compared with 4.1 years in the observation group (hazard ratio, 0.61; P less than .001).

“Subgroup analyses showed the substantial progression-free survival improvement associated with rituximab maintenance was independent of age, sex, induction immunochemotherapy regimen, response to induction, or [Follicular Lymphoma International Prognostic Index] risk score,” the investigators wrote.

Rituximab maintenance also prolonged the median time to next antilymphoma treatment (not reached vs. 6.1 years; hazard ratio, 0.66; P less than .001) and time to next chemotherapy treatment (not reached vs. 9.3 years; hazard ratio, 0.71; P less than .001).

But there was no significant difference in overall survival. Median overall survival was not reached in either group (hazard ratio, 1.04; P = .7948). The estimated 10-year overall survival rate was about 80% in both groups.

“This 9-year follow-up of the PRIMA study demonstrates that rituximab maintenance after induction immunochemotherapy provides a significant long-term [progression-free survival] benefit over observation,” the investigators wrote. “Despite the lack of [overall survival] advantage, it is noteworthy that more than half of the patients in the rituximab maintenance arm remain free of disease progression and have not required new antilymphoma treatment beyond 10 years.”

The trial was sponsored by the Lymphoma Study Association and supported by F. Hoffmann–La Roche and Biogen. Dr. Bachy reported financial disclosures related to Roche and other companies.

SOURCE: Bachy E et al. J Clin Oncol. 2019 Nov 1;37(31):2815-24.

The benefit of rituximab maintenance therapy in follicular lymphoma is long lasting and evident out to at least 9 years, according to the final efficacy analysis of the PRIMA phase 3, randomized, controlled trial.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Previously reported results of this pivotal trial showed prolongation of progression-free survival and time to next treatment with rituximab maintenance at a follow-up of 3 years and 6 years.

“Rituximab maintenance is now widely recommended for patients with follicular lymphoma responding to first-line rituximab-based immunochemotherapy,” Emmanuel Bachy, MD, PhD, of Institut National de la Santé et de la Recherche Médicale in Pierre-Bénite, France, and colleagues reported in the Journal of Clinical Oncology.

In PRIMA, patients with previously untreated high–tumor burden follicular lymphoma received any of three immunochemotherapy induction regimens. The 1,018 patients having a response were then randomly assigned to receive 2 years of rituximab (Rituxan) maintenance or observation only.

Dr. Bachy and colleagues performed the trial’s final efficacy analyses, now at a median follow-up of 9 years.

Among the 607 patients consenting to the extended follow-up, median progression-free survival was 10.5 years in the rituximab-maintenance group, compared with 4.1 years in the observation group (hazard ratio, 0.61; P less than .001).

“Subgroup analyses showed the substantial progression-free survival improvement associated with rituximab maintenance was independent of age, sex, induction immunochemotherapy regimen, response to induction, or [Follicular Lymphoma International Prognostic Index] risk score,” the investigators wrote.

Rituximab maintenance also prolonged the median time to next antilymphoma treatment (not reached vs. 6.1 years; hazard ratio, 0.66; P less than .001) and time to next chemotherapy treatment (not reached vs. 9.3 years; hazard ratio, 0.71; P less than .001).

But there was no significant difference in overall survival. Median overall survival was not reached in either group (hazard ratio, 1.04; P = .7948). The estimated 10-year overall survival rate was about 80% in both groups.

“This 9-year follow-up of the PRIMA study demonstrates that rituximab maintenance after induction immunochemotherapy provides a significant long-term [progression-free survival] benefit over observation,” the investigators wrote. “Despite the lack of [overall survival] advantage, it is noteworthy that more than half of the patients in the rituximab maintenance arm remain free of disease progression and have not required new antilymphoma treatment beyond 10 years.”

The trial was sponsored by the Lymphoma Study Association and supported by F. Hoffmann–La Roche and Biogen. Dr. Bachy reported financial disclosures related to Roche and other companies.

SOURCE: Bachy E et al. J Clin Oncol. 2019 Nov 1;37(31):2815-24.

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.

This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.

The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.

Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.

After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.

With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.

Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.

“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”

The investigators reported having no conflicts of interest.

SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.

Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.

Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.

Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.

The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.

SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.

Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.

Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.

Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.

The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.

SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.

For patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), adding polatuzumab vedotin to bendamustine and rituximab can improve complete response rates and extend overall survival, according to findings from a phase 1b/2 trial.

Adding polatuzumab decreased mortality risk by 58%, reported lead author Laurie H. Sehn, MD, of the University of British Columbia, Vancouver, and colleagues.

