B Cell Lymphoma

Key clinical point: The preexistence of depression, anxiety, or both is associated with shorter survival in older patients with diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; hazard ratio [HR] 1.37; 95% CI 1.29-1.44), with those with preexisting depression vs without any mental disorder having the worst rate (23.4% vs 38.0%; HR 1.37; P < .0001).

Study details: This retrospective cohort study analyzed the data of 13,244 patients age ≥ 67 years with DLBCL from the Surveillance, Epidemiology, and End Results-Medicare (SEER) registry, of which 2094 had depression, anxiety, or both at the time of their DLBCL diagnosis.

Disclosures: This study was funded by the American Society of Hematology and others. Some authors declared participating on Data Safety Monitoring or Advisory Boards or receiving financial support, royalties or licenses, or payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from various organizations.

Source: Kuczmarski TM et al. Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: A population-based study. Lancet Haematol. 2023 (Jun 1). doi: 10.1016/S2352-3026(23)00094-7

Key clinical point: The preexistence of depression, anxiety, or both is associated with shorter survival in older patients with diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; hazard ratio [HR] 1.37; 95% CI 1.29-1.44), with those with preexisting depression vs without any mental disorder having the worst rate (23.4% vs 38.0%; HR 1.37; P < .0001).

Study details: This retrospective cohort study analyzed the data of 13,244 patients age ≥ 67 years with DLBCL from the Surveillance, Epidemiology, and End Results-Medicare (SEER) registry, of which 2094 had depression, anxiety, or both at the time of their DLBCL diagnosis.

Disclosures: This study was funded by the American Society of Hematology and others. Some authors declared participating on Data Safety Monitoring or Advisory Boards or receiving financial support, royalties or licenses, or payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from various organizations.

Source: Kuczmarski TM et al. Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: A population-based study. Lancet Haematol. 2023 (Jun 1). doi: 10.1016/S2352-3026(23)00094-7

Key clinical point: The preexistence of depression, anxiety, or both is associated with shorter survival in older patients with diffuse large B-cell lymphoma (DLBCL).

Major finding: At a median follow-up of 2.0 years, patients with depression, anxiety, or both vs without any mental disorder had significantly lower 5-year overall survival rates (27.0% vs 37.4%; hazard ratio [HR] 1.37; 95% CI 1.29-1.44), with those with preexisting depression vs without any mental disorder having the worst rate (23.4% vs 38.0%; HR 1.37; P < .0001).

Study details: This retrospective cohort study analyzed the data of 13,244 patients age ≥ 67 years with DLBCL from the Surveillance, Epidemiology, and End Results-Medicare (SEER) registry, of which 2094 had depression, anxiety, or both at the time of their DLBCL diagnosis.

Disclosures: This study was funded by the American Society of Hematology and others. Some authors declared participating on Data Safety Monitoring or Advisory Boards or receiving financial support, royalties or licenses, or payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from various organizations.

Source: Kuczmarski TM et al. Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: A population-based study. Lancet Haematol. 2023 (Jun 1). doi: 10.1016/S2352-3026(23)00094-7

Key clinical point: Compared with the current standard-of-care chemoimmunotherapy, second-line axicabtagene ciloleucel (axi-cel) significantly prolongs the overall survival of patients with early relapsed or refractory large B-cell lymphoma (LBCL).

Major finding: At a median follow-up of 47.2 months, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 months; hazard ratio 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis.

Study details: This primary overall survival analysis of the phase 3 ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed after first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179).

Disclosures: This study was funded by Kite Pharma. Some authors, including the lead author, declared serving as advisory board members, consultants, or speakers for; receiving research support, speaker fees, travel expenses, or honoraria from; or owning stock or stock options in various sources, including Kite.

Source: Westin JR et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023 (Jun 5). doi: 10.1056/NEJMoa2301665

Key clinical point: Compared with the current standard-of-care chemoimmunotherapy, second-line axicabtagene ciloleucel (axi-cel) significantly prolongs the overall survival of patients with early relapsed or refractory large B-cell lymphoma (LBCL).

Major finding: At a median follow-up of 47.2 months, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 months; hazard ratio 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis.

Study details: This primary overall survival analysis of the phase 3 ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed after first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179).

Disclosures: This study was funded by Kite Pharma. Some authors, including the lead author, declared serving as advisory board members, consultants, or speakers for; receiving research support, speaker fees, travel expenses, or honoraria from; or owning stock or stock options in various sources, including Kite.

Source: Westin JR et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023 (Jun 5). doi: 10.1056/NEJMoa2301665

Key clinical point: Compared with the current standard-of-care chemoimmunotherapy, second-line axicabtagene ciloleucel (axi-cel) significantly prolongs the overall survival of patients with early relapsed or refractory large B-cell lymphoma (LBCL).

Major finding: At a median follow-up of 47.2 months, patients receiving axi-cel vs standard care had a significantly longer median overall survival (not reached vs 31.1 months; hazard ratio 0.73; P = .03) and an absolute improvement in overall survival (8.6 percentage points at 4 years). No new treatment-related deaths were reported since the primary event-free survival analysis.

Study details: This primary overall survival analysis of the phase 3 ZUMA-7 trial included 359 adults with LBCL (refractory to or relapsed after first-line treatment) who were randomly assigned to receive axi-cel (n = 180) or standard care (n = 179).

