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Venetoclax/rituximab boosts PFS in relapsed/refractory CLL
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
REPORTING FROM ASH 2017
Key clinical point: Compared with bendamustine/rituximab, venetoclax/rituximab was associated with significantly superior progression-free survival of relapsed/refractory chronic lymphocytic leukemia.
Major finding: The hazard ratio for PFS with venetoclax/rituximab was 0.17 (P less than .001).
Data source: A randomized phase 3, open-label trial in 389 patients with relapsed/refractory CLL.
Disclosures: The MURANO trial was funded by AbbVie and Genetech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
Source: Seymour J et al. ASH 2017 LBA-2.
VIDEO: Venetoclax/rituximab prolongs PFS in relapsed/refractory CLL
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
REPORTING FROM ASH 2017
CLL drug combinations induce MRD negativity
Atlanta – The potential of two- and three-drug combinations to induce deep, minimal residual disease (MRD)–negative responses in patients with chronic lymphocytic leukemia (CLL) was demonstrated in multiple studies presented at the annual meeting of the American Society of Hematology.
Previous studies have suggested that, in contrast to single-agent kinase inhibitor treatment, combinations of treatments, namely kinase or B-cell lyphoma 2 inhibitors combined with anti-CD20 antibodies, can induce MRD negativity at a high rate. For example, in a report on the CLL14 trial, 11 of 12 previously untreated patients were MRD negative after treatment with the BCL-2 inhibitor venetoclax and anti-CD20 antibody obinutuzumab (Blood. 2017;129:2702-5. doi:10.1182/blood-2017-01-761973).
This new batch of studies presented at ASH 2017 provided additional evidence for the venetoclax and obinutuzumab combination, as well as other combinations that appear to provide favorable rates of MRD-negative CLL, including obinutuzumab and venetoclax plus ibrutinib and, notably, a combination that included venetoclax and ibrutinib but no anti-CD20 antibody.
A phase II trial presented by Nitin Jain, MD, of MD Anderson Cancer Center, Houston, looked at the combination of venetoclax and ibrutinib for patients with previously untreated high-risk CLL or relapsed/refractory CLL. The regimen under evaluation starts with daily ibrutinib monotherapy for 3 months before venetoclax is added.
For the first line cohort of 36 patients, the bone marrow MRD-negativity proportion was 0% after 3 months of ibrutinib and 21% after 3 months of ibrutinib plus venetoclax, then 45%, 80%, and 100%, respectively, after 6, 9, and 12 months of combination therapy, Dr. Jain reported. In the relapsed/refractory cohort, MRD negativity was 8% after 3 months of combination therapy and 40% after 12 months. “Responses continue to improve with time, with many patients achieving bone marrow MRD-negative remission,” Dr. Jain said.
The study showed “very impressive MRD rates,” commented Ian W. Flinn, MD, of Sarah Cannon Research Institute, Nashville, Tenn. “I think it’s still up for further discussion and research to find which is the best combination.”
Dr. Flinn presented results from a phase Ib GP28331 study of venetoclax and obinutuzumab in patients with previously untreated CLL in which MRD was assessed in peripheral blood and bone marrow.
All 32 patients achieved peripheral blood negativity at some point on study, Dr. Flinn said, and 75% achieved bone marrow negativity. The complete response rate was 72% (23/32), but notably, high rates of undetectable bone marrow MRD were seen irrespective of response status, Dr. Flinn said.
All patients had at least one adverse event, with grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia reported most commonly.
Preliminary progression-free survival data (PFS) suggested “durable clinical outcomes” for the combination, with an estimated 18-month PFS of 90.5%, he said.
A third study assessed the combination of obinutuzumab, ibrutinib, and venetoclax, finding that the combination induced MRD negativity in 14 of 24 (58%) treatment-naive CLL patients, according to Kerry A. Rogers, MD, of Ohio State University, Columbus.
The combination had a 96% response rate and is “extremely effective at eliminating detectable CLL,” Dr. Rogers noted.
Most adverse events were hematologic, and high-grade adverse events were rare, she said.
Results for the study’s primary endpoint, rate of MRD-negative complete remission, are expected by May 2018, Dr. Rogers said, adding that further follow-up will be needed to determine PFS for the combination.
Session attendees asked presenters whether they felt there was scientific justification for inclusion of the anti-CD20 antibody rituximab in future trials designed in part to assess MRD negativity.
“I think that obinutuzumab has greater efficacy in patients with CLL, compared to rituximab, and so our hypothesis is that it is a superior antibody to combine with venetoclax,” Dr. Flinn said.
AbbVie provided funding for the study on venetoclax and ibrutinib. Dr. Jain reported disclosures from venetoclax makers AbbVie and Genentech, ibrutinib makers Janssen and Pharmacyclics, and others.
Genentech and AbbVie provided support for the study on venetoclax and obinutuzumab. Dr. Flinn reported disclosures related to both companies and others.
Dr. Rogers reported no conflicts related to the study on obinutuzumab, ibrutinib, and venetoclax. One of her associates reported disclosures related to ibrutinib makers Novartis and Pharmacylics, among others.
SOURCE: Jain N et al. ASH 2017 Abstract 429; Flinn I et al. ASH 2017 Abstract 430; Rogers K et al. ASH 2017 Abstract 431.
Atlanta – The potential of two- and three-drug combinations to induce deep, minimal residual disease (MRD)–negative responses in patients with chronic lymphocytic leukemia (CLL) was demonstrated in multiple studies presented at the annual meeting of the American Society of Hematology.
Previous studies have suggested that, in contrast to single-agent kinase inhibitor treatment, combinations of treatments, namely kinase or B-cell lyphoma 2 inhibitors combined with anti-CD20 antibodies, can induce MRD negativity at a high rate. For example, in a report on the CLL14 trial, 11 of 12 previously untreated patients were MRD negative after treatment with the BCL-2 inhibitor venetoclax and anti-CD20 antibody obinutuzumab (Blood. 2017;129:2702-5. doi:10.1182/blood-2017-01-761973).
This new batch of studies presented at ASH 2017 provided additional evidence for the venetoclax and obinutuzumab combination, as well as other combinations that appear to provide favorable rates of MRD-negative CLL, including obinutuzumab and venetoclax plus ibrutinib and, notably, a combination that included venetoclax and ibrutinib but no anti-CD20 antibody.
A phase II trial presented by Nitin Jain, MD, of MD Anderson Cancer Center, Houston, looked at the combination of venetoclax and ibrutinib for patients with previously untreated high-risk CLL or relapsed/refractory CLL. The regimen under evaluation starts with daily ibrutinib monotherapy for 3 months before venetoclax is added.
For the first line cohort of 36 patients, the bone marrow MRD-negativity proportion was 0% after 3 months of ibrutinib and 21% after 3 months of ibrutinib plus venetoclax, then 45%, 80%, and 100%, respectively, after 6, 9, and 12 months of combination therapy, Dr. Jain reported. In the relapsed/refractory cohort, MRD negativity was 8% after 3 months of combination therapy and 40% after 12 months. “Responses continue to improve with time, with many patients achieving bone marrow MRD-negative remission,” Dr. Jain said.
The study showed “very impressive MRD rates,” commented Ian W. Flinn, MD, of Sarah Cannon Research Institute, Nashville, Tenn. “I think it’s still up for further discussion and research to find which is the best combination.”
Dr. Flinn presented results from a phase Ib GP28331 study of venetoclax and obinutuzumab in patients with previously untreated CLL in which MRD was assessed in peripheral blood and bone marrow.
All 32 patients achieved peripheral blood negativity at some point on study, Dr. Flinn said, and 75% achieved bone marrow negativity. The complete response rate was 72% (23/32), but notably, high rates of undetectable bone marrow MRD were seen irrespective of response status, Dr. Flinn said.
All patients had at least one adverse event, with grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia reported most commonly.
Preliminary progression-free survival data (PFS) suggested “durable clinical outcomes” for the combination, with an estimated 18-month PFS of 90.5%, he said.
A third study assessed the combination of obinutuzumab, ibrutinib, and venetoclax, finding that the combination induced MRD negativity in 14 of 24 (58%) treatment-naive CLL patients, according to Kerry A. Rogers, MD, of Ohio State University, Columbus.
The combination had a 96% response rate and is “extremely effective at eliminating detectable CLL,” Dr. Rogers noted.
Most adverse events were hematologic, and high-grade adverse events were rare, she said.
Results for the study’s primary endpoint, rate of MRD-negative complete remission, are expected by May 2018, Dr. Rogers said, adding that further follow-up will be needed to determine PFS for the combination.