Combination therapy with polatuzumab, bendamustine, and rituximab “represents a novel, effective therapeutic regimen to address the unmet need of patients with transplantation-ineligible [relapsed/refractory] DLBCL,” the investigators wrote. Since just 25% of polatuzumab combination–treated patients had received prior autologous stem cell transplant, the investigators said they could not make definitive conclusions on this combination’s efficacy in the post-ASCT setting.

Additional trials involving polatuzumab in the relapsed/refractory setting are ongoing. For patients with treatment-naive DLBCL, a phase 3 trial (NCT03274492) is evaluating substitution of polatuzumab for vincristine in the R-CHOP regimen.

The study was funded by F. Hoffmann-La Roche and Genentech. The investigators reported additional relationships with AbbVie, Kite Pharma, Lundbeck, and others.

SOURCE: Sehn LH et al. J Clin Oncol. 2019 Nov 6. doi: 10.1200/JCO.19.00172.

The Food and Drug Administration has approved zanubrutinib (Brukinsa) for the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy.

Olivier Le Moal/Getty Images

The approval is based on results from two separate studies; in a global phase 1/2 trial, patients with relapsed or refractory MCL who received zanubrutinib had an overall response rate of 84%, with 22% experiencing a complete response and 62% experiencing partial response. Median duration of response was 18.5 months. The ORR in the second study – a multicenter phase 2 trial – was also 84%, but with 59% experiencing a complete response and 24% experiencing partial response; duration of response was 19.5 months.

The most common adverse events reported during the trials were decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, cough, musculoskeletal pain, pneumonia, urinary tract infection, hematuria, fatigue, constipation, and hemorrhage. The most common serious adverse events were pneumonia and hemorrhage.

Of the 118 patients with MCL treated with zanubrutinib over the two trials, 8 had to be discontinued because of adverse events.

The recommended dose of zanubrutinib is 320 mg, taken orally 160 mg twice daily or 320 mg once daily, with or without food.

“BTK [Bruton kinase] inhibition is an established mode of treatment for patients with MCL, but many patients treated with previously approved BTK inhibitors do not fully respond to BTK therapy or are forced to discontinue treatment early due to side effects. Today we have a new option for our adult patients who have received one prior systemic or targeted therapy and are living with MCL,” Luhua (Michael) Wang, MD, clinical trial investigator and professor in the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, said in a statement.

[email protected]

The Food and Drug Administration has approved zanubrutinib (Brukinsa) for the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy.

Olivier Le Moal/Getty Images

The approval is based on results from two separate studies; in a global phase 1/2 trial, patients with relapsed or refractory MCL who received zanubrutinib had an overall response rate of 84%, with 22% experiencing a complete response and 62% experiencing partial response. Median duration of response was 18.5 months. The ORR in the second study – a multicenter phase 2 trial – was also 84%, but with 59% experiencing a complete response and 24% experiencing partial response; duration of response was 19.5 months.

The most common adverse events reported during the trials were decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, cough, musculoskeletal pain, pneumonia, urinary tract infection, hematuria, fatigue, constipation, and hemorrhage. The most common serious adverse events were pneumonia and hemorrhage.

Of the 118 patients with MCL treated with zanubrutinib over the two trials, 8 had to be discontinued because of adverse events.

The recommended dose of zanubrutinib is 320 mg, taken orally 160 mg twice daily or 320 mg once daily, with or without food.

“BTK [Bruton kinase] inhibition is an established mode of treatment for patients with MCL, but many patients treated with previously approved BTK inhibitors do not fully respond to BTK therapy or are forced to discontinue treatment early due to side effects. Today we have a new option for our adult patients who have received one prior systemic or targeted therapy and are living with MCL,” Luhua (Michael) Wang, MD, clinical trial investigator and professor in the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, said in a statement.

[email protected]

The Food and Drug Administration has approved zanubrutinib (Brukinsa) for the treatment of mantle cell lymphoma (MCL) in adult patients who have received at least one prior therapy.

Olivier Le Moal/Getty Images

The approval is based on results from two separate studies; in a global phase 1/2 trial, patients with relapsed or refractory MCL who received zanubrutinib had an overall response rate of 84%, with 22% experiencing a complete response and 62% experiencing partial response. Median duration of response was 18.5 months. The ORR in the second study – a multicenter phase 2 trial – was also 84%, but with 59% experiencing a complete response and 24% experiencing partial response; duration of response was 19.5 months.

The most common adverse events reported during the trials were decreased neutrophil count, decreased platelet count, upper respiratory tract infection, decreased white blood cell count, decreased hemoglobin, rash, bruising, diarrhea, cough, musculoskeletal pain, pneumonia, urinary tract infection, hematuria, fatigue, constipation, and hemorrhage. The most common serious adverse events were pneumonia and hemorrhage.

