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For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
FROM EHA 2021