Session attendees asked presenters whether they felt there was scientific justification for inclusion of the anti-CD20 antibody rituximab in future trials designed in part to assess MRD negativity.
“I think that obinutuzumab has greater efficacy in patients with CLL, compared to rituximab, and so our hypothesis is that it is a superior antibody to combine with venetoclax,” Dr. Flinn said.
AbbVie provided funding for the study on venetoclax and ibrutinib. Dr. Jain reported disclosures from venetoclax makers AbbVie and Genentech, ibrutinib makers Janssen and Pharmacyclics, and others.
Genentech and AbbVie provided support for the study on venetoclax and obinutuzumab. Dr. Flinn reported disclosures related to both companies and others.
Dr. Rogers reported no conflicts related to the study on obinutuzumab, ibrutinib, and venetoclax. One of her associates reported disclosures related to ibrutinib makers Novartis and Pharmacylics, among others.
SOURCE: Jain N et al. ASH 2017 Abstract 429; Flinn I et al. ASH 2017 Abstract 430; Rogers K et al. ASH 2017 Abstract 431.
Atlanta – The potential of two- and three-drug combinations to induce deep, minimal residual disease (MRD)–negative responses in patients with chronic lymphocytic leukemia (CLL) was demonstrated in multiple studies presented at the annual meeting of the American Society of Hematology.
Previous studies have suggested that, in contrast to single-agent kinase inhibitor treatment, combinations of treatments, namely kinase or B-cell lyphoma 2 inhibitors combined with anti-CD20 antibodies, can induce MRD negativity at a high rate. For example, in a report on the CLL14 trial, 11 of 12 previously untreated patients were MRD negative after treatment with the BCL-2 inhibitor venetoclax and anti-CD20 antibody obinutuzumab (Blood. 2017;129:2702-5. doi:10.1182/blood-2017-01-761973).
This new batch of studies presented at ASH 2017 provided additional evidence for the venetoclax and obinutuzumab combination, as well as other combinations that appear to provide favorable rates of MRD-negative CLL, including obinutuzumab and venetoclax plus ibrutinib and, notably, a combination that included venetoclax and ibrutinib but no anti-CD20 antibody.
A phase II trial presented by Nitin Jain, MD, of MD Anderson Cancer Center, Houston, looked at the combination of venetoclax and ibrutinib for patients with previously untreated high-risk CLL or relapsed/refractory CLL. The regimen under evaluation starts with daily ibrutinib monotherapy for 3 months before venetoclax is added.
For the first line cohort of 36 patients, the bone marrow MRD-negativity proportion was 0% after 3 months of ibrutinib and 21% after 3 months of ibrutinib plus venetoclax, then 45%, 80%, and 100%, respectively, after 6, 9, and 12 months of combination therapy, Dr. Jain reported. In the relapsed/refractory cohort, MRD negativity was 8% after 3 months of combination therapy and 40% after 12 months. “Responses continue to improve with time, with many patients achieving bone marrow MRD-negative remission,” Dr. Jain said.
The study showed “very impressive MRD rates,” commented Ian W. Flinn, MD, of Sarah Cannon Research Institute, Nashville, Tenn. “I think it’s still up for further discussion and research to find which is the best combination.”
Dr. Flinn presented results from a phase Ib GP28331 study of venetoclax and obinutuzumab in patients with previously untreated CLL in which MRD was assessed in peripheral blood and bone marrow.
All 32 patients achieved peripheral blood negativity at some point on study, Dr. Flinn said, and 75% achieved bone marrow negativity. The complete response rate was 72% (23/32), but notably, high rates of undetectable bone marrow MRD were seen irrespective of response status, Dr. Flinn said.
All patients had at least one adverse event, with grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia reported most commonly.
Preliminary progression-free survival data (PFS) suggested “durable clinical outcomes” for the combination, with an estimated 18-month PFS of 90.5%, he said.
A third study assessed the combination of obinutuzumab, ibrutinib, and venetoclax, finding that the combination induced MRD negativity in 14 of 24 (58%) treatment-naive CLL patients, according to Kerry A. Rogers, MD, of Ohio State University, Columbus.
The combination had a 96% response rate and is “extremely effective at eliminating detectable CLL,” Dr. Rogers noted.
Most adverse events were hematologic, and high-grade adverse events were rare, she said.
Results for the study’s primary endpoint, rate of MRD-negative complete remission, are expected by May 2018, Dr. Rogers said, adding that further follow-up will be needed to determine PFS for the combination.
Session attendees asked presenters whether they felt there was scientific justification for inclusion of the anti-CD20 antibody rituximab in future trials designed in part to assess MRD negativity.
“I think that obinutuzumab has greater efficacy in patients with CLL, compared to rituximab, and so our hypothesis is that it is a superior antibody to combine with venetoclax,” Dr. Flinn said.
AbbVie provided funding for the study on venetoclax and ibrutinib. Dr. Jain reported disclosures from venetoclax makers AbbVie and Genentech, ibrutinib makers Janssen and Pharmacyclics, and others.
Genentech and AbbVie provided support for the study on venetoclax and obinutuzumab. Dr. Flinn reported disclosures related to both companies and others.
Dr. Rogers reported no conflicts related to the study on obinutuzumab, ibrutinib, and venetoclax. One of her associates reported disclosures related to ibrutinib makers Novartis and Pharmacylics, among others.
SOURCE: Jain N et al. ASH 2017 Abstract 429; Flinn I et al. ASH 2017 Abstract 430; Rogers K et al. ASH 2017 Abstract 431.
REPORTING FROM ASH 2017
CLARITY: Ibrutinib/venetoclax combo results look promising for relapsed/refractory CLL
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
[email protected]
SOURCE: Hillmen P et al., ASH abstract 428.
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
[email protected]
SOURCE: Hillmen P et al., ASH abstract 428.
ATLANTA – Combination therapy with ibrutinib and venetoclax is well tolerated and shows promise for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), according to initial results from the CLARITY feasibility trial.
Of 38 patients who received at least 6 months of treatment with combination ibrutinib (Imbruvica)/venetoclax (Venclexta) and reached month 8 – and therefore had computed tomography, clinical data, and peripheral blood and marrow assessments available – 15 (37%) achieved peripheral blood minimal residual disease (MRD) negativity, and 12 (32%) achieved bone marrow MRD negativity, Peter Hillmen, MBChB, PhD, reported during a press briefing at the annual meeting of the American Society of Hematology.
The rates of MRD negativity in the blood and marrow, and of normal trephine biopsy, were similar in subsets of patients who relapsed within 36 months of prior treatment with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR), and with prior idelalisib exposure, he noted.
“In terms of [International Workshop on Chronic Lymphocytic Leukemia] response criteria, which is a secondary endpoint, 47% of patients achieved a [complete remission or complete remission with incomplete hematologic recovery] and every patient has had an overall response, which for this group of patients is impressive,” he said.
Again, the findings were similar in those who were refractory to prior FCR/BR or to previous idelalisib, he noted.
Both ibrutinib and venetoclax are approved as single agents for the treatment of CLL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor that has had a major effect on patient outcomes, showing overall survival advantages in numerous trials, Dr. Hillmen said.
“However, ibrutinib does not eradicate disease, and patients remain on treatment indefinitely or until progression,” he said.
Venetoclax is a highly selective B cell lymphoma–2 inhibitor approved for refractory CLL in patients with 17p deletion. It has a rapid effect, which can lead to tumor lysis syndrome, but also leads to eradication of MRD in some patients, which can lead to prolonged survival, he said.
The CLARITY trial was designed to investigate the safety and efficacy of the two in combination in relapsed/refractory CLL patients.
The primary endpoint of the study is MRD eradication in the marrow after 12 months of treatment. The current analysis looks at a key secondary endpoint of the study – MRD eradication in the marrow after 6 months of treatment.
The study enrolled 54 patients, including 37 men and 17 women with a median age of 64 years; 20% have 17p deletion, and the population was heavily pretreated, with 81% having prior FCR or BR (44% with relapse within 3 years of treatment), and 20% with previous idelalisib exposure. Patients were excluded if they had prior exposure to ibrutinib or venetoclax.
Treatment involves ibrutinib monotherapy at a dose of 420 mg/day for 2 months to debulk the disease, after which venetoclax is added at a dose escalating from 20 mg to 400 mg/day over 2 months to reduce the risk of tumor lysis syndrome.