Of the 118 patients with MCL treated with zanubrutinib over the two trials, 8 had to be discontinued because of adverse events.

The recommended dose of zanubrutinib is 320 mg, taken orally 160 mg twice daily or 320 mg once daily, with or without food.

“BTK [Bruton kinase] inhibition is an established mode of treatment for patients with MCL, but many patients treated with previously approved BTK inhibitors do not fully respond to BTK therapy or are forced to discontinue treatment early due to side effects. Today we have a new option for our adult patients who have received one prior systemic or targeted therapy and are living with MCL,” Luhua (Michael) Wang, MD, clinical trial investigator and professor in the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, said in a statement.

[email protected]

A novel 17-gene expression signature may help guide the choice of initial treatment in patients with IGHV-unmutated chronic lymphocytic leukemia (CLL), according to findings of a retrospective dual cohort study.

copyright Kativ/iStockphoto

“[Fludarabine, cyclophosphamide, and rituximab] was the first regimen to improve progression-free survival and overall survival in patients with chronic lymphocytic leukaemia, and has become a gold-standard chemoimmunotherapy regimen in physically fit patients,” wrote the investigators, who were led by Carmen D. Herling, MD, of the Center for Integrated Oncology, Cologne, Germany; and Kevin R. Coombes, PhD, of Ohio State University, Columbus.

While several studies demonstrate that young, fit patients with mutated IGHV gene and no high-risk cytogenetic abnormalities achieve durable remission with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen, there have been no studies to identify if this is true for patients with unmutated IGHV gene, they reported in the Lancet Oncology.

The investigators performed transcriptional profiling using peripheral blood samples collected from two cohorts of patients with CLL who were treated with frontline FCR.

The discovery and training cohort consisted of 101 patients (65% with IGHV-unmutated disease) treated at the MD Anderson Cancer Center who had a median follow-up of about 12 years. The validation cohort consisted of 109 patients with IGHV-unmutated disease treated on the German CLL8 single-arm trial who had a median follow-up of about 6 years.

A total of 1,136 genes showed a significant univariate association with time to progression. Ultimately, 17 of these genes – most of them involved in purine metabolism and oxidative phosphorylation – were included in the expression signature.

Among patients with IGHV-unmutated CLL, the 17-gene signature discriminated between two groups having differing time to progression after their frontline FCR chemoimmunotherapy: an unfavorable prognosis group and an intermediate prognosis group.

The unfavorable prognosis group had a significantly higher relative risk of progression in both the discovery/training cohort (hazard ratio, 3.83; P less than .0001) and the validation cohort (HR, 1.90; P = .008). In the validation cohort, the median time to progression was 39 months among patients with a signature-defined unfavorable prognosis, compared with 59 months among patients with a signature-defined intermediate prognosis.

“We would recommend testing the value of the 17-gene signature in a prospective study that compares FCR treatment with alternative therapies, such as ibrutinib, as part of a randomised clinical trial,” the investigators wrote.

Dr. Herling reported financial disclosures related to Hoffmann-La Roche, and Dr. Coombes reported grants from the National Institutes of Health. The study was funded by the Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.

SOURCE: Herling CD et al. Lancet Oncol. 2019;20(11):1576-86.

A novel 17-gene expression signature may help guide the choice of initial treatment in patients with IGHV-unmutated chronic lymphocytic leukemia (CLL), according to findings of a retrospective dual cohort study.

copyright Kativ/iStockphoto

“[Fludarabine, cyclophosphamide, and rituximab] was the first regimen to improve progression-free survival and overall survival in patients with chronic lymphocytic leukaemia, and has become a gold-standard chemoimmunotherapy regimen in physically fit patients,” wrote the investigators, who were led by Carmen D. Herling, MD, of the Center for Integrated Oncology, Cologne, Germany; and Kevin R. Coombes, PhD, of Ohio State University, Columbus.

While several studies demonstrate that young, fit patients with mutated IGHV gene and no high-risk cytogenetic abnormalities achieve durable remission with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen, there have been no studies to identify if this is true for patients with unmutated IGHV gene, they reported in the Lancet Oncology.

The investigators performed transcriptional profiling using peripheral blood samples collected from two cohorts of patients with CLL who were treated with frontline FCR.

The discovery and training cohort consisted of 101 patients (65% with IGHV-unmutated disease) treated at the MD Anderson Cancer Center who had a median follow-up of about 12 years. The validation cohort consisted of 109 patients with IGHV-unmutated disease treated on the German CLL8 single-arm trial who had a median follow-up of about 6 years.