Disclosures: This study was funded by Kite Pharma. Some authors, including the lead author, declared serving as advisory board members, consultants, or speakers for; receiving research support, speaker fees, travel expenses, or honoraria from; or owning stock or stock options in various sources, including Kite.

Source: Westin JR et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023 (Jun 5). doi: 10.1056/NEJMoa2301665

Key clinical point: Pirtobrutinib demonstrated durable efficacy and a favorable safety profile in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated relapsed or refractory mantle cell lymphoma (MCL).

Major finding: The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5-not reached) months. Grade ≥3 treatment-related adverse events were not frequent, with neutropenia (8.5%) being the most common.

Study details: This multicenter phase 1/2 BRUIN trial included 90 cBTKi pretreated patients with relapsed or refractory MCL in the primary efficacy cohort who received 25-300 mg and 200 mg pirtobrutinib once daily orally in the phases 1 and 2 of the trial, respectively.

Disclosures: This study was sponsored by Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company. Some authors reported ties with Eli Lilly and others. Seven authors declared being employees of or stockholders in Eli Lilly.

Source: Wang ML et al. Pirtobrutinib in covalent BTK-inhibitor pre-treated mantle cell lymphoma. J Clin Oncol. 2023 (May 16). doi: 10.1200/JCO.23.00562

Key clinical point: Pirtobrutinib demonstrated durable efficacy and a favorable safety profile in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated relapsed or refractory mantle cell lymphoma (MCL).

Major finding: The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5-not reached) months. Grade ≥3 treatment-related adverse events were not frequent, with neutropenia (8.5%) being the most common.

Study details: This multicenter phase 1/2 BRUIN trial included 90 cBTKi pretreated patients with relapsed or refractory MCL in the primary efficacy cohort who received 25-300 mg and 200 mg pirtobrutinib once daily orally in the phases 1 and 2 of the trial, respectively.

Disclosures: This study was sponsored by Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company. Some authors reported ties with Eli Lilly and others. Seven authors declared being employees of or stockholders in Eli Lilly.

Source: Wang ML et al. Pirtobrutinib in covalent BTK-inhibitor pre-treated mantle cell lymphoma. J Clin Oncol. 2023 (May 16). doi: 10.1200/JCO.23.00562

Key clinical point: Pirtobrutinib demonstrated durable efficacy and a favorable safety profile in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated relapsed or refractory mantle cell lymphoma (MCL).

Major finding: The overall response rate was 57.8% (95% CI 46.9%-68.1%), with the complete response rate being 20.0%. At a median follow-up of 12 months, the median duration of response was 21.6 (95% CI 7.5-not reached) months. Grade ≥3 treatment-related adverse events were not frequent, with neutropenia (8.5%) being the most common.

Study details: This multicenter phase 1/2 BRUIN trial included 90 cBTKi pretreated patients with relapsed or refractory MCL in the primary efficacy cohort who received 25-300 mg and 200 mg pirtobrutinib once daily orally in the phases 1 and 2 of the trial, respectively.

Disclosures: This study was sponsored by Loxo Oncology Inc., a wholly owned subsidiary of Eli Lilly and Company. Some authors reported ties with Eli Lilly and others. Seven authors declared being employees of or stockholders in Eli Lilly.

Source: Wang ML et al. Pirtobrutinib in covalent BTK-inhibitor pre-treated mantle cell lymphoma. J Clin Oncol. 2023 (May 16). doi: 10.1200/JCO.23.00562

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.

Patients with chronic lymphocytic leukemia (CLL) – even those who have multiple comorbidities – experience long-term progression-free survival (PFS) benefits with 1 year of venetoclax plus obinutuzumab versus a chemotherapy-based regimen, a 6-year follow-up analysis from CLL14 showed. The research was presented June 9 at the annual meeting of the European Hematology Association.

Initial results from the trial were shown at the EHA 2019 annual meeting and reported at the time by this news organization.

They revealed that, among more than 430 CLL patients with a median age of over 70 years and multiple comorbidities, the combination of venetoclax, a B-cell lymphoma 2 protein blocker, plus obinutuzumab, an anti-CD20 monoclonal antibody, was associated with a 65% improvement in PFS, compared with chlorambucil, a chemotherapy agent, plus obinutuzumab.

On the strength of these findings, the venetoclax-obinutuzumab combination received Food and Drug Administration approval for previously untreated CLL and small lymphocytic lymphoma in March 2019.

The latest analysis, presented by Othman Al-Sawaf, MD, University Hospital of Cologne (Germany), showed that despite having just 12 cycles of treatment, patients treated with venetoclax-obinutuzumab continued to experience a significant PFS benefit over those given the chemotherapy-based regimen, including in high-risk patients, after more than 6 years of follow-up.

Dr. Al-Sawaf noted that more than 50% of patients given the experimental combination remained without a PFS event at the latest follow-up, and that over 60% had not required a second treatment, equating to a 66% reduction in the likelihood of needing a second treatment versus chlorambucil-obinutuzumab.

Dr. Al-Sawaf said at a press conference that, “clinically, the standard of care for any CLL if it is asymptomatic” is watch and wait, which is “true in the frontline setting, but also in the relapse setting.”

