User login
Inhibitor produces high response rate in relapsed/refractory FL
CHICAGO – The phosphoinositide 3-kinase–delta inhibitor ME-401, given with or without rituximab, produced an overall response rate of 80% in a phase 1b trial of patients with relapsed or refractory follicular lymphoma.
Response rates were similar between patients who received ME-401 alone and those who received it in combination with rituximab.
Response rates were also similar between patients on an intermittent dosing schedule and those on a continuous dosing schedule. However, intermittent dosing decreased the rate of delayed grade 3 adverse events (AEs).
“The idea that continuous inhibition of target is absolutely essential for activity of this class of drugs has not been proven,” said Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“The promising results of this somewhat novel intermittent schedule that we used with ME-401 suggests to me that we can maintain efficacy and reduce toxicity.”
Dr. Zelenetz and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.
Patients and dosing
Data were presented for 54 patients with relapsed/refractory follicular lymphoma enrolled on this study. The patients had a median age of 63.5 years, and 80% were male. They had received a median of 2 prior therapies (range, 1-10).
Initially, patients received ME-401 at 60 mg, 120 mg, or 180 mg once daily continuously on a 28-day cycle. However, the dose-escalation portion of the study was closed because response rates were comparable among the three doses, the safety profile was similar, and there were no dose-limiting toxicities.
Two additional groups of patients received ME-401 at 60 mg daily for two cycles, followed by an intermittent schedule (IS) of 60 mg on days 1-7, repeated every 28 days.
The researchers had observed delayed grade 3 AEs on the continuous schedule (CS), and they hypothesized that the IS might prevent these events. Patients could revert to the CS if they had stable disease or progressed on the IS.
“One of the advantages of this particular agent is the very long half-life,” Dr. Zelenetz said. “So, essentially, we have 2 weeks on drug and 2 weeks off [with the IS]. It takes about a week to clear the drug because it has about a 30-hour half-life.”
In all, 40 patients received ME-401 monotherapy, and 14 received ME-401 plus rituximab at 375 mg/m2 weekly for 4 weeks and then on day 1 of cycles 3-6. There were 31 patients who received ME-401 on the CS and 23 who received ME-401 on the IS.
Results
A total of 50 patients were evaluable for efficacy. The overall response rate in these patients was 80% (40/50), and 20% (10/50) achieved a complete response.
The overall response rate was 79% (30/38) in patients who received ME-401 alone, 83% (10/12) in those who received ME-401 plus rituximab, 83% (25/30) in patients on the CS, and 75% (15/20) in those on the IS.
The median duration of response and median progression-free survival have not been reached. The median follow-up for response duration is 8.8 months in the IS group and 8.3 months in the CS group. The median follow-up for progression-free survival is 5.5 months and 6.5 months, respectively.
A total of 18 patients on the IS (78%) were still on therapy at the data cutoff, as were 14 patients (45%) on the CS.
Seven patients (23%) on the CS and two patients (9%) on the IS discontinued treatment due to progression. Four patients in the IS group and two in the CS group who were switched to IS dosing reverted to CS dosing after experiencing progression.
Four CS patients (13%) discontinued treatment because of AEs, but none of the IS patients did.
AEs occurring in at least 15% of patients were diarrhea/colitis (40.7%), fatigue (35.2%), cough (33.3%), rash (24.1%), ALT increase (24.1%), nausea (24.1%), AST increase (22.2%), and decreased appetite (16.7%).
There were no grade 4-5 AEs. Grade 3 drug-related AEs of special interest (in the CS and IS groups, respectively) were diarrhea/colitis (16.1% and 8.7%), rash (12.9% and 0%), ALT increase (6.5% and 4.3%), AST increase (6.5% and 0%), pneumonia (6.5% and 0%), and mucositis (1.9% and 0%).
“[W]hile the grade 3 immune-related events seem to be very consistent in terms of class effects, they did seem to improve with transition to intermittent schedule,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.
“And I think that this novel design helps to create an opportunity to limit treatment and mitigate toxicity without necessarily compromising efficacy.”
The phase 1b trial is sponsored by MEI Pharma. Dr. Zelenetz reported relationships with MEI Pharma and several other companies. Dr. Casulo reported relationships with Gilead Sciences, Celgene, and Roche.
SOURCE: Zelenetz A et al. ASCO 2019, Abstract 7512.
CHICAGO – The phosphoinositide 3-kinase–delta inhibitor ME-401, given with or without rituximab, produced an overall response rate of 80% in a phase 1b trial of patients with relapsed or refractory follicular lymphoma.
Response rates were similar between patients who received ME-401 alone and those who received it in combination with rituximab.
Response rates were also similar between patients on an intermittent dosing schedule and those on a continuous dosing schedule. However, intermittent dosing decreased the rate of delayed grade 3 adverse events (AEs).
“The idea that continuous inhibition of target is absolutely essential for activity of this class of drugs has not been proven,” said Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“The promising results of this somewhat novel intermittent schedule that we used with ME-401 suggests to me that we can maintain efficacy and reduce toxicity.”
Dr. Zelenetz and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.
Patients and dosing
Data were presented for 54 patients with relapsed/refractory follicular lymphoma enrolled on this study. The patients had a median age of 63.5 years, and 80% were male. They had received a median of 2 prior therapies (range, 1-10).