A total of 1,136 genes showed a significant univariate association with time to progression. Ultimately, 17 of these genes – most of them involved in purine metabolism and oxidative phosphorylation – were included in the expression signature.

Among patients with IGHV-unmutated CLL, the 17-gene signature discriminated between two groups having differing time to progression after their frontline FCR chemoimmunotherapy: an unfavorable prognosis group and an intermediate prognosis group.

The unfavorable prognosis group had a significantly higher relative risk of progression in both the discovery/training cohort (hazard ratio, 3.83; P less than .0001) and the validation cohort (HR, 1.90; P = .008). In the validation cohort, the median time to progression was 39 months among patients with a signature-defined unfavorable prognosis, compared with 59 months among patients with a signature-defined intermediate prognosis.

“We would recommend testing the value of the 17-gene signature in a prospective study that compares FCR treatment with alternative therapies, such as ibrutinib, as part of a randomised clinical trial,” the investigators wrote.

Dr. Herling reported financial disclosures related to Hoffmann-La Roche, and Dr. Coombes reported grants from the National Institutes of Health. The study was funded by the Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.

SOURCE: Herling CD et al. Lancet Oncol. 2019;20(11):1576-86.

A novel 17-gene expression signature may help guide the choice of initial treatment in patients with IGHV-unmutated chronic lymphocytic leukemia (CLL), according to findings of a retrospective dual cohort study.

copyright Kativ/iStockphoto

“[Fludarabine, cyclophosphamide, and rituximab] was the first regimen to improve progression-free survival and overall survival in patients with chronic lymphocytic leukaemia, and has become a gold-standard chemoimmunotherapy regimen in physically fit patients,” wrote the investigators, who were led by Carmen D. Herling, MD, of the Center for Integrated Oncology, Cologne, Germany; and Kevin R. Coombes, PhD, of Ohio State University, Columbus.

While several studies demonstrate that young, fit patients with mutated IGHV gene and no high-risk cytogenetic abnormalities achieve durable remission with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen, there have been no studies to identify if this is true for patients with unmutated IGHV gene, they reported in the Lancet Oncology.

The investigators performed transcriptional profiling using peripheral blood samples collected from two cohorts of patients with CLL who were treated with frontline FCR.

The discovery and training cohort consisted of 101 patients (65% with IGHV-unmutated disease) treated at the MD Anderson Cancer Center who had a median follow-up of about 12 years. The validation cohort consisted of 109 patients with IGHV-unmutated disease treated on the German CLL8 single-arm trial who had a median follow-up of about 6 years.

A total of 1,136 genes showed a significant univariate association with time to progression. Ultimately, 17 of these genes – most of them involved in purine metabolism and oxidative phosphorylation – were included in the expression signature.

Among patients with IGHV-unmutated CLL, the 17-gene signature discriminated between two groups having differing time to progression after their frontline FCR chemoimmunotherapy: an unfavorable prognosis group and an intermediate prognosis group.

The unfavorable prognosis group had a significantly higher relative risk of progression in both the discovery/training cohort (hazard ratio, 3.83; P less than .0001) and the validation cohort (HR, 1.90; P = .008). In the validation cohort, the median time to progression was 39 months among patients with a signature-defined unfavorable prognosis, compared with 59 months among patients with a signature-defined intermediate prognosis.

“We would recommend testing the value of the 17-gene signature in a prospective study that compares FCR treatment with alternative therapies, such as ibrutinib, as part of a randomised clinical trial,” the investigators wrote.

Dr. Herling reported financial disclosures related to Hoffmann-La Roche, and Dr. Coombes reported grants from the National Institutes of Health. The study was funded by the Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute.

SOURCE: Herling CD et al. Lancet Oncol. 2019;20(11):1576-86.

NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.

Penn Medicine

ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.

Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.

Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.

Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).

There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.

In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.

Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.

The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.

Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.

Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.

[email protected]

SOURCE: Lu V et al. SITC 2019, Abstract O25.

NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.

Penn Medicine

ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.

Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.

Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.

Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).

There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.

In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.

Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.

The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.

Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.

Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.

[email protected]

SOURCE: Lu V et al. SITC 2019, Abstract O25.

NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.

Penn Medicine

ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.

Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.

Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.

Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).

There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.

In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.

Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.

The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.

Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.

Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.

[email protected]

SOURCE: Lu V et al. SITC 2019, Abstract O25.

EDINBURGH – Impaired renal function may indicate excess risk of tumor lysis syndrome (TLS) in venetoclax-treated chronic lymphocytic leukemia (CLL) patients and should be considered when assessing TLS risk, according to findings from a retrospective cohort study.