Bone marrow biopsies are performed at 6, 12, and 24 months. Treatment is discontinued at 12 months in those who achieve MRD negativity at 6 months, and is discontinued at 24 months in those who achieve MRD negativity at 12 months.
The combination treatment was well tolerated in the first 38 patients. Bruising (mainly grade 1) occurred in 33 patients, and neutropenia (including 16 grade 3 cases and 6 grade 4 cases) occurred in 25, and some GI toxicity occurred, but was largely grade 1 or 2, Dr. Hillmen said.
“There really was otherwise very acceptable toxicity,” he added, noting that a single case of tumor lysis syndrome occurred, but was managed successfully by delaying venetoclax.
“That patient re-escalated back onto treatment and is doing well,” he said.
No patients stopped treatment, and only seven had treatment interruption, and then only for a few days, he noted.
The findings are encouraging, and suggest a potent synergy between ibrutinib and venetoclax, said Dr. Hillmen.
“We’re seeing, even at this very early stage, over 30% of patients achieving MRD negative remission, which was our target at the 12-month bone marrow stage with this combination,” he said.
In light of these results, the ongoing phase 3 FLAIR trial, which is actively recruiting, has been modified to include combination ibrutinib and venetoclax in front-line CLL, he said.
Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham (England).
[email protected]
SOURCE: Hillmen P et al., ASH abstract 428.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: 37% and 32% of patients achieved peripheral blood and marrow MRD negativity, respectively.
Study details: Initial results from 38 patients in the CLARITY feasibility trial.
Disclosures: Dr. Hillmen reported financial relationships with AbbVie and several other pharmaceutical companies. The CLARITY trial is supported by AbbVie, Bloodwise, Experimental Cancer Medicine Centre, Janssen-Cilag, the National Institute for Health Research Clinical Research Network: Cancer, and the University of Birmingham.
Source: Hillmen P et al. ASH Abstract 428.
Late-breaking abstracts highlight treatment advances in CLL, myeloma, and more
.
In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.
In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.
The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.
In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.
In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.
“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.
Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.
In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.
Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”
Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.
With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.
The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.
This year’s late-breaking abstracts at ASH are:
LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.
LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.
LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.
LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).
LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.
LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study
.
In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.
In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.
The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.
In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.
In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.
“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.
Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.
In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.
Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”
Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.
With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.
The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.
This year’s late-breaking abstracts at ASH are:
LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.
LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.
LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.
LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).
LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.
LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study
.
In a preplanned interim analysis of data from 389 patients in the randomized phase III Murano trial, venetoclax and rituximab therapy proved “superior to the standard of care and well tolerated, and a major advance in the management of [relapsed/refractory] CLL,” ASH President Kenneth C. Anderson, MD said during a premeeting preview session for the media.
In Murano, venetoclax plus rituximab bettered bendamustine plus rituximab in progression-free survival, overall survival, overall and complete response rates, and number of patients achieving minimal residual disease (MRD) negativity, said Dr. Anderson, who is also director of the Lebow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, Boston.
The results were consistent in all risk subsets, including patients who had high-risk disease by virtue of chromosome 17p deletion, according Dr. Anderson.
In another late-breaking randomized phase III study, known as ALCYONE, adding the CD38-targeting monoclonal antibody daratumumab to standard therapy with bortezomib, melphalan, and prednisone (VMP) resulted in a “doubling” of progression-free survival in patients who had newly diagnosed multiple myeloma and were ineligible for transplantation, he reported.
In the trial of more than 700 patients, daratumumab plus VMP as initial treatment for nontransplant patients was well tolerated and improved outcomes, including overall response rate and the percent of patients who achieved MRD negative status.
“As we saw in CLL, so it’s true in this abstract in myeloma: this is a very major advance,” Dr. Anderson said.
Also during the preview session, ASH Secretary Robert A. Brodsky, MD, discussed the randomized, phase III HERCULES study results, which showed that patients with acquired thrombotic thrombocytopenic purpura (TTP) may benefit when caplacizumab is added to standard therapy. Caplacizumab targets the A1 domain of von Willebrand factor, which inhibits interaction between ultra-large von Willebrand factor and platelets.
In the trial, 145 patients were randomized to receive either plasma exchange alone or plasma exchange and caplacizumab.
Preliminary results suggest “this was a very positive trial” with a primary endpoint of time to platelet response that “greatly favored the caplacizumab arm,” said Dr. Brodsky, professor of medicine and oncology and director of the division of hematology at Johns Hopkins University, Baltimore. “Even the secondary composite endpoint of death, recurrence, and/or major thromboembolic events was much improved with caplacizumab, so this is a very positive trial and potentially a game-changing drug for the management of TTP, which can be very challenging.”
Dr. Brodsky also discussed the Hokusai VTE-Cancer Study, a randomized, open-label, blinded outcome assessment trial that showed the oral factor Xa inhibitor edoxaban was noninferior to subcutaneous dalteparin for the prevention of cancer-associated venous thromboembolism.
With more than 1,000 patients enrolled in 114 centers, the Hokusai VTE-Cancer Study had a primary outcome of the composite of the first recurrent VTE or major bleeding event during follow-up. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% of patients in the dalteparin group (P = .0056 for noninferiority), according to the preliminary published results.
The key question addressed by the trial is whether a newer oral anticoagulant, edoxaban, can substitute for the older, subcutaneously administered low-molecular-weight heparin, dalteparin. The results “confirmed that a newer oral anticoagulant is at least as good and as safe as the low molecular weight heparin,” allowing patients the convenience of an oral therapy, Dr. Brodsky noted.
This year’s late-breaking abstracts at ASH are:
LBA-1 Results of the Randomized, Double-Blind, Placebo-Controlled, Phase III Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura.
LBA-2 Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia - Results from Pre-Planned Interim Analysis of the Randomized Phase III Murano Study.
LBA-3 Mutations in SRP54 Gene Cause Severe Primary Neutropenia As Well As Shwachman-Diamond-like Syndrome.
LBA-4 Phase III Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE).
LBA-5 Prospective Molecular MRD Detection By NGS: A Powerful Independent Predictor for Relapse and Survival in Adults with Newly Diagnosed AML.
LBA-6 A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study
FROM ASH 2017
Studies need to address best follow-on therapy to ibrutinib in CLL
Reporting AT LYMPHOMA & MYELOMA 2017
NEW YORK – Clinical trials are needed to determine the best follow-on therapies when patients discontinue the ibrutinib due to adverse events or disease progression, according to a leading expert on chronic lymphocytic leukemia (CLL).
Anthony Mato, MD, MSCE, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, discussed how real-world experience with the use of ibrutinib (Imbruvica) can fill the gaps in knowledge left by clinical trials and point to the need for further study.
“Regulatory bodies around the world are more and more interested in what’s going on in the clinic, and there is a question about whether or not the experiences for patients that we take care of might actually answer some important questions that aren’t easily answered in the context of clinical research,” he said at the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies here.
“Are the experiences in practice with novel agents similar to experiences from clinical trials? I think that’s very important,” he added.
Other important questions that real-world experience may help to answer include whether it’s possible to refine adverse event profiles and reasons for ibrutinib discontinuation, what therapies should be prescribed after ibrutinib, and what is the optimal sequencing of therapies for CLL.
For example, in the RESONATE-2 trial, an open-label, international phase 3 study comparing ibrutinib with chlorambucil in previously untreated patients 65 and older, ibrutinib was found to be superior to chlorambucil in terms of progression-free survival (PFS), overall survival (OS), response rate, and improvements in hematologic variables.
However, this trial excluded patients with the deleterious chromosome 17p deletion (del17p) and included only patients 65 and older, a population that does not necessarily reflect clinical experience.
To get a better sense of how ibrutinib is used to treat CLL in the front-line setting Dr. Mato and colleagues conducted a retrospective cohort study of 391 patients treated in 19 US and international academic and community centers.
The median age of the sample was 68 years, but 41% of the patients were younger than 65. In all, 62% were male, and 80% had Rai stage 2 or greater disease. Genetic analyses showed that 30% of the patients were positive for del17p, and 17% had both del17p and the 11q deletion (del11q). Mutations in TP53 were seen in 20% of patients, 23% had a complex karyotype, and 67% had an unmutated immuglobulin heavy chain variable region (IGHV). Only 57 patients (14.5%) were classified as genetically low risk.
Additionally, only 79 of the 391 patients had complete data for CLL International Prognostic Index (CLL-IPI) scoring, “which goes, I think, to show how often this is actually being tested and utilized in clinical practice,” Dr. Mato said.