Initially, patients received ME-401 at 60 mg, 120 mg, or 180 mg once daily continuously on a 28-day cycle. However, the dose-escalation portion of the study was closed because response rates were comparable among the three doses, the safety profile was similar, and there were no dose-limiting toxicities.
Two additional groups of patients received ME-401 at 60 mg daily for two cycles, followed by an intermittent schedule (IS) of 60 mg on days 1-7, repeated every 28 days.
The researchers had observed delayed grade 3 AEs on the continuous schedule (CS), and they hypothesized that the IS might prevent these events. Patients could revert to the CS if they had stable disease or progressed on the IS.
“One of the advantages of this particular agent is the very long half-life,” Dr. Zelenetz said. “So, essentially, we have 2 weeks on drug and 2 weeks off [with the IS]. It takes about a week to clear the drug because it has about a 30-hour half-life.”
In all, 40 patients received ME-401 monotherapy, and 14 received ME-401 plus rituximab at 375 mg/m2 weekly for 4 weeks and then on day 1 of cycles 3-6. There were 31 patients who received ME-401 on the CS and 23 who received ME-401 on the IS.
Results
A total of 50 patients were evaluable for efficacy. The overall response rate in these patients was 80% (40/50), and 20% (10/50) achieved a complete response.
The overall response rate was 79% (30/38) in patients who received ME-401 alone, 83% (10/12) in those who received ME-401 plus rituximab, 83% (25/30) in patients on the CS, and 75% (15/20) in those on the IS.
The median duration of response and median progression-free survival have not been reached. The median follow-up for response duration is 8.8 months in the IS group and 8.3 months in the CS group. The median follow-up for progression-free survival is 5.5 months and 6.5 months, respectively.
A total of 18 patients on the IS (78%) were still on therapy at the data cutoff, as were 14 patients (45%) on the CS.
Seven patients (23%) on the CS and two patients (9%) on the IS discontinued treatment due to progression. Four patients in the IS group and two in the CS group who were switched to IS dosing reverted to CS dosing after experiencing progression.
Four CS patients (13%) discontinued treatment because of AEs, but none of the IS patients did.
AEs occurring in at least 15% of patients were diarrhea/colitis (40.7%), fatigue (35.2%), cough (33.3%), rash (24.1%), ALT increase (24.1%), nausea (24.1%), AST increase (22.2%), and decreased appetite (16.7%).
There were no grade 4-5 AEs. Grade 3 drug-related AEs of special interest (in the CS and IS groups, respectively) were diarrhea/colitis (16.1% and 8.7%), rash (12.9% and 0%), ALT increase (6.5% and 4.3%), AST increase (6.5% and 0%), pneumonia (6.5% and 0%), and mucositis (1.9% and 0%).
“[W]hile the grade 3 immune-related events seem to be very consistent in terms of class effects, they did seem to improve with transition to intermittent schedule,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.
“And I think that this novel design helps to create an opportunity to limit treatment and mitigate toxicity without necessarily compromising efficacy.”
The phase 1b trial is sponsored by MEI Pharma. Dr. Zelenetz reported relationships with MEI Pharma and several other companies. Dr. Casulo reported relationships with Gilead Sciences, Celgene, and Roche.
SOURCE: Zelenetz A et al. ASCO 2019, Abstract 7512.
CHICAGO – The phosphoinositide 3-kinase–delta inhibitor ME-401, given with or without rituximab, produced an overall response rate of 80% in a phase 1b trial of patients with relapsed or refractory follicular lymphoma.
Response rates were similar between patients who received ME-401 alone and those who received it in combination with rituximab.
Response rates were also similar between patients on an intermittent dosing schedule and those on a continuous dosing schedule. However, intermittent dosing decreased the rate of delayed grade 3 adverse events (AEs).
“The idea that continuous inhibition of target is absolutely essential for activity of this class of drugs has not been proven,” said Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“The promising results of this somewhat novel intermittent schedule that we used with ME-401 suggests to me that we can maintain efficacy and reduce toxicity.”
Dr. Zelenetz and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.
Patients and dosing
Data were presented for 54 patients with relapsed/refractory follicular lymphoma enrolled on this study. The patients had a median age of 63.5 years, and 80% were male. They had received a median of 2 prior therapies (range, 1-10).
Initially, patients received ME-401 at 60 mg, 120 mg, or 180 mg once daily continuously on a 28-day cycle. However, the dose-escalation portion of the study was closed because response rates were comparable among the three doses, the safety profile was similar, and there were no dose-limiting toxicities.
Two additional groups of patients received ME-401 at 60 mg daily for two cycles, followed by an intermittent schedule (IS) of 60 mg on days 1-7, repeated every 28 days.
The researchers had observed delayed grade 3 AEs on the continuous schedule (CS), and they hypothesized that the IS might prevent these events. Patients could revert to the CS if they had stable disease or progressed on the IS.
“One of the advantages of this particular agent is the very long half-life,” Dr. Zelenetz said. “So, essentially, we have 2 weeks on drug and 2 weeks off [with the IS]. It takes about a week to clear the drug because it has about a 30-hour half-life.”
In all, 40 patients received ME-401 monotherapy, and 14 received ME-401 plus rituximab at 375 mg/m2 weekly for 4 weeks and then on day 1 of cycles 3-6. There were 31 patients who received ME-401 on the CS and 23 who received ME-401 on the IS.