Therefore, these patients “do not need to initiate the next line of treatment, and that’s why time to next treatment is so interesting.”

He added that there also were no new safety signals, with adverse event rates dropping markedly once treatment was over, although there was a suggestion of an increase in second malignancies with venetoclax-obinutuzumab.

“We’ve seen, in many studies now that use fixed-duration approaches, that there is virtually no posttreatment toxicity once patients are able to get off treatment,” Dr. Al-Sawaf said, adding: “This really highlights the benefit” of stopping treatment, “which is a clear advantage compared to having any kind of continuous treatment.”

Approached for comment, William G. Wierda, MD, PhD, professor, department of leukemia, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, emphasized the value of the 6-year follow-up of the study, adding that these are “very impressive data.”

He told this news organization that, in terms of the ongoing PFS improvement, “we wouldn’t expect anything otherwise” with venetoclax-obinutuzumab when compared with the chemotherapy-based regimen, but that the trend for an improvement in overall survival is of particular interest.

This “is a notable feature of the update,” Dr. Wierda said, and “we will continue to watch the long-term overall survival curves with a longer follow-up,” especially as the separation of the curves between the two regimens is “more prominent” than in previous analyses of CLL14.

He also pointed to the low incidence of grade ≥ 3 adverse events in patients who are in remission, which “support the use of fixed-duration chemo-free” treatments, and the longer follow-up now allowing the contribution of high-risk features to outcomes to be teased out in multivariate analysis.

“The data that we’re looking for in the next update of this is some indication about improved outcomes between patients with a mutated and unmutated immunoglobulin heavy chain gene [IgHV], in regard to undetectable MRD [minimal residual disease] status,” Dr. Wierda said.

“We know that mutational status correlates with progression free survival,” he explained. “What we would like to see moving forward is how that is associated with undetectable MRD status at the end of treatment.”

Dr. Wierda said that the next hotly anticipated trial in the field is CLL17, which is comparing ibrutinib monotherapy to fixed-duration venetoclax-obinutuzumab to fixed-duration ibrutinib-venetoclax in patients with previously untreated CLL.

“That’s the next question: Is there any advantage of a BTK [Bruton’s tyrosine kinase] inhibitor with venetoclax over venetoclax plus the CD20 antibody?”

Dr. Al-Sawaf, in presenting the latest analysis, reminded the audience that CLL14 was a randomized phase 3 study focusing on patients with previously untreated CLL and coexisting conditions who were randomized to either venetoclax-obinutuzumab for six cycles, followed by six cycles of venetoclax, or chlorambucil-obinutuzumab for six cycles, followed by chlorambucil for six cycles.

The patients, who were enrolled between 2015 and 2016, were required to have a Cumulative Illness Rating Scale (CIRS) score > 6 and/or creatinine clearance < 70 mL/min, which Dr. Al-Sawaf explained serves as “indicator of the unfitness of the patients.”

A total of 432 patients took part in the study. The median age across the two treatment groups was 71-72 years, and the median total CIRS score was 8-9. The majority of patients (79%-80%) had Binet stage B or C CLL. An intermediate tumor lysis syndrome risk was identified in 64%-68%.

“We also had a fair share of patients with high-risk disease,” Dr. Al-Sawaf noted, with approximately 60% having an unmutated IGHV status, and 12% having a TP53 mutation, both of which are associated with a poorer prognosis.

He added that the “aim of these long-term observations that we try to do every year is not so much to do the comparisons to chlorambucil-obinutuzumab, which we appreciate is not necessarily a standard of care anymore,” but rather to understand the safety and effectiveness of venetoclax-obinutuzumab “in the long run, given that all patients are off treatment.”

Beginning with the safety data, Dr. Al-Sawaf showed that rates of grade ≥ 3 adverse events plummeted after the treatment period, with rates of neutropenia falling from 51.9% with venetoclax-obinutuzumab and 47.2% with chlorambucil-obinutuzumab during treatment to 3.8% and 1.9%, respectively, post treatment.

Similarly, rates of thrombocytopenia decreased from 14.2% on treatment to 0.5% off treatment in patients given venetoclax-obinutuzumab, and from 15.0% to 0.0% in the chlorambucil-obinutuzumab group.

One note of caution was sounded over the proportion of patients with at least one second primary malignancy following treatment, which was numerically higher with venetoclax-obinutuzumab, at 14.2% versus 8.4% with the chemotherapy-based regimen.

“But this is a rather a heterogeneous pattern of solid organ tumors and melanoma,” Dr. Al-Sawaf said, referring to the additional malignancies in the venetoclax-obinutuzumab arm. These included lung cancer, prostate cancer and breast cancer.

He said, however, there was no “specific pattern that we can really pinpoint ... and, importantly, the difference is not statistically significant.”

Turning to the efficacy outcomes, Dr. Al-Sawaf showed that, after median follow-up of 76.4 months, the separation in PFS between the two treatment arms continued, with the median PFS 76.2 months with venetoclax-obinutuzumab versus 36.4 months with chlorambucil-obinutuzumab, at a hazard ratio 0.40 (P < .0001).