Off-label use of ibrutinib in combination therapy was given to 16% of patients, most commonly with an anti-CD20 inhibitor such as rituximab.
In all, 17% of patients required permanent dose reductions; and 42% had a dose interruption, with a median hiatus of 12 days.
Grade 3 or 4 adverse events were uncommon, but more than 20% of patients experienced arthralgias or myalgias of any kind, about 19% reported fatigue, 18% had dermatologic toxicities, 18% reported bruising, 17% had diarrhea or colitis and 15% had infections.
The toxicities seen in RESONATE-2 were somewhat similar, but generally occurred in higher frequencies in the trial than in real-world practice.
Dr. Mato and colleagues found that at a median of 12 months of follow-up, 24% of patients had discontinued ibrutinib. In contrast, in RESONATE-2, after 18 months of follow-up, 13% of patients had discontinued the drug.
The most common reasons for discontinuation in clinical practice were for toxicities (59.5% of 94 discontinuations) including atrial fibrillation in 20% of the patients who discontinued, arthralgias/myalgias and skin toxicities in 14.5% each, and bleeding in 9.1%.
Other reasons for discontinuation included Richter’s transformation in 9.6%, doctor or patient preference in 7.4%, and deaths that were not secondary to CLL progression in 3.2%.
“We also tried to get a sense of whether or not cost was a factor for patients, and in this series and the relapsed refractory setting, 1% or less of patients discontinued due to financial issues,” Dr. Mato said.
Outcomes in the real word were quite good, he noted, with an overall response rate (ORR) of 81.7%, which included 17.4% complete responses (CR), Neither median PFS nor OS have been reached and the respective PFS and OS at 12 months were 92% and 95%. The respective PFS and OS rates for patients with del17p were 87% and 89%. An analysis of predictors of survival showed that only the presence of del17p was associated with inferior PFS (odds ratio 1.91, P = .035)
Dr. Mato noted that there was no clear standard treatment approach for patients who discontinued ibrutinib or for whom ibrutinib did not work. The top three second-line approaches used included an anti-CD20 agent combined with chlorambucil, venetoclax (Venclexta), or a different kinase inhibitor. Chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab was given to only 5 patients as a second line therapy.
Dr. Mato disclosed serving as a consultant for AbbVie, AstraZeneca, Janssen/Pharmacyclics, and TG Therapeutics.
Reporting AT LYMPHOMA & MYELOMA 2017
NEW YORK – Clinical trials are needed to determine the best follow-on therapies when patients discontinue the ibrutinib due to adverse events or disease progression, according to a leading expert on chronic lymphocytic leukemia (CLL).
Anthony Mato, MD, MSCE, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, discussed how real-world experience with the use of ibrutinib (Imbruvica) can fill the gaps in knowledge left by clinical trials and point to the need for further study.
“Regulatory bodies around the world are more and more interested in what’s going on in the clinic, and there is a question about whether or not the experiences for patients that we take care of might actually answer some important questions that aren’t easily answered in the context of clinical research,” he said at the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies here.
“Are the experiences in practice with novel agents similar to experiences from clinical trials? I think that’s very important,” he added.
Other important questions that real-world experience may help to answer include whether it’s possible to refine adverse event profiles and reasons for ibrutinib discontinuation, what therapies should be prescribed after ibrutinib, and what is the optimal sequencing of therapies for CLL.
For example, in the RESONATE-2 trial, an open-label, international phase 3 study comparing ibrutinib with chlorambucil in previously untreated patients 65 and older, ibrutinib was found to be superior to chlorambucil in terms of progression-free survival (PFS), overall survival (OS), response rate, and improvements in hematologic variables.
However, this trial excluded patients with the deleterious chromosome 17p deletion (del17p) and included only patients 65 and older, a population that does not necessarily reflect clinical experience.
To get a better sense of how ibrutinib is used to treat CLL in the front-line setting Dr. Mato and colleagues conducted a retrospective cohort study of 391 patients treated in 19 US and international academic and community centers.
The median age of the sample was 68 years, but 41% of the patients were younger than 65. In all, 62% were male, and 80% had Rai stage 2 or greater disease. Genetic analyses showed that 30% of the patients were positive for del17p, and 17% had both del17p and the 11q deletion (del11q). Mutations in TP53 were seen in 20% of patients, 23% had a complex karyotype, and 67% had an unmutated immuglobulin heavy chain variable region (IGHV). Only 57 patients (14.5%) were classified as genetically low risk.
Additionally, only 79 of the 391 patients had complete data for CLL International Prognostic Index (CLL-IPI) scoring, “which goes, I think, to show how often this is actually being tested and utilized in clinical practice,” Dr. Mato said.
Off-label use of ibrutinib in combination therapy was given to 16% of patients, most commonly with an anti-CD20 inhibitor such as rituximab.
In all, 17% of patients required permanent dose reductions; and 42% had a dose interruption, with a median hiatus of 12 days.
Grade 3 or 4 adverse events were uncommon, but more than 20% of patients experienced arthralgias or myalgias of any kind, about 19% reported fatigue, 18% had dermatologic toxicities, 18% reported bruising, 17% had diarrhea or colitis and 15% had infections.
The toxicities seen in RESONATE-2 were somewhat similar, but generally occurred in higher frequencies in the trial than in real-world practice.
Dr. Mato and colleagues found that at a median of 12 months of follow-up, 24% of patients had discontinued ibrutinib. In contrast, in RESONATE-2, after 18 months of follow-up, 13% of patients had discontinued the drug.
The most common reasons for discontinuation in clinical practice were for toxicities (59.5% of 94 discontinuations) including atrial fibrillation in 20% of the patients who discontinued, arthralgias/myalgias and skin toxicities in 14.5% each, and bleeding in 9.1%.
Other reasons for discontinuation included Richter’s transformation in 9.6%, doctor or patient preference in 7.4%, and deaths that were not secondary to CLL progression in 3.2%.
“We also tried to get a sense of whether or not cost was a factor for patients, and in this series and the relapsed refractory setting, 1% or less of patients discontinued due to financial issues,” Dr. Mato said.
Outcomes in the real word were quite good, he noted, with an overall response rate (ORR) of 81.7%, which included 17.4% complete responses (CR), Neither median PFS nor OS have been reached and the respective PFS and OS at 12 months were 92% and 95%. The respective PFS and OS rates for patients with del17p were 87% and 89%. An analysis of predictors of survival showed that only the presence of del17p was associated with inferior PFS (odds ratio 1.91, P = .035)
Dr. Mato noted that there was no clear standard treatment approach for patients who discontinued ibrutinib or for whom ibrutinib did not work. The top three second-line approaches used included an anti-CD20 agent combined with chlorambucil, venetoclax (Venclexta), or a different kinase inhibitor. Chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab was given to only 5 patients as a second line therapy.
Dr. Mato disclosed serving as a consultant for AbbVie, AstraZeneca, Janssen/Pharmacyclics, and TG Therapeutics.
Reporting AT LYMPHOMA & MYELOMA 2017
NEW YORK – Clinical trials are needed to determine the best follow-on therapies when patients discontinue the ibrutinib due to adverse events or disease progression, according to a leading expert on chronic lymphocytic leukemia (CLL).
Anthony Mato, MD, MSCE, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, discussed how real-world experience with the use of ibrutinib (Imbruvica) can fill the gaps in knowledge left by clinical trials and point to the need for further study.
“Regulatory bodies around the world are more and more interested in what’s going on in the clinic, and there is a question about whether or not the experiences for patients that we take care of might actually answer some important questions that aren’t easily answered in the context of clinical research,” he said at the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies here.
“Are the experiences in practice with novel agents similar to experiences from clinical trials? I think that’s very important,” he added.
Other important questions that real-world experience may help to answer include whether it’s possible to refine adverse event profiles and reasons for ibrutinib discontinuation, what therapies should be prescribed after ibrutinib, and what is the optimal sequencing of therapies for CLL.
For example, in the RESONATE-2 trial, an open-label, international phase 3 study comparing ibrutinib with chlorambucil in previously untreated patients 65 and older, ibrutinib was found to be superior to chlorambucil in terms of progression-free survival (PFS), overall survival (OS), response rate, and improvements in hematologic variables.
However, this trial excluded patients with the deleterious chromosome 17p deletion (del17p) and included only patients 65 and older, a population that does not necessarily reflect clinical experience.
To get a better sense of how ibrutinib is used to treat CLL in the front-line setting Dr. Mato and colleagues conducted a retrospective cohort study of 391 patients treated in 19 US and international academic and community centers.