Complex karyotype may also affect TLS risk, Anthony Mato, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Of 339 CLL patients who were treated with venetoclax, 38%, 34%, and 28% were considered to have low, medium, or high risk for TLS, respectively, according to the standard definition based on absolute lymphocyte count as a measure of tumor burden and/or lymph node size.

TLS occurred in 35 patients (10%), including 26 cases of laboratory-confirmed TLS and 9 clinical TLS cases; 1 patient required dialysis and 1 death occurred, which was attributable to the TLS, Dr. Mato of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported in a poster at the workshop.

Univariate analysis was performed to “understand baseline factors associated with TLS development during dose escalation,” and it examined sex, creatinine clearance (CrCl), complex karyotype, immunoglobulin heavy chain variable mutation status, prior ibrutinib exposure, venetoclax monotherapy vs. combination therapy, and TLS risk group. The investigators observed no significant difference between the low- and medium-risk patients, therefore those two groups were combined and compared with the high-risk patients.

The univariate analysis showed significant associations between TLS and CrCl (odds ratio, 2.9 for 80 mL/min or less vs. greater than 80 mL/min), complex karyotype (OR, 2.2), and low/medium vs. high TLS risk based on the standard definition (OR, 2.56).

A multivariable analysis of the predictors identified as significant in the univariate analyses showed that standard TLS risk group and CrCl remained independent predictors of TLS.

“Although the odds ratio for complex karyotype suggested potential clinical significance, this did not meet the threshold for statistical significance and was not included in the final model,” they wrote.

The area under the receiver operating characteristic curve for a model including TLS risk group and CrCl was 74.6%, compared with 65% for the area under the ROC curve using the standard tumor burden/lymph node size approach for defining TLS risk, which is described in the venetoclax package insert.

Patients included in the study had a median age of 67 years at venetoclax initiation, 69% were men, 85% were white, and 13% were treated on a clinical trial. Complex karyotype was present in 39%, del(17p) in 43%, and 84% had immunoglobulin heavy chain variable–unmutated disease.

Most patients received venetoclax monotherapy (79%), had relapsed/refractory disease (94%), and had previously received ibrutinib (78%). The median number of prior therapies was 3, but the number ranged from 0-15, the investigators noted.

The findings of this study suggest that, in addition to defining risk based on absolute lymphocyte count and lymph node size, patients with CrCl less than 80 mL/min – indicating impaired renal function – have excess risk of TLS.

Although complex karyotype did not reach statistical significance as an independent predictor of TLS, the findings in this study suggest it “may impact TLS risk and is worthy of further study in larger samples,” they said, concluding that consideration of baseline renal function, and possibly karyotype, could “further guide practitioners in their approach to prophylaxis and patient counseling, allowing for improved safety in the use of this effective agent in CLL.”

Additional planned analyses will focus on TLS risk score development and further refinement of TLS risk stratification, they noted.

Dr. Mato has received grant support, consulting fees, and/or fees for serving on a data and safety monitoring board or advisory board from AbbVie, AstraZeneca, Celgene, Janssen, TG Therapeutics, Pharmacyclics, Loxo, Sunesis, prIME Oncology, Pfizer, Johnson & Johnson, and Regeneron.

[email protected]

EDINBURGH – Impaired renal function may indicate excess risk of tumor lysis syndrome (TLS) in venetoclax-treated chronic lymphocytic leukemia (CLL) patients and should be considered when assessing TLS risk, according to findings from a retrospective cohort study.

Complex karyotype may also affect TLS risk, Anthony Mato, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Of 339 CLL patients who were treated with venetoclax, 38%, 34%, and 28% were considered to have low, medium, or high risk for TLS, respectively, according to the standard definition based on absolute lymphocyte count as a measure of tumor burden and/or lymph node size.

TLS occurred in 35 patients (10%), including 26 cases of laboratory-confirmed TLS and 9 clinical TLS cases; 1 patient required dialysis and 1 death occurred, which was attributable to the TLS, Dr. Mato of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported in a poster at the workshop.

Univariate analysis was performed to “understand baseline factors associated with TLS development during dose escalation,” and it examined sex, creatinine clearance (CrCl), complex karyotype, immunoglobulin heavy chain variable mutation status, prior ibrutinib exposure, venetoclax monotherapy vs. combination therapy, and TLS risk group. The investigators observed no significant difference between the low- and medium-risk patients, therefore those two groups were combined and compared with the high-risk patients.

The univariate analysis showed significant associations between TLS and CrCl (odds ratio, 2.9 for 80 mL/min or less vs. greater than 80 mL/min), complex karyotype (OR, 2.2), and low/medium vs. high TLS risk based on the standard definition (OR, 2.56).