The 6-year PFS rate in patients treated with venetoclax-obinutuzumab was 53.1% versus 21.7% with the chemotherapy-based regimen. Looking at the high-risk groups, Dr. Al-Sawaf reported that there was a similar pattern of benefit with venetoclax-obinutuzumab.

Among patients with a TP53 mutation, the median PFS was 51.9 months with the combination versus 20.8 months in those given chlorambucil-obinutuzumab, while the corresponding durations in patients with unmutated IGHV were 64.8 months and 26.9 months, respectively.

Multivariate analysis demonstrated that IGHV status was an independent predictor of PFS in patients treated with venetoclax-obinutuzumab, as was the presence of a TP53 mutation, and lymph node size ≥ 5 cm.

There was no significant difference in overall survival between the two treatment groups, although there was a numerical difference in 6-year overall survival rates, at 78.7% with the experimental combination versus 69.2% with chlorambucil-obinutuzumab.

Patients with a minimal residual disease (MRD) count ≥ 10-4 had a shorter overall survival than did those with MRD < 10-4.

“We are currently working up to understand which group of patients experiences these tremendous long term remissions,” Dr. Al-Sawaf said, “and we will keep you posted on this.”

He also showed that the time to next treatment (TTNT), defined as time to death or next anti-leukemic treatment, was significantly longer with venetoclax-obinutuzumab, with the median not reached before the current data lock versus 52.9 months with the chemotherapy-based regimen.

This equated to a hazard ratio in favor of the experimental combination of 0.44 (P < .0001), and a 6-year TTNT rate of 65.2% versus 37.1% for chlorambucil-obinutuzumab.

That second treatment was a Bruton’s tyrosine kinase inhibitor in 59.0% of cases in the venetoclax-obinutuzumab arm and 53.4% in the chlorambucil-obinutuzumab group.

Dr. Al-Sawaf noted, however, that 23.1% and 30.1%, respectively, of patients were given a chemotherapy or chemo-immunotherapy regimen, “which we nowadays would not necessarily consider a standard of care.”

“This ultimately reflects, as in many global clinical studies, the disparities that we still have across the world in terms of access to state-of-the-art therapies.”

The study was sponsored by Hoffmann–La Roche, and conducted in collaboration with AbbVie, and the German CLL Study Group. Dr. Al-Sawaf disclosed relationships with AbbVie, Adaptive, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, and Roche.

The Food and Drug Administration has granted accelerated approval for glofitamab (Columvi) for use in certain types of lymphoma.

The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.

The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.

These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.

Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.

“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.

Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
 

Most common form of non-Hodgkin’s lymphoma

DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.

“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”

The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.

Glofitamab was given to all patients as a fixed course for 8.5 months.

More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.

The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).

Results from the NP30179 trial were published in December 2022.

The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”

The Food and Drug Administration has granted accelerated approval for glofitamab (Columvi) for use in certain types of lymphoma.

The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.

The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.

These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.

Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.

“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.

Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
 

Most common form of non-Hodgkin’s lymphoma

DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.

“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”

The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.

Glofitamab was given to all patients as a fixed course for 8.5 months.

More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.

The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).

Results from the NP30179 trial were published in December 2022.

The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”

The Food and Drug Administration has granted accelerated approval for glofitamab (Columvi) for use in certain types of lymphoma.

The indication is for use in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified or with LBCL arising from follicular lymphoma who have received two or more lines of systemic therapy.

The product is a T cell–engaging bispecific antibody developed by Genentech, which has a similar product, mosunetuzumab-axgb (Lunsumio), for the treatment of follicular lymphoma. Lunsumio was approved in December 2022.

These drugs could be considered a first choice in the setting of third-line therapy, suggests an expert writing recently in The New England Journal of Medicine.

Nancy Bartlett, MD, from the Siteman Cancer Center, Washington University in St. Louis, is the author of an editorial that accompanied the publication of results with glofitamab in the pivotal trial that led to its approval.

“Bispecific agents will be an excellent option for the 60% of patients in whom second-line CAR [chimeric antigen receptor] T-cell therapy fails,” she wrote in her editorial.

Dr. Bartlett suggests that these agents may be preferred over CAR T cells. “If longer follow-up confirms that the majority of complete remissions with bispecific agents are durable, on the basis of the advantages of availability (including in the community setting) and more favorable immediate and late toxic-effect profiles, bispecific agents could be considered as the initial choice. ... CAR T-cell therapy could be held in reserve for patients who do not have a complete response or who have a relapse after a complete response.”
 

Most common form of non-Hodgkin’s lymphoma

DLBCL is the most common form of non-Hodgkin’s lymphoma in the United States, the company noted in a press release. While many people with DLBCL are responsive to treatment, the majority of those who experience relapse or whose condition is refractory to subsequent treatments have poor outcomes.

“Patients with relapsed or refractory diffuse large B-cell lymphoma may experience rapid progression of their cancer and often urgently need an effective treatment option that can be administered without delay,” commented Krish Patel, MD, director of the lymphoma program at the Swedish Cancer Institute in Seattle, who is an investigator on the clinical trial that led to the product’s approval. He said that the results from trials suggest that glofitamab gives patients “a chance for complete remission with a fixed-duration immunotherapy and that such remissions can potentially be sustained after the end of their treatment.”