The median age of the sample was 68 years, but 41% of the patients were younger than 65. In all, 62% were male, and 80% had Rai stage 2 or greater disease. Genetic analyses showed that 30% of the patients were positive for del17p, and 17% had both del17p and the 11q deletion (del11q). Mutations in TP53 were seen in 20% of patients, 23% had a complex karyotype, and 67% had an unmutated immuglobulin heavy chain variable region (IGHV). Only 57 patients (14.5%) were classified as genetically low risk.
Additionally, only 79 of the 391 patients had complete data for CLL International Prognostic Index (CLL-IPI) scoring, “which goes, I think, to show how often this is actually being tested and utilized in clinical practice,” Dr. Mato said.
Off-label use of ibrutinib in combination therapy was given to 16% of patients, most commonly with an anti-CD20 inhibitor such as rituximab.
In all, 17% of patients required permanent dose reductions; and 42% had a dose interruption, with a median hiatus of 12 days.
Grade 3 or 4 adverse events were uncommon, but more than 20% of patients experienced arthralgias or myalgias of any kind, about 19% reported fatigue, 18% had dermatologic toxicities, 18% reported bruising, 17% had diarrhea or colitis and 15% had infections.
The toxicities seen in RESONATE-2 were somewhat similar, but generally occurred in higher frequencies in the trial than in real-world practice.
Dr. Mato and colleagues found that at a median of 12 months of follow-up, 24% of patients had discontinued ibrutinib. In contrast, in RESONATE-2, after 18 months of follow-up, 13% of patients had discontinued the drug.
The most common reasons for discontinuation in clinical practice were for toxicities (59.5% of 94 discontinuations) including atrial fibrillation in 20% of the patients who discontinued, arthralgias/myalgias and skin toxicities in 14.5% each, and bleeding in 9.1%.
Other reasons for discontinuation included Richter’s transformation in 9.6%, doctor or patient preference in 7.4%, and deaths that were not secondary to CLL progression in 3.2%.
“We also tried to get a sense of whether or not cost was a factor for patients, and in this series and the relapsed refractory setting, 1% or less of patients discontinued due to financial issues,” Dr. Mato said.
Outcomes in the real word were quite good, he noted, with an overall response rate (ORR) of 81.7%, which included 17.4% complete responses (CR), Neither median PFS nor OS have been reached and the respective PFS and OS at 12 months were 92% and 95%. The respective PFS and OS rates for patients with del17p were 87% and 89%. An analysis of predictors of survival showed that only the presence of del17p was associated with inferior PFS (odds ratio 1.91, P = .035)
Dr. Mato noted that there was no clear standard treatment approach for patients who discontinued ibrutinib or for whom ibrutinib did not work. The top three second-line approaches used included an anti-CD20 agent combined with chlorambucil, venetoclax (Venclexta), or a different kinase inhibitor. Chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab was given to only 5 patients as a second line therapy.
Dr. Mato disclosed serving as a consultant for AbbVie, AstraZeneca, Janssen/Pharmacyclics, and TG Therapeutics.
Idelalisib efficacy against CLL tarnished by toxicity
NEW YORK – PI3K inhibitors are highly active against B-cell malignancies, but this class of drugs, led by
Idelalisib is a potent inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K) that in a phase 1 trial was associated at higher dose levels with a median progression-free survival (PFS) of 32 months in patients with CLL who had received a median of five prior lines of therapy, noted Jennifer R. Brown, MD, PhD, director of the CLL center at the Dana-Farber Cancer Institute in Boston.
“This is really a very effective drug. So what’s happened? Why aren’t we using it more?” she asked rhetorically at an international congress on hematologic malignancies.
“This relates to a pattern of toxicities that has becoming increasingly familiar to us,” she added.
There is increasing evidence to suggest that the toxicities associated with idelalisib are immune mediated, indicating both the need for caution among clinicians who think about prescribing the drug, and a potential future use for this and other PI3K inhibitors as immunomodulatory agents, Dr. Brown said.
Registration trial toxicities
Among 760 patients enrolled in trials for the idelalisib registration programs, grade 3 or greater diarrhea and/or colitis and transaminitis each occurred in 14% of patients, rash occurred in 6%, and pneumonitis of any grade was seen in 3%.
Among patients with relapsed disease, transaminitis was often self-limiting and usually resolved when the drug was withheld, and about 75% of patients were successfully restarted on idelalisib at the same or lower dose, Dr. Brown noted.
Rashes, which can occur any time with therapy, were also successfully managed by withholding drug and then rechallenging, with the addition of corticosteroids as necessary.
Patients who developed drug-related pneumonitis were less likely than those with other toxicities to be rechallenged, and most required steroids until the infections resolved.
“The steroid responsiveness of many of these side effects suggested that they were autoimmune,” Dr. Brown said.
Drugs only work when you take them
The toxicities seen with idelalisib have had a marked effect on the use of the drug. In registration trials for idelalisib in combination with rituximab or ofatumumab (Arzerra), each of which had at least 2 years of follow-up, only 22.5% of 369 patients remained on idelalisib, primarily because of toxicities rather than disease progression. The combined 2-year progression in these trials was 13.3% In contrast, 40.7% of patients discontinued idelalisib because of adverse events.
Out to about 7 months, survival rates for patients who discontinued idelalisib because of disease progression or adverse events were roughly similar, but survival for the patients who stopped because of side effects began to plateau out to 2 years, Dr. Brown noted.
As of March 2016, 23.2% of patients who received idelalisib in clinical trials in combination with other agents as second- or third-line therapy had died, compared with 31% of controls, indicating a clear survival benefit with the drug.
“This is probably because the benefit of disease control in that setting overwhelmed the adverse event or infections problem,” she said.
Many of the deaths in registration trials were related to opportunistic infections, including Pneumocystis jiroveci pneumonia, fungal infection, and cytomegalovirus.
“Idelalisib, I think, is a prototypical delta inhibitor with a pattern of immune-mediated toxicity that remains unpredictable and can be severe. We now have pretty good data, based on the Gilead [sponsor] trials, that younger age and less prior therapy predispose to this toxicity,” Dr. Brown said.
Evidence is less robust, but growing, that mutated IGHV and a decrease in regulatory T cells may be also be risk factors for immune-mediated toxicities with idelalisib. Immune modulation with the drug may also account for associated neutropenia, sepsis, and opportunistic infections seen with idelalisib therapy, she added.
So how to use it?
Currently, the best uses for idelalisib and other PI3K inhibitors in CLL appear to be in single-agent therapy in patients with relapsed disease who cannot tolerate a Bruton’s tyrosine kinase (BTK) inhibitor such as ibrutinib (Imbruvica) or in patients whose disease has progressed on a BTK inhibitor.
“Where I think about this drug is in older, more heavily pretreated patients, who are generally at less risk for toxicities, and if they have significant comorbidities that may impact BTK-inhibitor tolerability, usually cardiac,” Dr. Brown said.
Future expansion of PI3K inhibitors in B-cell malignancies may require identifying a biomarker for tolerance, alternative dosing schedules, or identification of an idelalisib/drug X combination that might mitigate the toxicity, she said.
The immune-activation properties of PI3K-delta inhibitors suggests that they might also play a role as antitumor immunomodulatory agents in treatment of both hematologic malignancies and solid tumors, Dr. Brown concluded.
Idelalisib trials were sponsored by Gilead Sciences. Dr. Brown disclosed serving as a consultant for Gilead and other companies.
NEW YORK – PI3K inhibitors are highly active against B-cell malignancies, but this class of drugs, led by
Idelalisib is a potent inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K) that in a phase 1 trial was associated at higher dose levels with a median progression-free survival (PFS) of 32 months in patients with CLL who had received a median of five prior lines of therapy, noted Jennifer R. Brown, MD, PhD, director of the CLL center at the Dana-Farber Cancer Institute in Boston.
“This is really a very effective drug. So what’s happened? Why aren’t we using it more?” she asked rhetorically at an international congress on hematologic malignancies.
“This relates to a pattern of toxicities that has becoming increasingly familiar to us,” she added.
There is increasing evidence to suggest that the toxicities associated with idelalisib are immune mediated, indicating both the need for caution among clinicians who think about prescribing the drug, and a potential future use for this and other PI3K inhibitors as immunomodulatory agents, Dr. Brown said.
Registration trial toxicities
Among 760 patients enrolled in trials for the idelalisib registration programs, grade 3 or greater diarrhea and/or colitis and transaminitis each occurred in 14% of patients, rash occurred in 6%, and pneumonitis of any grade was seen in 3%.