A multivariable analysis of the predictors identified as significant in the univariate analyses showed that standard TLS risk group and CrCl remained independent predictors of TLS.

“Although the odds ratio for complex karyotype suggested potential clinical significance, this did not meet the threshold for statistical significance and was not included in the final model,” they wrote.

The area under the receiver operating characteristic curve for a model including TLS risk group and CrCl was 74.6%, compared with 65% for the area under the ROC curve using the standard tumor burden/lymph node size approach for defining TLS risk, which is described in the venetoclax package insert.

Patients included in the study had a median age of 67 years at venetoclax initiation, 69% were men, 85% were white, and 13% were treated on a clinical trial. Complex karyotype was present in 39%, del(17p) in 43%, and 84% had immunoglobulin heavy chain variable–unmutated disease.

Most patients received venetoclax monotherapy (79%), had relapsed/refractory disease (94%), and had previously received ibrutinib (78%). The median number of prior therapies was 3, but the number ranged from 0-15, the investigators noted.

The findings of this study suggest that, in addition to defining risk based on absolute lymphocyte count and lymph node size, patients with CrCl less than 80 mL/min – indicating impaired renal function – have excess risk of TLS.

Although complex karyotype did not reach statistical significance as an independent predictor of TLS, the findings in this study suggest it “may impact TLS risk and is worthy of further study in larger samples,” they said, concluding that consideration of baseline renal function, and possibly karyotype, could “further guide practitioners in their approach to prophylaxis and patient counseling, allowing for improved safety in the use of this effective agent in CLL.”

Additional planned analyses will focus on TLS risk score development and further refinement of TLS risk stratification, they noted.

Dr. Mato has received grant support, consulting fees, and/or fees for serving on a data and safety monitoring board or advisory board from AbbVie, AstraZeneca, Celgene, Janssen, TG Therapeutics, Pharmacyclics, Loxo, Sunesis, prIME Oncology, Pfizer, Johnson & Johnson, and Regeneron.

[email protected]

EDINBURGH – Impaired renal function may indicate excess risk of tumor lysis syndrome (TLS) in venetoclax-treated chronic lymphocytic leukemia (CLL) patients and should be considered when assessing TLS risk, according to findings from a retrospective cohort study.

Complex karyotype may also affect TLS risk, Anthony Mato, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.

Of 339 CLL patients who were treated with venetoclax, 38%, 34%, and 28% were considered to have low, medium, or high risk for TLS, respectively, according to the standard definition based on absolute lymphocyte count as a measure of tumor burden and/or lymph node size.

TLS occurred in 35 patients (10%), including 26 cases of laboratory-confirmed TLS and 9 clinical TLS cases; 1 patient required dialysis and 1 death occurred, which was attributable to the TLS, Dr. Mato of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported in a poster at the workshop.

Univariate analysis was performed to “understand baseline factors associated with TLS development during dose escalation,” and it examined sex, creatinine clearance (CrCl), complex karyotype, immunoglobulin heavy chain variable mutation status, prior ibrutinib exposure, venetoclax monotherapy vs. combination therapy, and TLS risk group. The investigators observed no significant difference between the low- and medium-risk patients, therefore those two groups were combined and compared with the high-risk patients.

The univariate analysis showed significant associations between TLS and CrCl (odds ratio, 2.9 for 80 mL/min or less vs. greater than 80 mL/min), complex karyotype (OR, 2.2), and low/medium vs. high TLS risk based on the standard definition (OR, 2.56).

A multivariable analysis of the predictors identified as significant in the univariate analyses showed that standard TLS risk group and CrCl remained independent predictors of TLS.

“Although the odds ratio for complex karyotype suggested potential clinical significance, this did not meet the threshold for statistical significance and was not included in the final model,” they wrote.

The area under the receiver operating characteristic curve for a model including TLS risk group and CrCl was 74.6%, compared with 65% for the area under the ROC curve using the standard tumor burden/lymph node size approach for defining TLS risk, which is described in the venetoclax package insert.

Patients included in the study had a median age of 67 years at venetoclax initiation, 69% were men, 85% were white, and 13% were treated on a clinical trial. Complex karyotype was present in 39%, del(17p) in 43%, and 84% had immunoglobulin heavy chain variable–unmutated disease.

Most patients received venetoclax monotherapy (79%), had relapsed/refractory disease (94%), and had previously received ibrutinib (78%). The median number of prior therapies was 3, but the number ranged from 0-15, the investigators noted.

The findings of this study suggest that, in addition to defining risk based on absolute lymphocyte count and lymph node size, patients with CrCl less than 80 mL/min – indicating impaired renal function – have excess risk of TLS.