The accelerated approval is based on response rate and durability of response results from the phase 1/2 NP30179 study.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

This trial involved 132 patients with DLBCL who experienced relapse or whose condition was refractory to prior therapies. About one-third of patients (30%) had received prior CAR T-cell therapy. Additionally, for 83% of patients, the condition was refractory to their most recent therapy.

Glofitamab was given to all patients as a fixed course for 8.5 months.

More than half (56%) achieved an overall response, and 43% achieved a complete response. Over two-thirds (68.5%) of those who responded continued to respond for at least 9 months The median duration of response was 1.5 years.

The most common adverse events were cytokine release syndrome (CRS; 70%), which may be serious or life-threatening; musculoskeletal pain (21%); fatigue (20%); and rash (20%). CRS was generally of low grade (52% of patients experienced grade 1 CRS, and 14% experienced grade 2).

Results from the NP30179 trial were published in December 2022.

The complete response rates seen with glofitamab rivals the durable complete response that has been observed with CAR T-cell therapy, Dr. Bartlett noted in the accompanying editorial. “Although these results are promising, it is still too early to estimate the curative potential of glofitamab.”

At a median follow-up of 47.2 months, axicabtagene ciloleucel (axi-cel, Yescarta) significantly improved overall survival compared with standard second-line treatments in patients with early relapsed or refractory large B-cell lymphoma, according to a phase 3 investigation reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.

The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.

Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.

“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.

The study was published in the New England Journal of Medicine to coincide with the presentations.

Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).


 

Study details

Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.

Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.

Significantly, the better PFS appears to have translated into better overall survival (OS).

At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).

The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.

Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.

Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.

The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.

At a median follow-up of 47.2 months, axicabtagene ciloleucel (axi-cel, Yescarta) significantly improved overall survival compared with standard second-line treatments in patients with early relapsed or refractory large B-cell lymphoma, according to a phase 3 investigation reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.

The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.

Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.

“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.

The study was published in the New England Journal of Medicine to coincide with the presentations.

Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).


 

Study details

Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.

Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.

Significantly, the better PFS appears to have translated into better overall survival (OS).

At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).

The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.

Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.

Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.

The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.

At a median follow-up of 47.2 months, axicabtagene ciloleucel (axi-cel, Yescarta) significantly improved overall survival compared with standard second-line treatments in patients with early relapsed or refractory large B-cell lymphoma, according to a phase 3 investigation reported at the annual meeting of the American Society of Clinical Oncology (ASCO).

The anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy was approved for second-line treatment in 2022 based on better event-free survival, but standard second-line treatment – chemoimmunotherapy followed by high-dose chemotherapy and autologous stem-cell transplant in responders – still remains the prevailing approach, explained Jason Westin, MD, director of lymphoma research at MD Anderson Cancer Center, Houston. Dr. Westin, lead investigator, presented the trial, dubbed ZUMA-7, at the ASCO meeting.

The new findings might change that. ZUMA-7 “conclusively demonstrates that trying chemotherapy in the second line and saving cell therapy for the third line is an inferior approach ... ZUMA-7 confirms axi-cel is a second-line standard of care for patients with refractory or early relapsed large B cell lymphoma based on superior overall survival,” said Dr. Westin.

Study discussant Asher A. Chanan-Khan, MD, a CAR-T specialist at the Mayo Clinic in Jacksonville, Fla., agreed.

“This data must alter the current standard of care making CAR-T or axi-cel, based on the data we heard, a preferred second-line treatment ... Moving CAR-T earlier in the treatment paradigm is likely a better choice for our patients,” he said.

The study was published in the New England Journal of Medicine to coincide with the presentations.

Dr. Westin noted that axi-cel is now under investigation in ZUMA-23 for first-line treatment of high-risk large B-cell lymphoma (LBCL).


 

Study details

Zuma-7 randomized 180 LBCL patients to a one-time axi-cel infusion and 179 to standard care. Patients were refractory to first line chemoimmunotherapy or had relapsed within 12 months; just 36% of patients in the standard care group did well enough on treatment to go on to stem-cell transplant.

Median progression-free survival (PFS) was 14.7 months with axi-cel versus 3.7 months with standard care.

Significantly, the better PFS appears to have translated into better overall survival (OS).

At a median of almost 4 years, 82 patients in the axi-cel group had died, compared with 95 patients with standard care who had died. Estimated 4-year OS was 54.6% with axi-cel versus 46% with standard care (HR 0.73, P = .03).

The OS benefit held in high-risk subgroups, including patients over 64 years old, those refractory to first-line treatment, and patients with high-grade disease.

Adverse events were in keeping with labeling. Cytokine release syndrome was more common in the axi-cel arm, including grade 3 or worse CRS in 6% of axi-cel patients versus none on standard care. Grade 3 or worse infections were also more common at 16.5% versus 11.9% with standard care. Over 11% of axi-cel patients developed hypogammaglobulinemia versus 0.6% in the standard care group.

Overall, there were no new serious or fatal adverse events since the initial PFS results were reported in 2022, when eight fatal adverse events were reported with axi-cel versus two with standard care.

The work was funded by axi-cel maker Kite Pharma, a subsidiary of Gilead. Investigators included Kite/Gilead employees and others who reported financial relationships with the companies, including Dr. Westin, a Kite/Gilead researcher and adviser. Dr. Chanan-Khan disclosed ties with Cellectar, Starton Therapeutics, Ascentage Pharma, and others.