Among patients with relapsed disease, transaminitis was often self-limiting and usually resolved when the drug was withheld, and about 75% of patients were successfully restarted on idelalisib at the same or lower dose, Dr. Brown noted.
Rashes, which can occur any time with therapy, were also successfully managed by withholding drug and then rechallenging, with the addition of corticosteroids as necessary.
Patients who developed drug-related pneumonitis were less likely than those with other toxicities to be rechallenged, and most required steroids until the infections resolved.
“The steroid responsiveness of many of these side effects suggested that they were autoimmune,” Dr. Brown said.
Drugs only work when you take them
The toxicities seen with idelalisib have had a marked effect on the use of the drug. In registration trials for idelalisib in combination with rituximab or ofatumumab (Arzerra), each of which had at least 2 years of follow-up, only 22.5% of 369 patients remained on idelalisib, primarily because of toxicities rather than disease progression. The combined 2-year progression in these trials was 13.3% In contrast, 40.7% of patients discontinued idelalisib because of adverse events.
Out to about 7 months, survival rates for patients who discontinued idelalisib because of disease progression or adverse events were roughly similar, but survival for the patients who stopped because of side effects began to plateau out to 2 years, Dr. Brown noted.
As of March 2016, 23.2% of patients who received idelalisib in clinical trials in combination with other agents as second- or third-line therapy had died, compared with 31% of controls, indicating a clear survival benefit with the drug.
“This is probably because the benefit of disease control in that setting overwhelmed the adverse event or infections problem,” she said.
Many of the deaths in registration trials were related to opportunistic infections, including Pneumocystis jiroveci pneumonia, fungal infection, and cytomegalovirus.
“Idelalisib, I think, is a prototypical delta inhibitor with a pattern of immune-mediated toxicity that remains unpredictable and can be severe. We now have pretty good data, based on the Gilead [sponsor] trials, that younger age and less prior therapy predispose to this toxicity,” Dr. Brown said.
Evidence is less robust, but growing, that mutated IGHV and a decrease in regulatory T cells may be also be risk factors for immune-mediated toxicities with idelalisib. Immune modulation with the drug may also account for associated neutropenia, sepsis, and opportunistic infections seen with idelalisib therapy, she added.
So how to use it?
Currently, the best uses for idelalisib and other PI3K inhibitors in CLL appear to be in single-agent therapy in patients with relapsed disease who cannot tolerate a Bruton’s tyrosine kinase (BTK) inhibitor such as ibrutinib (Imbruvica) or in patients whose disease has progressed on a BTK inhibitor.
“Where I think about this drug is in older, more heavily pretreated patients, who are generally at less risk for toxicities, and if they have significant comorbidities that may impact BTK-inhibitor tolerability, usually cardiac,” Dr. Brown said.
Future expansion of PI3K inhibitors in B-cell malignancies may require identifying a biomarker for tolerance, alternative dosing schedules, or identification of an idelalisib/drug X combination that might mitigate the toxicity, she said.
The immune-activation properties of PI3K-delta inhibitors suggests that they might also play a role as antitumor immunomodulatory agents in treatment of both hematologic malignancies and solid tumors, Dr. Brown concluded.
Idelalisib trials were sponsored by Gilead Sciences. Dr. Brown disclosed serving as a consultant for Gilead and other companies.
NEW YORK – PI3K inhibitors are highly active against B-cell malignancies, but this class of drugs, led by
Idelalisib is a potent inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K) that in a phase 1 trial was associated at higher dose levels with a median progression-free survival (PFS) of 32 months in patients with CLL who had received a median of five prior lines of therapy, noted Jennifer R. Brown, MD, PhD, director of the CLL center at the Dana-Farber Cancer Institute in Boston.
“This is really a very effective drug. So what’s happened? Why aren’t we using it more?” she asked rhetorically at an international congress on hematologic malignancies.
“This relates to a pattern of toxicities that has becoming increasingly familiar to us,” she added.
There is increasing evidence to suggest that the toxicities associated with idelalisib are immune mediated, indicating both the need for caution among clinicians who think about prescribing the drug, and a potential future use for this and other PI3K inhibitors as immunomodulatory agents, Dr. Brown said.
Registration trial toxicities
Among 760 patients enrolled in trials for the idelalisib registration programs, grade 3 or greater diarrhea and/or colitis and transaminitis each occurred in 14% of patients, rash occurred in 6%, and pneumonitis of any grade was seen in 3%.
Among patients with relapsed disease, transaminitis was often self-limiting and usually resolved when the drug was withheld, and about 75% of patients were successfully restarted on idelalisib at the same or lower dose, Dr. Brown noted.
Rashes, which can occur any time with therapy, were also successfully managed by withholding drug and then rechallenging, with the addition of corticosteroids as necessary.
Patients who developed drug-related pneumonitis were less likely than those with other toxicities to be rechallenged, and most required steroids until the infections resolved.
“The steroid responsiveness of many of these side effects suggested that they were autoimmune,” Dr. Brown said.
Drugs only work when you take them
The toxicities seen with idelalisib have had a marked effect on the use of the drug. In registration trials for idelalisib in combination with rituximab or ofatumumab (Arzerra), each of which had at least 2 years of follow-up, only 22.5% of 369 patients remained on idelalisib, primarily because of toxicities rather than disease progression. The combined 2-year progression in these trials was 13.3% In contrast, 40.7% of patients discontinued idelalisib because of adverse events.
Out to about 7 months, survival rates for patients who discontinued idelalisib because of disease progression or adverse events were roughly similar, but survival for the patients who stopped because of side effects began to plateau out to 2 years, Dr. Brown noted.
As of March 2016, 23.2% of patients who received idelalisib in clinical trials in combination with other agents as second- or third-line therapy had died, compared with 31% of controls, indicating a clear survival benefit with the drug.
“This is probably because the benefit of disease control in that setting overwhelmed the adverse event or infections problem,” she said.
Many of the deaths in registration trials were related to opportunistic infections, including Pneumocystis jiroveci pneumonia, fungal infection, and cytomegalovirus.
“Idelalisib, I think, is a prototypical delta inhibitor with a pattern of immune-mediated toxicity that remains unpredictable and can be severe. We now have pretty good data, based on the Gilead [sponsor] trials, that younger age and less prior therapy predispose to this toxicity,” Dr. Brown said.
Evidence is less robust, but growing, that mutated IGHV and a decrease in regulatory T cells may be also be risk factors for immune-mediated toxicities with idelalisib. Immune modulation with the drug may also account for associated neutropenia, sepsis, and opportunistic infections seen with idelalisib therapy, she added.
So how to use it?
Currently, the best uses for idelalisib and other PI3K inhibitors in CLL appear to be in single-agent therapy in patients with relapsed disease who cannot tolerate a Bruton’s tyrosine kinase (BTK) inhibitor such as ibrutinib (Imbruvica) or in patients whose disease has progressed on a BTK inhibitor.
“Where I think about this drug is in older, more heavily pretreated patients, who are generally at less risk for toxicities, and if they have significant comorbidities that may impact BTK-inhibitor tolerability, usually cardiac,” Dr. Brown said.
Future expansion of PI3K inhibitors in B-cell malignancies may require identifying a biomarker for tolerance, alternative dosing schedules, or identification of an idelalisib/drug X combination that might mitigate the toxicity, she said.
The immune-activation properties of PI3K-delta inhibitors suggests that they might also play a role as antitumor immunomodulatory agents in treatment of both hematologic malignancies and solid tumors, Dr. Brown concluded.
Idelalisib trials were sponsored by Gilead Sciences. Dr. Brown disclosed serving as a consultant for Gilead and other companies.
EXPERT ANALYSIS FROM LYMPHOMA & MYELOMA
Deep remission or long-term control? Choice is key in early CLL
SAN FRANCISCO – Pursue a deep remission that allows a patient to stay treatment free for some period of time, or go for long-term disease control that might not allow for a drug holiday?
It’s a key decision facing physicians in the frontline setting of chronic lymphocytic leukemia, William Wierda, MD, PhD, said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
For those with del(17p) or TP53 mutations, it’s probably best to aim for durable disease control with ibrutinib or high-dose methylprednisolone, plus an anti-CD20 monoclonal antibody, explained Dr. Wierda, medical director of the department of leukemia at MD Anderson Cancer Center, Houston.
The decision is more uncertain for those who are older or frail, he added.
“This is really where we need to select the option based on what our preference is, what our patient’s preference is, and have an understanding of the durability and toxicities with remission with the oral agent versus the toxicities and responses with regard to the chemoimmunotherapy regimens,” Dr. Wierda explained.