Although complex karyotype did not reach statistical significance as an independent predictor of TLS, the findings in this study suggest it “may impact TLS risk and is worthy of further study in larger samples,” they said, concluding that consideration of baseline renal function, and possibly karyotype, could “further guide practitioners in their approach to prophylaxis and patient counseling, allowing for improved safety in the use of this effective agent in CLL.”

Additional planned analyses will focus on TLS risk score development and further refinement of TLS risk stratification, they noted.

Dr. Mato has received grant support, consulting fees, and/or fees for serving on a data and safety monitoring board or advisory board from AbbVie, AstraZeneca, Celgene, Janssen, TG Therapeutics, Pharmacyclics, Loxo, Sunesis, prIME Oncology, Pfizer, Johnson & Johnson, and Regeneron.

[email protected]

The programmed death-ligand 1 (PD-L1) inhibitor pembrolizumab showed manageable safety and promising clinical activity in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to results from two early-phase studies.

The phase 1b KEYNOTE-013 study included an expansion cohort that evaluated pembrolizumab monotherapy in patients with relapsed/refractory PMBCL. Based on preliminary findings from KEYNOTE-013, the phase 2 KEYNOTE-170 study was initiated to validate these results.

Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues reported results from 53 patients in KEYNOTE-170 and extended follow-up of 21 patients in KEYNOTE-013. Data from these two trials formed the basis of an accelerated approval by the Food and Drug Administration of pembrolizumab in patients with relapsed/refractory PMBCL in June 2018.

“Frequent amplification and translocation events occur at 9p24.1 in PMBCL, resulting in tumor expression of the programmed cell death-1 (PD-1) ligands PD-L1 and PD-L2. This suggests susceptibility of PMBCL to PD-1 blockade,” the researchers wrote in the Journal of Clinical Oncology.

KEYNOTE-170 included patients with relapsed or refractory disease who were transplant-ineligible and had failed a minimum of two prior lines of treatment. KEYNOTE-013 enrolled patients who relapsed following autologous stem cell transplantation or were ineligible for transplant.

Among patients in KEYNOTE-013 and KEYNOTE-170, the objective response rates were 48% and 45%, respectively. In total, 33% of patients in KEYNOTE-013 and 13% of patients in KEYNOTE-170 achieved a complete response. Among these patients, no disease progression was observed.

The median progression-free survival in KEYNOTE-170 was 5.5 months and 10.4 months in KEYNOTE-013. In KEYNOTE-170, median overall survival was not reached, while in KEYNOTE-013, the median overall survival was 31.4 months.

After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either trial, the researchers reported.

With respect to safety, pembrolizumab-related grade 3 or 4 adverse events were observed in 23% and 24% of patients in KEYNOTE-170 and KEYNOTE-013, respectively. The most common adverse event in both trials was neutropenia. No deaths related to pembrolizumab were observed.

Response rates were lower in KEYNOTE-170, compared with KEYNOTE-013, but the researchers noted that longer follow-up could change these results.

“Although the small numbers allow only a tentative hypothesis, they raise the question of whether PD-1 blockade in this setting might resensitize tumors to chemotherapy, as recently suggested. If this can be further validated, it could have profound implication for the management of patients with [relapsed/refractory] PMBCL,” the researchers wrote.

The study was supported by Merck Sharp & Dohme, the Harold and Virginia Lash Foundation, the Leukemia and Lymphoma Society, and the Center for Immuno-Oncology of the Dana-Farber Cancer Institute. The authors reported financial affiliations with Merck Sharp & Dohme and several other companies.

SOURCE: Armand P et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.01389.

The programmed death-ligand 1 (PD-L1) inhibitor pembrolizumab showed manageable safety and promising clinical activity in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to results from two early-phase studies.

The phase 1b KEYNOTE-013 study included an expansion cohort that evaluated pembrolizumab monotherapy in patients with relapsed/refractory PMBCL. Based on preliminary findings from KEYNOTE-013, the phase 2 KEYNOTE-170 study was initiated to validate these results.

Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues reported results from 53 patients in KEYNOTE-170 and extended follow-up of 21 patients in KEYNOTE-013. Data from these two trials formed the basis of an accelerated approval by the Food and Drug Administration of pembrolizumab in patients with relapsed/refractory PMBCL in June 2018.

“Frequent amplification and translocation events occur at 9p24.1 in PMBCL, resulting in tumor expression of the programmed cell death-1 (PD-1) ligands PD-L1 and PD-L2. This suggests susceptibility of PMBCL to PD-1 blockade,” the researchers wrote in the Journal of Clinical Oncology.