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel, Bristol-Myers Squibb), showed efficacy in achieving complete responses among patients with relapsed or refractory chronic lymphocytic leukemia (r/r CLL) or small lymphocytic lymphoma (SLL), after treatment with a Bruton kinase inhibitor (BTKi) and BCL2 inhibitor.

The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.

“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.

Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.

“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.

With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.

In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.

The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 10⁶ CAR-positive viable T cells of liso-cel.

With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).

Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.

The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.

The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).

The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.

The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.

In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.

Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.

Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.

For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.

Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.

One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.

“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.

She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.

“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.

For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”

Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.

“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
 

Largest data set to date

Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.

“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.

“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”

Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.

Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.

In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”

Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.

“The results of this study are very exciting,” she said during her discussion in the session.

“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”

Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”

The results were also published in The Lancet.

The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.

For patients with primary mediastinal B-cell lymphoma (PMBCL) who achieved a complete metabolic response after immunochemotherapy, radiation therapy may be safely omitted without heightening their risks of relapse or disease progression – thereby sparing them the toxicity and costs of this additional treatment.

“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).

The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.

While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.

However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.

In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.

Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.

With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.

The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.

Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.

With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).

After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.

The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.

“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.

Overall survival after 3 years was excellent and identical in both arms, at about 99%.

To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.

Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.

“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.

“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”

Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.

“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.

In further comments, he added that “these results will inform and likely change clinical practice.”

Dr. Speers said the study is notable for being the first of its kind.

“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.

“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.

“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.

The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.

“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”

Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.

“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.

The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.

For patients with primary mediastinal B-cell lymphoma (PMBCL) who achieved a complete metabolic response after immunochemotherapy, radiation therapy may be safely omitted without heightening their risks of relapse or disease progression – thereby sparing them the toxicity and costs of this additional treatment.

“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).

The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.

While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.

However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.

In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.

Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.

With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.

The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.

Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.

With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).

After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.

The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.

“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.

Overall survival after 3 years was excellent and identical in both arms, at about 99%.

To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.

Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.

“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.

“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”

Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.

“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.

In further comments, he added that “these results will inform and likely change clinical practice.”

Dr. Speers said the study is notable for being the first of its kind.

“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.

“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.

“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.

The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.

“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”

Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.

“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.

The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.

For patients with primary mediastinal B-cell lymphoma (PMBCL) who achieved a complete metabolic response after immunochemotherapy, radiation therapy may be safely omitted without heightening their risks of relapse or disease progression – thereby sparing them the toxicity and costs of this additional treatment.

“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).

The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.

While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.

However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.

In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.

Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.

With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.

The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.

Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.

With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).

After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.

The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.

“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.

Overall survival after 3 years was excellent and identical in both arms, at about 99%.

To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.

Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.

“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.

“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”

Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.

“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.

In further comments, he added that “these results will inform and likely change clinical practice.”

Dr. Speers said the study is notable for being the first of its kind.

“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.

“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.

“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.

The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.

“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”

Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.

“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.

The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.

Novel therapies have transformed the management of chronic lymphocytic leukemia (CLL) over the past decade. With the advent of new options, the optimal therapy for newly diagnosed patients has become less clear. Bruton tyrosine kinase (BTK) inhibitors have led to improvement in outcomes for most patients with CLL compared with chemoimmunotherapy (CIT).^1,2 Second-generation BTK inhibitors, such as acalabrutinib and zanubrutinib, are also available and appear to have an improved safety profile compared with ibrutinib. Similarly, the B-cell lymphoma 2 (BCL2) inhibitor venetoclax, in combination with obinutuzumab, is an effective option in first-line treatment that offers a time-limited approach.³ Studies combining BTK and BCL2 inhibitors are also promising in this setting.

Recently, the phase 3 GAIA-CLL13 study aimed to address the question of optimal time-limited first-line treatment for fit patients with CLL. Of note, patients with TP53 aberrations were excluded. Patients were randomly assigned to one of four treatment arms: CIT (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-obinutuzumab, venetoclax-rituximab, or venetoclax-obinutuzumab-ibrutinub.

At 15 months, the rate of undetectable minimal residual disease (uMRD) was higher in the venetoclax-obinutuzumab group (86.5%; 97.5% CI 80.6-91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI 87.3-95.7) compared with the CIT group (52.0%; 97.5% CI 44.4-59.5; P < .001 for both comparisons). The rate of uMRD for the venetoclax-rituximab group, however, was not higher than the rate in the CIT group (57.0%; 97.5%, CI 49.5-64.2; P = .32). The 3-year progression-free survival (PFS) was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the CIT group (hazard ratio [HR] for disease progression or death 0.32; 97.5% CI 0.19-0.54; P < .001). PFS at 3 years was also higher in the venetoclax-obinutuzumab group (87.7%; HR for disease progression or death, 0.42; 97.5% CI 0.26-0.68; P < .001), but not with venetoclax-rituximab group (80.8%; HR 0.79; 97.5% CI 0.53-1.18; P = .18). Grade 3 and grade 4 infections were more common with CIT (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).