Results
A total of 50 patients were evaluable for efficacy. The overall response rate in these patients was 80% (40/50), and 20% (10/50) achieved a complete response.
The overall response rate was 79% (30/38) in patients who received ME-401 alone, 83% (10/12) in those who received ME-401 plus rituximab, 83% (25/30) in patients on the CS, and 75% (15/20) in those on the IS.
The median duration of response and median progression-free survival have not been reached. The median follow-up for response duration is 8.8 months in the IS group and 8.3 months in the CS group. The median follow-up for progression-free survival is 5.5 months and 6.5 months, respectively.
A total of 18 patients on the IS (78%) were still on therapy at the data cutoff, as were 14 patients (45%) on the CS.
Seven patients (23%) on the CS and two patients (9%) on the IS discontinued treatment due to progression. Four patients in the IS group and two in the CS group who were switched to IS dosing reverted to CS dosing after experiencing progression.
Four CS patients (13%) discontinued treatment because of AEs, but none of the IS patients did.
AEs occurring in at least 15% of patients were diarrhea/colitis (40.7%), fatigue (35.2%), cough (33.3%), rash (24.1%), ALT increase (24.1%), nausea (24.1%), AST increase (22.2%), and decreased appetite (16.7%).
There were no grade 4-5 AEs. Grade 3 drug-related AEs of special interest (in the CS and IS groups, respectively) were diarrhea/colitis (16.1% and 8.7%), rash (12.9% and 0%), ALT increase (6.5% and 4.3%), AST increase (6.5% and 0%), pneumonia (6.5% and 0%), and mucositis (1.9% and 0%).
“[W]hile the grade 3 immune-related events seem to be very consistent in terms of class effects, they did seem to improve with transition to intermittent schedule,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.
“And I think that this novel design helps to create an opportunity to limit treatment and mitigate toxicity without necessarily compromising efficacy.”
The phase 1b trial is sponsored by MEI Pharma. Dr. Zelenetz reported relationships with MEI Pharma and several other companies. Dr. Casulo reported relationships with Gilead Sciences, Celgene, and Roche.
SOURCE: Zelenetz A et al. ASCO 2019, Abstract 7512.
REPORTING FROM ASCO 2019
FDA approves Polivy for DLBCL
The Food and Drug Administration has granted accelerated approval to Polivy (polatuzumab vedotin-piiq), in conjunction with bendamustine and a rituximab product, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have undergone at least two prior therapies.
The FDA approval is based on results of an open-label, multicenter clinical trial of 80 patients with DLBCL who had undergone at least one prior regimen. Patients received either Polivy plus bendamustine and rituximab or only bendamustine and rituximab for six 21-day cycles. At the completion of therapy, 40% of patients who received Polivy in conjunction with bendamustine and rituximab achieved a complete response, compared with 18% of patients who received only bendamustine and rituximab; total response was 63% in those who received Polivy and 25% in those who did not.
The most common adverse events included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Serious adverse events occurred in 64% of patients, most commonly from infection; the most common cause for treatment discontinuation was cytopenia.
The recommended dose of Polivy is 1.8 mg/kg as an intravenous infusion over 90 minutes every 21 days for six cycles in combination with bendamustine and a rituximab product, the FDA said. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated.
Find the full press release on the FDA website.
The Food and Drug Administration has granted accelerated approval to Polivy (polatuzumab vedotin-piiq), in conjunction with bendamustine and a rituximab product, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have undergone at least two prior therapies.
The FDA approval is based on results of an open-label, multicenter clinical trial of 80 patients with DLBCL who had undergone at least one prior regimen. Patients received either Polivy plus bendamustine and rituximab or only bendamustine and rituximab for six 21-day cycles. At the completion of therapy, 40% of patients who received Polivy in conjunction with bendamustine and rituximab achieved a complete response, compared with 18% of patients who received only bendamustine and rituximab; total response was 63% in those who received Polivy and 25% in those who did not.
The most common adverse events included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Serious adverse events occurred in 64% of patients, most commonly from infection; the most common cause for treatment discontinuation was cytopenia.
The recommended dose of Polivy is 1.8 mg/kg as an intravenous infusion over 90 minutes every 21 days for six cycles in combination with bendamustine and a rituximab product, the FDA said. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated.
Find the full press release on the FDA website.
The Food and Drug Administration has granted accelerated approval to Polivy (polatuzumab vedotin-piiq), in conjunction with bendamustine and a rituximab product, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have undergone at least two prior therapies.
The FDA approval is based on results of an open-label, multicenter clinical trial of 80 patients with DLBCL who had undergone at least one prior regimen. Patients received either Polivy plus bendamustine and rituximab or only bendamustine and rituximab for six 21-day cycles. At the completion of therapy, 40% of patients who received Polivy in conjunction with bendamustine and rituximab achieved a complete response, compared with 18% of patients who received only bendamustine and rituximab; total response was 63% in those who received Polivy and 25% in those who did not.
The most common adverse events included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. Serious adverse events occurred in 64% of patients, most commonly from infection; the most common cause for treatment discontinuation was cytopenia.
The recommended dose of Polivy is 1.8 mg/kg as an intravenous infusion over 90 minutes every 21 days for six cycles in combination with bendamustine and a rituximab product, the FDA said. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated.