For those who are younger and fit, a chemoimmunotherapy regimen likely makes the most sense for those with a mutated IgHV gene, he said, because those patients have been shown to have a better prognosis on the fludarabine-cyclophosphamide-rituximab (FCR) combination.
Those with an unmutated IgHV gene probably should be approached differently, he added. “I know if they get FCR treatment, they will eventually relapse and progress. So, saving chemoimmunotherapy for later is an important endpoint.”
For relapsed patients who’ve had prior chemoimmunotherapy or who have del(17p) or TP53 mutations, options include ibrutinib, venetoclax with or without rituximab, idelalisib with or without rituximab, high-dose methylprednisolone plus an anti-CD20 monoclonal antibody, or lenalidomide plus an anti-CD20 monoclonal antibody.
For patients who’ve already had prior experience with a BTK inhibitor such as ibrutinib, Dr. Wierda suggested venetoclax, idelalisib with or without rituximab, chemoimmunotherapy if they’ve had no prior treatment, or high-dose methylprednisolone with an anti-CD20 monoclonal antibody.
It’s important to keep in mind ibrutinib’s effectiveness in that setting, Dr. Wierda noted. “You can effectively salvage patients with ibrutinib nearly as effectively as you can in the frontline setting.”
A recent study found that, for patients refractory to a kinase inhibitor, switching to a different kinase inhibitor was better than chemoimmunotherapy combinations. Researchers also found that using venetoclax after ibrutinib failure could be better than idelalisib (Ann Oncol. 2017 May 1;28[5]:1050-6)
Trials underway are testing first-line chemoimmunotherapy regimens to reach minimal residual disease-negativity, Dr. Wierda said, and examining combinations in the sequencing of small-molecule inhibitors for patients who have the unmutated IgHV gene.
“We’re also looking at consolidation strategies and have a definite interest in making progress for Richter’s transformation,” he added, an uncommon phenomenon that, in most cases, involves slow-growing CLL becoming aggressive diffuse large B-cell lymphoma. “We don’t know as much as we should know about it, and we have very few effective therapies for it.”
Dr. Wierda reported financial relationships with AbbVie, Celgene, Genentech, Merck, Novartis, Roche, and other companies.
SAN FRANCISCO – Pursue a deep remission that allows a patient to stay treatment free for some period of time, or go for long-term disease control that might not allow for a drug holiday?
It’s a key decision facing physicians in the frontline setting of chronic lymphocytic leukemia, William Wierda, MD, PhD, said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
For those with del(17p) or TP53 mutations, it’s probably best to aim for durable disease control with ibrutinib or high-dose methylprednisolone, plus an anti-CD20 monoclonal antibody, explained Dr. Wierda, medical director of the department of leukemia at MD Anderson Cancer Center, Houston.
The decision is more uncertain for those who are older or frail, he added.
“This is really where we need to select the option based on what our preference is, what our patient’s preference is, and have an understanding of the durability and toxicities with remission with the oral agent versus the toxicities and responses with regard to the chemoimmunotherapy regimens,” Dr. Wierda explained.
For those who are younger and fit, a chemoimmunotherapy regimen likely makes the most sense for those with a mutated IgHV gene, he said, because those patients have been shown to have a better prognosis on the fludarabine-cyclophosphamide-rituximab (FCR) combination.
Those with an unmutated IgHV gene probably should be approached differently, he added. “I know if they get FCR treatment, they will eventually relapse and progress. So, saving chemoimmunotherapy for later is an important endpoint.”
For relapsed patients who’ve had prior chemoimmunotherapy or who have del(17p) or TP53 mutations, options include ibrutinib, venetoclax with or without rituximab, idelalisib with or without rituximab, high-dose methylprednisolone plus an anti-CD20 monoclonal antibody, or lenalidomide plus an anti-CD20 monoclonal antibody.
For patients who’ve already had prior experience with a BTK inhibitor such as ibrutinib, Dr. Wierda suggested venetoclax, idelalisib with or without rituximab, chemoimmunotherapy if they’ve had no prior treatment, or high-dose methylprednisolone with an anti-CD20 monoclonal antibody.
It’s important to keep in mind ibrutinib’s effectiveness in that setting, Dr. Wierda noted. “You can effectively salvage patients with ibrutinib nearly as effectively as you can in the frontline setting.”
A recent study found that, for patients refractory to a kinase inhibitor, switching to a different kinase inhibitor was better than chemoimmunotherapy combinations. Researchers also found that using venetoclax after ibrutinib failure could be better than idelalisib (Ann Oncol. 2017 May 1;28[5]:1050-6)
Trials underway are testing first-line chemoimmunotherapy regimens to reach minimal residual disease-negativity, Dr. Wierda said, and examining combinations in the sequencing of small-molecule inhibitors for patients who have the unmutated IgHV gene.
“We’re also looking at consolidation strategies and have a definite interest in making progress for Richter’s transformation,” he added, an uncommon phenomenon that, in most cases, involves slow-growing CLL becoming aggressive diffuse large B-cell lymphoma. “We don’t know as much as we should know about it, and we have very few effective therapies for it.”
Dr. Wierda reported financial relationships with AbbVie, Celgene, Genentech, Merck, Novartis, Roche, and other companies.
SAN FRANCISCO – Pursue a deep remission that allows a patient to stay treatment free for some period of time, or go for long-term disease control that might not allow for a drug holiday?
It’s a key decision facing physicians in the frontline setting of chronic lymphocytic leukemia, William Wierda, MD, PhD, said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
For those with del(17p) or TP53 mutations, it’s probably best to aim for durable disease control with ibrutinib or high-dose methylprednisolone, plus an anti-CD20 monoclonal antibody, explained Dr. Wierda, medical director of the department of leukemia at MD Anderson Cancer Center, Houston.
The decision is more uncertain for those who are older or frail, he added.
“This is really where we need to select the option based on what our preference is, what our patient’s preference is, and have an understanding of the durability and toxicities with remission with the oral agent versus the toxicities and responses with regard to the chemoimmunotherapy regimens,” Dr. Wierda explained.
For those who are younger and fit, a chemoimmunotherapy regimen likely makes the most sense for those with a mutated IgHV gene, he said, because those patients have been shown to have a better prognosis on the fludarabine-cyclophosphamide-rituximab (FCR) combination.
Those with an unmutated IgHV gene probably should be approached differently, he added. “I know if they get FCR treatment, they will eventually relapse and progress. So, saving chemoimmunotherapy for later is an important endpoint.”
For relapsed patients who’ve had prior chemoimmunotherapy or who have del(17p) or TP53 mutations, options include ibrutinib, venetoclax with or without rituximab, idelalisib with or without rituximab, high-dose methylprednisolone plus an anti-CD20 monoclonal antibody, or lenalidomide plus an anti-CD20 monoclonal antibody.
For patients who’ve already had prior experience with a BTK inhibitor such as ibrutinib, Dr. Wierda suggested venetoclax, idelalisib with or without rituximab, chemoimmunotherapy if they’ve had no prior treatment, or high-dose methylprednisolone with an anti-CD20 monoclonal antibody.
It’s important to keep in mind ibrutinib’s effectiveness in that setting, Dr. Wierda noted. “You can effectively salvage patients with ibrutinib nearly as effectively as you can in the frontline setting.”
A recent study found that, for patients refractory to a kinase inhibitor, switching to a different kinase inhibitor was better than chemoimmunotherapy combinations. Researchers also found that using venetoclax after ibrutinib failure could be better than idelalisib (Ann Oncol. 2017 May 1;28[5]:1050-6)
Trials underway are testing first-line chemoimmunotherapy regimens to reach minimal residual disease-negativity, Dr. Wierda said, and examining combinations in the sequencing of small-molecule inhibitors for patients who have the unmutated IgHV gene.
“We’re also looking at consolidation strategies and have a definite interest in making progress for Richter’s transformation,” he added, an uncommon phenomenon that, in most cases, involves slow-growing CLL becoming aggressive diffuse large B-cell lymphoma. “We don’t know as much as we should know about it, and we have very few effective therapies for it.”
Dr. Wierda reported financial relationships with AbbVie, Celgene, Genentech, Merck, Novartis, Roche, and other companies.
AT NCCN HEMATOLOGIC MALIGNANCIES CONGRESS
M13-982 trial in del(17p) CLL: High, durable response rates to venetoclax
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
New York – Venetoclax monotherapy is associated with high and durable objective response rates in patients with del(17p) chronic lymphocytic leukemia (CLL), according to efficacy findings from the open-label M13-982 trial.