This study confirms the role of fixed-duration venetoclax-based therapy for younger, fit patients with CLL. Interestingly, this study also suggests that rates of uMRD and PFS are superior with the use of obinutuzumab rather than with rituximab. Also of note, though the uMRD and PFS were highest with the triplet combination, it was not clearly superior to venetoclax-obinutuzumab alone and was associated with greater rates of toxicity.

Another ongoing randomized trial in first-line treatment of CLL is the FLAIR trial. This study was initially designed to compare ibrutinib-rituximab with standard CIT, though it was later modified to include an arm of ibrutinib alone and ibrutinib-venetoclax. Recently, the results of the first formal interim analysis comparing fludarabine, cyclophosphamide, and rituximab (n = 385) to ibrutinib-rituximb (n = 386), were published. This study, like the ECOG1912 study², demonstrated improved outcomes with a BTK inhibitor over standard CIT in fit patients with CLL. After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib-rituximab and was 67 months (95% CI 63 to not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (HR 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib-rituximab group.

Though questions regarding optimal treatment remain, there are now multiple studies to suggest an advantage of novel agents over traditional CIT. Furthermore, regardless of approach, outcomes appear favorable for patients with CLL, even among higher-risk patients.

Other studies are also evaluating alternative ways to sequence therapy. A recent phase 2 study, for example, evaluated venetoclax consolidation for patients on ibrutinib. Forty-five patients with CLL and detectable disease (≥ 0.01% minimal residual disease in bone marrow [BM]) after treatment with ibrutinib for 12 or more months who had one or more high-risk feature for disease progression were included. Patients received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for 24 or less cycles. Venetoclax was continued until patients achieved uMRD. Patients with uMRD also had the option of discontinuing ibrutinib. Adding venetoclax to ibrutinib led to a cumulative BM uMRD rate of 73%. BM uMRD was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively. This trial highlights the potential use of MRD to guide treatment as well as consolidation strategies to allow for time-limited treatment.

Additional References

1. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528. doi: 10.1056/NEJMoa1812836
2. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073
3. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi: 10.1056/NEJMoa1815281

Novel therapies have transformed the management of chronic lymphocytic leukemia (CLL) over the past decade. With the advent of new options, the optimal therapy for newly diagnosed patients has become less clear. Bruton tyrosine kinase (BTK) inhibitors have led to improvement in outcomes for most patients with CLL compared with chemoimmunotherapy (CIT).^1,2 Second-generation BTK inhibitors, such as acalabrutinib and zanubrutinib, are also available and appear to have an improved safety profile compared with ibrutinib. Similarly, the B-cell lymphoma 2 (BCL2) inhibitor venetoclax, in combination with obinutuzumab, is an effective option in first-line treatment that offers a time-limited approach.³ Studies combining BTK and BCL2 inhibitors are also promising in this setting.

Recently, the phase 3 GAIA-CLL13 study aimed to address the question of optimal time-limited first-line treatment for fit patients with CLL. Of note, patients with TP53 aberrations were excluded. Patients were randomly assigned to one of four treatment arms: CIT (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-obinutuzumab, venetoclax-rituximab, or venetoclax-obinutuzumab-ibrutinub.

At 15 months, the rate of undetectable minimal residual disease (uMRD) was higher in the venetoclax-obinutuzumab group (86.5%; 97.5% CI 80.6-91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI 87.3-95.7) compared with the CIT group (52.0%; 97.5% CI 44.4-59.5; P < .001 for both comparisons). The rate of uMRD for the venetoclax-rituximab group, however, was not higher than the rate in the CIT group (57.0%; 97.5%, CI 49.5-64.2; P = .32). The 3-year progression-free survival (PFS) was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the CIT group (hazard ratio [HR] for disease progression or death 0.32; 97.5% CI 0.19-0.54; P < .001). PFS at 3 years was also higher in the venetoclax-obinutuzumab group (87.7%; HR for disease progression or death, 0.42; 97.5% CI 0.26-0.68; P < .001), but not with venetoclax-rituximab group (80.8%; HR 0.79; 97.5% CI 0.53-1.18; P = .18). Grade 3 and grade 4 infections were more common with CIT (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).

This study confirms the role of fixed-duration venetoclax-based therapy for younger, fit patients with CLL. Interestingly, this study also suggests that rates of uMRD and PFS are superior with the use of obinutuzumab rather than with rituximab. Also of note, though the uMRD and PFS were highest with the triplet combination, it was not clearly superior to venetoclax-obinutuzumab alone and was associated with greater rates of toxicity.

Another ongoing randomized trial in first-line treatment of CLL is the FLAIR trial. This study was initially designed to compare ibrutinib-rituximab with standard CIT, though it was later modified to include an arm of ibrutinib alone and ibrutinib-venetoclax. Recently, the results of the first formal interim analysis comparing fludarabine, cyclophosphamide, and rituximab (n = 385) to ibrutinib-rituximb (n = 386), were published. This study, like the ECOG1912 study², demonstrated improved outcomes with a BTK inhibitor over standard CIT in fit patients with CLL. After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib-rituximab and was 67 months (95% CI 63 to not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (HR 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib-rituximab group.

Though questions regarding optimal treatment remain, there are now multiple studies to suggest an advantage of novel agents over traditional CIT. Furthermore, regardless of approach, outcomes appear favorable for patients with CLL, even among higher-risk patients.