Find the full press release on the FDA website.
Chemo-free Smart Start regimen looks promising in poor-prognosis DLBCL
CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.
The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.
The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.
That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.
“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”
Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.
“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”
Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.
The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.
“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.
Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.
There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.
The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.
“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”
Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.
The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.
SOURCE: Westin J et al. ASCO 2019, Abstract 7508.
CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.
The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.
The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.
That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.
“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”
Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.
“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”
Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.
The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.
“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.
Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.
There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.
The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.
“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”
Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.
The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.
SOURCE: Westin J et al. ASCO 2019, Abstract 7508.
CHICAGO – A chemotherapy-free regimen has produced promising early response and survival outcomes in patients with a particularly poor-prognosis subtype of diffuse large B-cell lymphoma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.
The overall response rate was 86% after two cycles of combined rituximab, lenalidomide, and ibrutinib – or RLI – in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) of the non–germinal center (non-GCB) subtype, said Jason Westin, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.
The response rate increased to 96% after subsequent cycles of RLI plus standard chemotherapy, said Dr.Westin, who added that the rates of progression-free and overall survival at 1 year were also 96% in the investigator initiated, single-arm, open-label, phase 2 study, called Smart Start.
That looks quite favorable, compared with what’s been achieved in previous studies in this poor-prognosis group of patients, Dr. Westin said during a podium presentation of Smart Start data, though he cautioned against direct comparison to historical studies and added that further follow-up is needed.
“Our survival outcomes appear excellent with about a year’s worth of follow-up,” he said during his presentation. “I’d say the novel/novel combinations, with and without chemotherapy, are feasible for large cell, and next step studies are warranted.”
Jasmine M. Zain, MD, of City of Hope Comprehensive Cancer Center, said these results so far raise the possibility of an effective chemotherapy-free treatment regimen for aggressive lymphomas.
“This regimen, particularly for non-GCB subtypes, is extremely promising,” Dr. Zain said during a podium discussion of the study. “I think we were all oohing and aahing over the results, and it could possibly even be practice changing.”
Moving to a nonchemotherapy regimen could raise new questions for treatment of non-GCB and possibly also GCB subtypes of DLBCL, such as when the treatments could be stopped, or whether a maintenance approach would be useful, she added.
The Smart Start study enrolled a total of 60 patients with non-GCB DLBCL. The patients received RLI for two 21-day cycles, followed by another six cycles of RLI plus chemotherapy, which was either EPOCH or CHOP, at the investigators’ discretion.
“With a median follow-up of 362 days, we’ve had three progression events,” Dr. Westin said in his discussion of the preliminary efficacy results.
Adverse events were similar to what would be expected for standard chemotherapy, according to Dr. Westin, except for rash, which was seen mainly in cycles one and two.
There were two deaths on study protocol, including one fatal fungal infection that investigators attributed to high dose corticosteroids and RLI. There were no subsequent fungal infections after a protocol amendment prohibiting corticosteroids during the RLI-only cycles, according to the investigators’ report.
The high response rates following the initial lead-in phase made investigators wonder what would happen without subsequent chemotherapy, Dr. Westin told attendees during his oral presentation. In one case, a 74-year-old man did complete the two lead-in cycles of RLI and declined further therapy.
“He’s now nearly 2 years out, without any additional therapy, and has not relapsed to date,” Dr. Westin said. “This is, again, with 6 weeks worth of RLI therapy.”
Final results and minimal residual disease data from the Smart Start study will be presented at a conference later in 2019, Dr. Westin said.
The study received research support and funding from the ASCO Conquer Cancer Foundation. The trial drug and support were provided by Celgene and Janssen. Dr. Westin reported disclosures related to Celgene, Genentech/Abbvie, Kite Pharma, Kite/Gilead, Novartis, ProNAi, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Karyopharm Therapeutics.
SOURCE: Westin J et al. ASCO 2019, Abstract 7508.
REPORTING FROM ASCO 2019
Fixed-duration venetoclax-obinutuzumab superior to standard CLL therapy
CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.
At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.
The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.
“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.
Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.
“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.
“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.
The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.
In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.
The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.
The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.
Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.
There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).
Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.
F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.
SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.
CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.
At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.
The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.
“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.
Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.
“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.
“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.
The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.
In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.
The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.
The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.
Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.
There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).
Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.
F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.
SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.
CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.
At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.
The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.
“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.
Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.
“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.
“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.
The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.
In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.
The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.
The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.
Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.
There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).
Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.
F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.
SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.
REPORTING FROM ASCO 2019
Venetoclax plus ibrutinib appears to suit elderly and high-risk patients with CLL
A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.
About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.
There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.
“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”
In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”
The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.
In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.
The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.
Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.
After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.
After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.
Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.
One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.
The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.
Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).
Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.
“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.
The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.
SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.
In addition to noting the “impressive” results from combining venetoclax and ibrutinib as frontline CLL therapy, Adrian Wiestner, MD, PhD, highlighted the lack of a Kaplan-Meier curve in the paper published by Jain et al. in the New England Journal of Medicine.
“Here, assessment of minimal residual disease has replaced the progression-free survival curve of old, indicating a possible shift in focus away from traditional clinical trial endpoints and toward even more stringent measures of clinical efficacy that may be central to regulatory decisions,” Dr. Wiestner wrote.