Additionally, a safety expansion of the pivotal phase 2 study showed that treatment was well tolerated, and assessment of minimal residual disease (MRD) status in the peripheral blood and bone marrow of study participants correlated with the 24-month progression-free survival estimate of 100% for patients with complete remission/complete remission with incomplete blood count recovery (CR/CRi), Stephan Stilgenbauer, MD, of the University of Ulm, Germany, and his colleagues reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
That response was maintained at 1 year in 85% of participants.
The current findings, which represent data through April 2017 for those 107 patients from the main cohort, as well as for 51 patients in the safety expansion study, show an overall response rate of 77%, with 20% CR/CRi.
The median time to first response was 1 month, and time to CR/CRi was 9.8 months, they said.
Estimates at 24 months for duration of response, progression-free survival, and overall survival were 66%, 54%, and 73%, respectively.
Additionally, objective responses were seen in four of five previously untreated patients who were enrolled in the safety expansion, and two of them had complete remissions. One patient with best response of stable disease decided to discontinue treatment but remained in follow-up with stable disease.
“All patients were alive at the time of analysis and remain progression free,” the investigators wrote.
In 18 patients who received prior B-cell receptor pathway inhibitor (BCRi) therapy, the objective response rate was 61% and the complete remission rate was 11%, with 12-month, progression-free and overall survival estimates of 50% and 54%, respectively.
Treatment-emergent adverse events of any grade occurred in 98% of patients, and led to dosing interruption in 40% and dosing adjustment in 17%. The most common adverse event was neutropenia; grade 3/4 neutropenia occurred in 40% of patients.
Neutropenia lead to a dose reduction in 8% of patients and to treatment interruption in 6% of patients; no discontinuations were reported.
Infections occurred in 81% of 158 patients, and grade 3/4 infections occurred in 23%; these infections were consistent with the underlying disease, the investigators said.
Laboratory tumor lysis syndrome (TLS) occurred in 5% of patients, but there were no episodes of clinical TLS, they said, noting that five TLS patients required dose interruptions. TLS occurred in four patients with medium risk at screening and in four with high risk. All episodes of TLS occurred during initial dosing or ramp-up, and all resolved. Affected patients were able to resume venetoclax with dose escalation to 400 mg/day.
The rate of minimal residual disease negativity was 30% in the intention-to-treat population as demonstrated by flow cytometry and confirmed by next generation sequencing (NGS) in 21 of 29 patients with an evaluable matched time point specimen. Bone marrow MRD negativity was observed in 20 patients by flow cytometry, and in 9 patients by NGS.
When looking at flow cytometry and NGS data combined, the MRD negativity rate in peripheral blood was 25% overall and 40% in evaluable patients, and the MRD negativity rate in bone marrow was 11% overall and 24% in evaluable patients.
Of those who achieved CR/CRi, 69% were MRD negative in peripheral blood by flow cytometry, with a 24-month, progression-free survival estimate of 100%, and 13 of those had confirmed MRD-negative blood by NGS, 2 had MRD-positive blood by NGS at a matched flow cytometry assessment, and 7 were not evaluated by NGS. For the remaining CR/CRi patients, who were MRD-positive by flow cytometry, the 24-month progression-free survival estimate was 86%.
Study participants in the main cohort were adults with a median age of 67 years who had relapsed/refractory CLL with an indication for treatment by iwCLL criteria, del(17p), good performance status, adequate bone marrow function, and creatinine clearance of at least 50 mg/min. They received a single test dose of 20 mg on day 1, with gradual ramp up to 400 mg over 4-5 weeks based on laboratory assessments. All were hospitalized for the first 20 mg and 50 mg venetoclax doses during ramp up.
Those in the safety expansion were treated with once-daily oral venetoclax starting at a dose of 20 mg/day for 1 week and ramped up to 400 mg by week 5. To mitigate TLS risk, uric acid–lowering agents and hydration were started at least 72 hours prior to administering the first dose. Those with high TLS risk – and some with medium risk – were hospitalized for the first 20-mg and 50-mg doses. Those with low TLS risk – and most with medium risk – received initial venetoclax dosing in an outpatient setting.
“Continued follow-up of patients in this trial will provide additional data on the durability of response with venetoclax in patients with del(17p) CLL,” the investigators wrote.
This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
AT THE iwCLL MEETING
Key clinical point:
Major finding: At April 2017 data analysis, the overall response rate was 77% with 20% CR/CRi.
Data source: The phase 2 open-label M13-982 Trial and safety expansion cohort of 158 total patients.
Disclosures: This study was supported by AbbVie and Genentech. Dr. Stilgenbauer received research funding, honoraria, and travel support from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi.
Ibrutinib and bleeding complications in Mohs surgery
Clinically significant bleeding events occurred in two elderly men who were taking ibrutinib and underwent Mohs micrographic surgery for squamous cell carcinomas, Cindy E. Parra and her colleagues reported in JAMA Dermatology.
On day 3 after his Mohs procedure, one 73-year-old man taking ibrutinib for Waldenstrom macroglobulinemia developed extensive bilateral periorbital ecchymosis that extended down to his upper chest. The other patient, an 88-year-old man taking ibrutinib for chronic lymphocytic leukemia, developed ecchymosis down to the chin. The first patient discontinued ibrutinib 3 days before his surgery; the second patient was taking ibrutinib at the time of his surgery.
“The increased incidence of nonmelanoma skin cancer and poorer outcomes in patients with non-Hodgkin lymphoma and CLL is well recognized, as is the importance of aggressive dermatologic management,” the researchers wrote (JAMA Dermatol. 2017 Jul 12. doi: 10.1001/jamadermatol.2017.1877). “It may be prudent to withhold ibrutinib treatment prior to dermatologic surgery to avoid potential bleeding complications.”
The findings argue for close collaboration between the dermatologic surgeon and the patient’s hematologist when scheduling extended-duration dermatologic procedures in patients taking ibrutinib.
Find the full summary here.
Clinically significant bleeding events occurred in two elderly men who were taking ibrutinib and underwent Mohs micrographic surgery for squamous cell carcinomas, Cindy E. Parra and her colleagues reported in JAMA Dermatology.
On day 3 after his Mohs procedure, one 73-year-old man taking ibrutinib for Waldenstrom macroglobulinemia developed extensive bilateral periorbital ecchymosis that extended down to his upper chest. The other patient, an 88-year-old man taking ibrutinib for chronic lymphocytic leukemia, developed ecchymosis down to the chin. The first patient discontinued ibrutinib 3 days before his surgery; the second patient was taking ibrutinib at the time of his surgery.
“The increased incidence of nonmelanoma skin cancer and poorer outcomes in patients with non-Hodgkin lymphoma and CLL is well recognized, as is the importance of aggressive dermatologic management,” the researchers wrote (JAMA Dermatol. 2017 Jul 12. doi: 10.1001/jamadermatol.2017.1877). “It may be prudent to withhold ibrutinib treatment prior to dermatologic surgery to avoid potential bleeding complications.”
The findings argue for close collaboration between the dermatologic surgeon and the patient’s hematologist when scheduling extended-duration dermatologic procedures in patients taking ibrutinib.
Find the full summary here.
Clinically significant bleeding events occurred in two elderly men who were taking ibrutinib and underwent Mohs micrographic surgery for squamous cell carcinomas, Cindy E. Parra and her colleagues reported in JAMA Dermatology.
On day 3 after his Mohs procedure, one 73-year-old man taking ibrutinib for Waldenstrom macroglobulinemia developed extensive bilateral periorbital ecchymosis that extended down to his upper chest. The other patient, an 88-year-old man taking ibrutinib for chronic lymphocytic leukemia, developed ecchymosis down to the chin. The first patient discontinued ibrutinib 3 days before his surgery; the second patient was taking ibrutinib at the time of his surgery.
“The increased incidence of nonmelanoma skin cancer and poorer outcomes in patients with non-Hodgkin lymphoma and CLL is well recognized, as is the importance of aggressive dermatologic management,” the researchers wrote (JAMA Dermatol. 2017 Jul 12. doi: 10.1001/jamadermatol.2017.1877). “It may be prudent to withhold ibrutinib treatment prior to dermatologic surgery to avoid potential bleeding complications.”
The findings argue for close collaboration between the dermatologic surgeon and the patient’s hematologist when scheduling extended-duration dermatologic procedures in patients taking ibrutinib.
Find the full summary here.
FROM JAMA DERMATOLOGY