Other studies are also evaluating alternative ways to sequence therapy. A recent phase 2 study, for example, evaluated venetoclax consolidation for patients on ibrutinib. Forty-five patients with CLL and detectable disease (≥ 0.01% minimal residual disease in bone marrow [BM]) after treatment with ibrutinib for 12 or more months who had one or more high-risk feature for disease progression were included. Patients received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for 24 or less cycles. Venetoclax was continued until patients achieved uMRD. Patients with uMRD also had the option of discontinuing ibrutinib. Adding venetoclax to ibrutinib led to a cumulative BM uMRD rate of 73%. BM uMRD was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively. This trial highlights the potential use of MRD to guide treatment as well as consolidation strategies to allow for time-limited treatment.

Additional References

1. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528. doi: 10.1056/NEJMoa1812836
2. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073
3. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi: 10.1056/NEJMoa1815281

Novel therapies have transformed the management of chronic lymphocytic leukemia (CLL) over the past decade. With the advent of new options, the optimal therapy for newly diagnosed patients has become less clear. Bruton tyrosine kinase (BTK) inhibitors have led to improvement in outcomes for most patients with CLL compared with chemoimmunotherapy (CIT).^1,2 Second-generation BTK inhibitors, such as acalabrutinib and zanubrutinib, are also available and appear to have an improved safety profile compared with ibrutinib. Similarly, the B-cell lymphoma 2 (BCL2) inhibitor venetoclax, in combination with obinutuzumab, is an effective option in first-line treatment that offers a time-limited approach.³ Studies combining BTK and BCL2 inhibitors are also promising in this setting.

Recently, the phase 3 GAIA-CLL13 study aimed to address the question of optimal time-limited first-line treatment for fit patients with CLL. Of note, patients with TP53 aberrations were excluded. Patients were randomly assigned to one of four treatment arms: CIT (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-obinutuzumab, venetoclax-rituximab, or venetoclax-obinutuzumab-ibrutinub.

At 15 months, the rate of undetectable minimal residual disease (uMRD) was higher in the venetoclax-obinutuzumab group (86.5%; 97.5% CI 80.6-91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI 87.3-95.7) compared with the CIT group (52.0%; 97.5% CI 44.4-59.5; P < .001 for both comparisons). The rate of uMRD for the venetoclax-rituximab group, however, was not higher than the rate in the CIT group (57.0%; 97.5%, CI 49.5-64.2; P = .32). The 3-year progression-free survival (PFS) was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the CIT group (hazard ratio [HR] for disease progression or death 0.32; 97.5% CI 0.19-0.54; P < .001). PFS at 3 years was also higher in the venetoclax-obinutuzumab group (87.7%; HR for disease progression or death, 0.42; 97.5% CI 0.26-0.68; P < .001), but not with venetoclax-rituximab group (80.8%; HR 0.79; 97.5% CI 0.53-1.18; P = .18). Grade 3 and grade 4 infections were more common with CIT (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).

This study confirms the role of fixed-duration venetoclax-based therapy for younger, fit patients with CLL. Interestingly, this study also suggests that rates of uMRD and PFS are superior with the use of obinutuzumab rather than with rituximab. Also of note, though the uMRD and PFS were highest with the triplet combination, it was not clearly superior to venetoclax-obinutuzumab alone and was associated with greater rates of toxicity.

Another ongoing randomized trial in first-line treatment of CLL is the FLAIR trial. This study was initially designed to compare ibrutinib-rituximab with standard CIT, though it was later modified to include an arm of ibrutinib alone and ibrutinib-venetoclax. Recently, the results of the first formal interim analysis comparing fludarabine, cyclophosphamide, and rituximab (n = 385) to ibrutinib-rituximb (n = 386), were published. This study, like the ECOG1912 study², demonstrated improved outcomes with a BTK inhibitor over standard CIT in fit patients with CLL. After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib-rituximab and was 67 months (95% CI 63 to not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (HR 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib-rituximab group.

Though questions regarding optimal treatment remain, there are now multiple studies to suggest an advantage of novel agents over traditional CIT. Furthermore, regardless of approach, outcomes appear favorable for patients with CLL, even among higher-risk patients.

Other studies are also evaluating alternative ways to sequence therapy. A recent phase 2 study, for example, evaluated venetoclax consolidation for patients on ibrutinib. Forty-five patients with CLL and detectable disease (≥ 0.01% minimal residual disease in bone marrow [BM]) after treatment with ibrutinib for 12 or more months who had one or more high-risk feature for disease progression were included. Patients received combined treatment with ibrutinib (previously tolerated dose) and venetoclax (escalated to 400 mg once daily) for 24 or less cycles. Venetoclax was continued until patients achieved uMRD. Patients with uMRD also had the option of discontinuing ibrutinib. Adding venetoclax to ibrutinib led to a cumulative BM uMRD rate of 73%. BM uMRD was achieved by 71% of patients after venetoclax therapy completion and by 38% and 57% of patients after 6 and 12 cycles, respectively. This trial highlights the potential use of MRD to guide treatment as well as consolidation strategies to allow for time-limited treatment.

Additional References

1. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528. doi: 10.1056/NEJMoa1812836
2. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073
3. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi: 10.1056/NEJMoa1815281