Dr. Wiestner of the National Institutes of Health made his remarks in an accompanying editorial (N Engl J Med. 2019 May 29. doi: 10.1056/NEJMe1904362). He reported grants from with Merck, Pharmacyclics (an AbbVie company), and Acerta Pharma.
In addition to noting the “impressive” results from combining venetoclax and ibrutinib as frontline CLL therapy, Adrian Wiestner, MD, PhD, highlighted the lack of a Kaplan-Meier curve in the paper published by Jain et al. in the New England Journal of Medicine.
“Here, assessment of minimal residual disease has replaced the progression-free survival curve of old, indicating a possible shift in focus away from traditional clinical trial endpoints and toward even more stringent measures of clinical efficacy that may be central to regulatory decisions,” Dr. Wiestner wrote.
Dr. Wiestner of the National Institutes of Health made his remarks in an accompanying editorial (N Engl J Med. 2019 May 29. doi: 10.1056/NEJMe1904362). He reported grants from with Merck, Pharmacyclics (an AbbVie company), and Acerta Pharma.
In addition to noting the “impressive” results from combining venetoclax and ibrutinib as frontline CLL therapy, Adrian Wiestner, MD, PhD, highlighted the lack of a Kaplan-Meier curve in the paper published by Jain et al. in the New England Journal of Medicine.
“Here, assessment of minimal residual disease has replaced the progression-free survival curve of old, indicating a possible shift in focus away from traditional clinical trial endpoints and toward even more stringent measures of clinical efficacy that may be central to regulatory decisions,” Dr. Wiestner wrote.
Dr. Wiestner of the National Institutes of Health made his remarks in an accompanying editorial (N Engl J Med. 2019 May 29. doi: 10.1056/NEJMe1904362). He reported grants from with Merck, Pharmacyclics (an AbbVie company), and Acerta Pharma.
A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.
About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.
There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.
“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”
In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”
The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.
In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.
The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.
Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.
After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.
After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.
Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.
One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.
The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.
Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).
Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.
“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.
The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.
SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.
A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.
About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.
There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.
“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”
In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”
The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.
In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.
The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.
Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.
After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.
After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.
Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.
One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.
The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.
Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).
Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.
“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.
The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.
SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: After 12 cycles of treatment with venetoclax and ibrutinib, 88% of patients had complete remission or complete remission with incomplete count recovery.
Study details: A randomized, open-label, phase 2 study involving 80 elderly and high-risk patients with chronic lymphocytic leukemia.
Disclosures: The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.
Source: Jain N et al. N Engl J Med. 2019;380:2095-103.
FDA approves lenalidomide/rituximab for previously treated FL, MZL
The Food and Drug Administration has approved lenalidomide (Revlimid), in combination with rituximab, for the treatment of adult patients with previously treated follicular or marginal zone lymphoma.
FDA approval is based on results from the randomized, double-blind, phase 3 AUGMENT trial, which evaluated lenalidomide/rituximab versus rituximab and placebo in patients with previously treated follicular or marginal zone lymphoma. The median progression-free survival in those receiving lenalidomide/rituximab was 39.4 months, compared with 14.1 months for those receiving rituximab/placebo (odds ratio, 0.46; 95% confidence interval, 0.34-0.62; P less than .0001).
A numeric trend was seen in overall survival over the follow-up period of 28.3 months (16 vs. 26 deaths; hazard ratio, 0.61; 95% CI, 0.33-1.13).
The most common adverse events associated with lenalidomide/rituximab are neutropenia, diarrhea, constipation, cough, fatigue, rash, pyrexia, leukopenia, pruritus, upper respiratory tract infections, abdominal pain, anemia, headache, and thrombocytopenia. Lenalidomide also contains a boxed warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.
“Chemotherapy continues to be a standard of care for indolent forms of NHL, but most patients will relapse or become refractory to their current treatment. This approval represents a new therapeutic option for previously treated patients with follicular and marginal zone lymphomas, including those who relapse or no longer respond to initial treatment,” Meghan Gutierrez, CEO of the Lymphoma Research Foundation, said in a statement.
The Food and Drug Administration has approved lenalidomide (Revlimid), in combination with rituximab, for the treatment of adult patients with previously treated follicular or marginal zone lymphoma.
FDA approval is based on results from the randomized, double-blind, phase 3 AUGMENT trial, which evaluated lenalidomide/rituximab versus rituximab and placebo in patients with previously treated follicular or marginal zone lymphoma. The median progression-free survival in those receiving lenalidomide/rituximab was 39.4 months, compared with 14.1 months for those receiving rituximab/placebo (odds ratio, 0.46; 95% confidence interval, 0.34-0.62; P less than .0001).
A numeric trend was seen in overall survival over the follow-up period of 28.3 months (16 vs. 26 deaths; hazard ratio, 0.61; 95% CI, 0.33-1.13).
The most common adverse events associated with lenalidomide/rituximab are neutropenia, diarrhea, constipation, cough, fatigue, rash, pyrexia, leukopenia, pruritus, upper respiratory tract infections, abdominal pain, anemia, headache, and thrombocytopenia. Lenalidomide also contains a boxed warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.
“Chemotherapy continues to be a standard of care for indolent forms of NHL, but most patients will relapse or become refractory to their current treatment. This approval represents a new therapeutic option for previously treated patients with follicular and marginal zone lymphomas, including those who relapse or no longer respond to initial treatment,” Meghan Gutierrez, CEO of the Lymphoma Research Foundation, said in a statement.