KEYNOTE-170 included patients with relapsed or refractory disease who were transplant-ineligible and had failed a minimum of two prior lines of treatment. KEYNOTE-013 enrolled patients who relapsed following autologous stem cell transplantation or were ineligible for transplant.

Among patients in KEYNOTE-013 and KEYNOTE-170, the objective response rates were 48% and 45%, respectively. In total, 33% of patients in KEYNOTE-013 and 13% of patients in KEYNOTE-170 achieved a complete response. Among these patients, no disease progression was observed.

The median progression-free survival in KEYNOTE-170 was 5.5 months and 10.4 months in KEYNOTE-013. In KEYNOTE-170, median overall survival was not reached, while in KEYNOTE-013, the median overall survival was 31.4 months.

After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either trial, the researchers reported.

With respect to safety, pembrolizumab-related grade 3 or 4 adverse events were observed in 23% and 24% of patients in KEYNOTE-170 and KEYNOTE-013, respectively. The most common adverse event in both trials was neutropenia. No deaths related to pembrolizumab were observed.

Response rates were lower in KEYNOTE-170, compared with KEYNOTE-013, but the researchers noted that longer follow-up could change these results.

“Although the small numbers allow only a tentative hypothesis, they raise the question of whether PD-1 blockade in this setting might resensitize tumors to chemotherapy, as recently suggested. If this can be further validated, it could have profound implication for the management of patients with [relapsed/refractory] PMBCL,” the researchers wrote.

The study was supported by Merck Sharp & Dohme, the Harold and Virginia Lash Foundation, the Leukemia and Lymphoma Society, and the Center for Immuno-Oncology of the Dana-Farber Cancer Institute. The authors reported financial affiliations with Merck Sharp & Dohme and several other companies.

SOURCE: Armand P et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.01389.

The programmed death-ligand 1 (PD-L1) inhibitor pembrolizumab showed manageable safety and promising clinical activity in patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL), according to results from two early-phase studies.

The phase 1b KEYNOTE-013 study included an expansion cohort that evaluated pembrolizumab monotherapy in patients with relapsed/refractory PMBCL. Based on preliminary findings from KEYNOTE-013, the phase 2 KEYNOTE-170 study was initiated to validate these results.

Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute, Boston, and colleagues reported results from 53 patients in KEYNOTE-170 and extended follow-up of 21 patients in KEYNOTE-013. Data from these two trials formed the basis of an accelerated approval by the Food and Drug Administration of pembrolizumab in patients with relapsed/refractory PMBCL in June 2018.

“Frequent amplification and translocation events occur at 9p24.1 in PMBCL, resulting in tumor expression of the programmed cell death-1 (PD-1) ligands PD-L1 and PD-L2. This suggests susceptibility of PMBCL to PD-1 blockade,” the researchers wrote in the Journal of Clinical Oncology.

KEYNOTE-170 included patients with relapsed or refractory disease who were transplant-ineligible and had failed a minimum of two prior lines of treatment. KEYNOTE-013 enrolled patients who relapsed following autologous stem cell transplantation or were ineligible for transplant.

Among patients in KEYNOTE-013 and KEYNOTE-170, the objective response rates were 48% and 45%, respectively. In total, 33% of patients in KEYNOTE-013 and 13% of patients in KEYNOTE-170 achieved a complete response. Among these patients, no disease progression was observed.

The median progression-free survival in KEYNOTE-170 was 5.5 months and 10.4 months in KEYNOTE-013. In KEYNOTE-170, median overall survival was not reached, while in KEYNOTE-013, the median overall survival was 31.4 months.

After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either trial, the researchers reported.

With respect to safety, pembrolizumab-related grade 3 or 4 adverse events were observed in 23% and 24% of patients in KEYNOTE-170 and KEYNOTE-013, respectively. The most common adverse event in both trials was neutropenia. No deaths related to pembrolizumab were observed.

Response rates were lower in KEYNOTE-170, compared with KEYNOTE-013, but the researchers noted that longer follow-up could change these results.

“Although the small numbers allow only a tentative hypothesis, they raise the question of whether PD-1 blockade in this setting might resensitize tumors to chemotherapy, as recently suggested. If this can be further validated, it could have profound implication for the management of patients with [relapsed/refractory] PMBCL,” the researchers wrote.

The study was supported by Merck Sharp & Dohme, the Harold and Virginia Lash Foundation, the Leukemia and Lymphoma Society, and the Center for Immuno-Oncology of the Dana-Farber Cancer Institute. The authors reported financial affiliations with Merck Sharp & Dohme and several other companies.

SOURCE: Armand P et al. J Clin Oncol. 2019 Sep 10. doi: 10.1200/JCO.19.01389.