The Food and Drug Administration has approved lenalidomide (Revlimid), in combination with rituximab, for the treatment of adult patients with previously treated follicular or marginal zone lymphoma.
FDA approval is based on results from the randomized, double-blind, phase 3 AUGMENT trial, which evaluated lenalidomide/rituximab versus rituximab and placebo in patients with previously treated follicular or marginal zone lymphoma. The median progression-free survival in those receiving lenalidomide/rituximab was 39.4 months, compared with 14.1 months for those receiving rituximab/placebo (odds ratio, 0.46; 95% confidence interval, 0.34-0.62; P less than .0001).
A numeric trend was seen in overall survival over the follow-up period of 28.3 months (16 vs. 26 deaths; hazard ratio, 0.61; 95% CI, 0.33-1.13).
The most common adverse events associated with lenalidomide/rituximab are neutropenia, diarrhea, constipation, cough, fatigue, rash, pyrexia, leukopenia, pruritus, upper respiratory tract infections, abdominal pain, anemia, headache, and thrombocytopenia. Lenalidomide also contains a boxed warning for embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.
“Chemotherapy continues to be a standard of care for indolent forms of NHL, but most patients will relapse or become refractory to their current treatment. This approval represents a new therapeutic option for previously treated patients with follicular and marginal zone lymphomas, including those who relapse or no longer respond to initial treatment,” Meghan Gutierrez, CEO of the Lymphoma Research Foundation, said in a statement.
Genetic analysis identifies prognostic markers in CLL
A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.
Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.
The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.
The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.
Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.
After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.
When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.
“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.
The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.
The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.
SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.
A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.
Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.
The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.
The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.
Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.
After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.
When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.
“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.
The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.
The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.
SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.
A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.
Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.
The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.
The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.
Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.
After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.
When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.
“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.
The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.
The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.
SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.
FROM LEUKEMIA RESEARCH
CD23 expression linked to improved survival in MCL
In a large cohort of patients with mantle cell lymphoma (MCL), CD23 expression was associated with significantly improved survival outcomes, according to a retrospective analysis.
“Mantle cell lymphoma has a distinctive immunophenotype, typically positive for pan B-cell markers, CD5 and cyclin D1, but negative for CD10, CD23, and CD200. Although most cases show this immunophenotype, some MCL cases have atypical immunophenotypic features, such as expression of CD10, CD23, or rarely CD200 or lack of expression of CD5,” wrote Annapurna Saksena, MD, of MD Anderson Cancer Center, Houston, and colleagues. Their report is in Human Pathology.
They retrospectively reviewed medical records from a pathology database at MD Anderson from the period of 2008-2016. In all, 798 patients with MCL were identified, of which 103 were classified as CD23-positive via flow cytometry.
The team collected data related to the immunophenotypic and clinicopathologic characteristics of the disease, in addition to survival-related outcomes, including progression-free survival (PFS) and overall survival (OS). They compared outcomes for the CD23-positive group against 240 patients with CD23-negative MCL.
After analysis, Dr. Saksena and colleagues found that patients with CD23-positive MCL more frequently had bone marrow involvement (89% vs. 78%, P = .02), a leukemic nonnodal presentation (42% vs. 11%, P = .0001), an elevated leukocyte count (33% vs. 18%, P = .009), and stage 4 disease (87% vs. 77%, P = .03).
The researchers reported that CD23 expression was associated with significantly improved PFS and OS (P = .029 and P = .02, respectively) in the univariate analysis.
However, the prognostic significance was partially lost when leukemic nonnodal cases were excluded, the researchers reported.
In addition to the higher frequency of leukemic nonnodal presentation with CD23-positive MCL cases, there was a higher frequency of CD200 expression and a lower frequency of SOX11 expression.
The researchers acknowledged that a key limitation of the study was the loss of prognostic significance in the multivariate analysis. Further studies are needed to fully understand the links between CD23 expression and MCL survival, they noted.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Saksena A et al. Hum Pathol. 2019 May 2. doi: 10.1016/j.humpath.2019.04.010.
In a large cohort of patients with mantle cell lymphoma (MCL), CD23 expression was associated with significantly improved survival outcomes, according to a retrospective analysis.
“Mantle cell lymphoma has a distinctive immunophenotype, typically positive for pan B-cell markers, CD5 and cyclin D1, but negative for CD10, CD23, and CD200. Although most cases show this immunophenotype, some MCL cases have atypical immunophenotypic features, such as expression of CD10, CD23, or rarely CD200 or lack of expression of CD5,” wrote Annapurna Saksena, MD, of MD Anderson Cancer Center, Houston, and colleagues. Their report is in Human Pathology.
They retrospectively reviewed medical records from a pathology database at MD Anderson from the period of 2008-2016. In all, 798 patients with MCL were identified, of which 103 were classified as CD23-positive via flow cytometry.
The team collected data related to the immunophenotypic and clinicopathologic characteristics of the disease, in addition to survival-related outcomes, including progression-free survival (PFS) and overall survival (OS). They compared outcomes for the CD23-positive group against 240 patients with CD23-negative MCL.
After analysis, Dr. Saksena and colleagues found that patients with CD23-positive MCL more frequently had bone marrow involvement (89% vs. 78%, P = .02), a leukemic nonnodal presentation (42% vs. 11%, P = .0001), an elevated leukocyte count (33% vs. 18%, P = .009), and stage 4 disease (87% vs. 77%, P = .03).
The researchers reported that CD23 expression was associated with significantly improved PFS and OS (P = .029 and P = .02, respectively) in the univariate analysis.
However, the prognostic significance was partially lost when leukemic nonnodal cases were excluded, the researchers reported.
In addition to the higher frequency of leukemic nonnodal presentation with CD23-positive MCL cases, there was a higher frequency of CD200 expression and a lower frequency of SOX11 expression.
The researchers acknowledged that a key limitation of the study was the loss of prognostic significance in the multivariate analysis. Further studies are needed to fully understand the links between CD23 expression and MCL survival, they noted.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Saksena A et al. Hum Pathol. 2019 May 2. doi: 10.1016/j.humpath.2019.04.010.
In a large cohort of patients with mantle cell lymphoma (MCL), CD23 expression was associated with significantly improved survival outcomes, according to a retrospective analysis.
“Mantle cell lymphoma has a distinctive immunophenotype, typically positive for pan B-cell markers, CD5 and cyclin D1, but negative for CD10, CD23, and CD200. Although most cases show this immunophenotype, some MCL cases have atypical immunophenotypic features, such as expression of CD10, CD23, or rarely CD200 or lack of expression of CD5,” wrote Annapurna Saksena, MD, of MD Anderson Cancer Center, Houston, and colleagues. Their report is in Human Pathology.
They retrospectively reviewed medical records from a pathology database at MD Anderson from the period of 2008-2016. In all, 798 patients with MCL were identified, of which 103 were classified as CD23-positive via flow cytometry.
The team collected data related to the immunophenotypic and clinicopathologic characteristics of the disease, in addition to survival-related outcomes, including progression-free survival (PFS) and overall survival (OS). They compared outcomes for the CD23-positive group against 240 patients with CD23-negative MCL.
After analysis, Dr. Saksena and colleagues found that patients with CD23-positive MCL more frequently had bone marrow involvement (89% vs. 78%, P = .02), a leukemic nonnodal presentation (42% vs. 11%, P = .0001), an elevated leukocyte count (33% vs. 18%, P = .009), and stage 4 disease (87% vs. 77%, P = .03).
The researchers reported that CD23 expression was associated with significantly improved PFS and OS (P = .029 and P = .02, respectively) in the univariate analysis.
However, the prognostic significance was partially lost when leukemic nonnodal cases were excluded, the researchers reported.
In addition to the higher frequency of leukemic nonnodal presentation with CD23-positive MCL cases, there was a higher frequency of CD200 expression and a lower frequency of SOX11 expression.
The researchers acknowledged that a key limitation of the study was the loss of prognostic significance in the multivariate analysis. Further studies are needed to fully understand the links between CD23 expression and MCL survival, they noted.
No funding sources were reported. The authors reported having no conflicts of interest.
SOURCE: Saksena A et al. Hum Pathol. 2019 May 2. doi: 10.1016/j.humpath.2019.04.010.
FROM HUMAN PATHOLOGY
Trial follow-up spotlights survival gains in follicular lymphoma
Results from a 13-year follow-up of a trial comparing two types of rituximab-based chemotherapy as upfront treatment for patients with follicular lymphoma show an “extraordinary improvement” in overall survival, compared with the prerituximab era.
In a finding that the researchers termed “somewhat unexpected,” complete remission was the strongest factor in long-term survival.
Between March 2000 and May 2005, researchers enrolled 136 high-risk follicular lymphoma patients in the GITMO-IIL trial to evaluate the superiority of high-dose chemotherapy with rituximab and autograft (R-HDS) versus conventional chemotherapy with rituximab (R-CHOP) as frontline therapy. At a median follow-up of 4 years, there was no survival advantage for R-HDS.
In the current analysis – that had a 13-year median follow-up – median survival had not yet been reached. As of February 2017, two-thirds of all patients were alive at their last follow-up. Overall survival was 68.5% in the R-CHOP arm and 64.5% in the R-HDS arm, Riccardo Bruna, MD, of the European Institute of Oncology in Milano, Italy, and his colleagues, reported in Haematologica.
The main causes of death for the 46 patients who had died as of long-term follow-up were disease progression and secondary malignancies. Other causes included cardiovascular events, infections, graft failure following autograft, anaphylactic shock, and late sudden death.
Complete remission was seen in 98 patients (73.1%) overall – 59.1% in the R-CHOP arm and 86.7% in the R-HDS arm. Achieving durable complete remission was associated with prolonged survival, the researchers reported. Of the 79 patients in complete remission at 2 years after the start of treatment, 65 (82.3%) were alive at 13 years, compared with 21 (58.3%) of 36 patients who had an early relapse (P = .003).
“[Complete remission] achievement was the most important factor for prolonged survival,” the researchers wrote. “The importance of disease response is further emphasized by the first-time observation that [molecular remission] achievement is associated with survival duration and a high proportion of patients had prolonged survival in the absence of disease recurrence.”
The researchers reported that this is longest ever follow-up reported for first-line treatment of follicular lymphoma with rituximab-based chemotherapy.
This work was supported in part by the Ministero Italiano Università e Ricerca and by Banca del Piemonte. The initial clinical trial was supported by Compagnia di San Paolo, Regione Piemonte, and Roche, which provided rituximab for the study.
SOURCE: Bruna R et al. Haematologica. 2019 Apr 11. doi: 10.3324/haematol.2018.209932.
Results from a 13-year follow-up of a trial comparing two types of rituximab-based chemotherapy as upfront treatment for patients with follicular lymphoma show an “extraordinary improvement” in overall survival, compared with the prerituximab era.
In a finding that the researchers termed “somewhat unexpected,” complete remission was the strongest factor in long-term survival.
Between March 2000 and May 2005, researchers enrolled 136 high-risk follicular lymphoma patients in the GITMO-IIL trial to evaluate the superiority of high-dose chemotherapy with rituximab and autograft (R-HDS) versus conventional chemotherapy with rituximab (R-CHOP) as frontline therapy. At a median follow-up of 4 years, there was no survival advantage for R-HDS.
In the current analysis – that had a 13-year median follow-up – median survival had not yet been reached. As of February 2017, two-thirds of all patients were alive at their last follow-up. Overall survival was 68.5% in the R-CHOP arm and 64.5% in the R-HDS arm, Riccardo Bruna, MD, of the European Institute of Oncology in Milano, Italy, and his colleagues, reported in Haematologica.
The main causes of death for the 46 patients who had died as of long-term follow-up were disease progression and secondary malignancies. Other causes included cardiovascular events, infections, graft failure following autograft, anaphylactic shock, and late sudden death.
Complete remission was seen in 98 patients (73.1%) overall – 59.1% in the R-CHOP arm and 86.7% in the R-HDS arm. Achieving durable complete remission was associated with prolonged survival, the researchers reported. Of the 79 patients in complete remission at 2 years after the start of treatment, 65 (82.3%) were alive at 13 years, compared with 21 (58.3%) of 36 patients who had an early relapse (P = .003).
“[Complete remission] achievement was the most important factor for prolonged survival,” the researchers wrote. “The importance of disease response is further emphasized by the first-time observation that [molecular remission] achievement is associated with survival duration and a high proportion of patients had prolonged survival in the absence of disease recurrence.”
The researchers reported that this is longest ever follow-up reported for first-line treatment of follicular lymphoma with rituximab-based chemotherapy.
This work was supported in part by the Ministero Italiano Università e Ricerca and by Banca del Piemonte. The initial clinical trial was supported by Compagnia di San Paolo, Regione Piemonte, and Roche, which provided rituximab for the study.
SOURCE: Bruna R et al. Haematologica. 2019 Apr 11. doi: 10.3324/haematol.2018.209932.
Results from a 13-year follow-up of a trial comparing two types of rituximab-based chemotherapy as upfront treatment for patients with follicular lymphoma show an “extraordinary improvement” in overall survival, compared with the prerituximab era.
In a finding that the researchers termed “somewhat unexpected,” complete remission was the strongest factor in long-term survival.
Between March 2000 and May 2005, researchers enrolled 136 high-risk follicular lymphoma patients in the GITMO-IIL trial to evaluate the superiority of high-dose chemotherapy with rituximab and autograft (R-HDS) versus conventional chemotherapy with rituximab (R-CHOP) as frontline therapy. At a median follow-up of 4 years, there was no survival advantage for R-HDS.
In the current analysis – that had a 13-year median follow-up – median survival had not yet been reached. As of February 2017, two-thirds of all patients were alive at their last follow-up. Overall survival was 68.5% in the R-CHOP arm and 64.5% in the R-HDS arm, Riccardo Bruna, MD, of the European Institute of Oncology in Milano, Italy, and his colleagues, reported in Haematologica.
The main causes of death for the 46 patients who had died as of long-term follow-up were disease progression and secondary malignancies. Other causes included cardiovascular events, infections, graft failure following autograft, anaphylactic shock, and late sudden death.
Complete remission was seen in 98 patients (73.1%) overall – 59.1% in the R-CHOP arm and 86.7% in the R-HDS arm. Achieving durable complete remission was associated with prolonged survival, the researchers reported. Of the 79 patients in complete remission at 2 years after the start of treatment, 65 (82.3%) were alive at 13 years, compared with 21 (58.3%) of 36 patients who had an early relapse (P = .003).
“[Complete remission] achievement was the most important factor for prolonged survival,” the researchers wrote. “The importance of disease response is further emphasized by the first-time observation that [molecular remission] achievement is associated with survival duration and a high proportion of patients had prolonged survival in the absence of disease recurrence.”
The researchers reported that this is longest ever follow-up reported for first-line treatment of follicular lymphoma with rituximab-based chemotherapy.
This work was supported in part by the Ministero Italiano Università e Ricerca and by Banca del Piemonte. The initial clinical trial was supported by Compagnia di San Paolo, Regione Piemonte, and Roche, which provided rituximab for the study.
SOURCE: Bruna R et al. Haematologica. 2019 Apr 11. doi: 10.3324/haematol.2018.209932.
FROM HAEMATOLOGICA
FDA approves venetoclax/obinutuzumab combo for CLL
The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.
The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.
Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.
The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).
Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.
The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.
The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.
The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.
Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.
The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).
Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.
The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.
The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.
The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.
Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.
The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).
Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.
The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.