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Ibrutinib + venetoclax: High-risk features don’t lessen CLL response
In the new analysis, published in Clinical Cancer Research, investigators compared outcomes in 66 adults without genetic risk factors to 129 with deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain, all of which are associated with poor outcomes and poor responses to chemoimmunotherapy.
Over 95% of patients responded regardless of risk factors, with complete response in 61% of patients with and 53% of subjects without high-risk features. Progression free-survival (PFS) lasted at least 3 years in 88% of the high-risk group and 92% of low-risk patients, with over 95% of patients in both groups alive at 3 years
“Since high-risk genetic features inform treatment selection, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk CLL is important to determine how this regimen fits in the first-line treatment algorithm for the disease,” hematologic oncologist John Allan, MD, a CLL specialist at Weill Cornell Medical Center in New York and the lead investigator, said in a press release from American Association for Cancer Research, publisher of CCR.
Although the analysis was not powered to perform statistical comparisons between the two groups, Dr. Allan said the results “support fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population.”
The press release also noted that the outcomes “compare favorably” to other upfront targeted therapy approaches for CLL.
Experts respond
Asked for comment, Thomas LeBlanc, MD, a hematologic oncologist at Duke University in Durham, N.C., said “the advent of some fixed duration regimens with novel therapies has been an exciting thing for patients especially, recognizing that at the start of treatment one already knows the completion date, and one can also thus forgo much of the potentially cumulative physical, psychological, and financial toxicity of an indefinite oral therapy.”
As for the new findings, he said they show “that even in this high-risk population ... we can achieve remarkable remission rates and levels of [minimal residual disease] negativity by combining the two best drug classes to date in CLL: BTK inhibitors and venetoclax.”
Another expert, hematologic oncologist John Byrd, MD, a leukemia specialist at the University of Cincinnati, was more cautious.
“These findings confirm the results of many other prior studies of targeted therapies where high complete response rates with absence of detectable disease is observed,” he said.
However, while “such therapeutic combinations for sure enable treatment discontinuation,” Dr. Byrd noted, they “lack long-term follow-up. Given the added toxicities associated with these combinations and lack of long-term follow up, use of treatments such as those brought forth in the CAPTIVATE trial should be considered only in the context of a well-designed clinical trial.”
Study details
The new findings follow previous reports of CAPTIVATE, which found strong first-line response across CLL patients but did not focus as specifically on patients with high-risk genetic features.
Subjects received three 28-day cycles of ibrutinib 420 mg/day followed by twelve 28-day cycles of ibrutinib plus venetoclax, with a 5-week venetoclax ramp-up to 400 mg/day.
Side effects were similar regardless of high-risk features and included, most commonly, diarrhea, neutropenia, nausea, and arthralgia. The most common grade 3/4 treatment-emergent adverse events were neutropenia in 36% of patients in both groups and hypertension in 9% of patients with and 3% of patients without high-risk features.
The study was funded by Pharmacyclics/AbbVie, maker/marketer of both ibrutinib and venetoclax. Investigators had numerous ties to the companies, including Dr. Allan, who reported grants and/or personal fees. Dr. LeBlanc reported speaker/consulting honoraria from AbbVie as well as institutional research funding. Dr. Byrd did not have any connections to the companies.
In the new analysis, published in Clinical Cancer Research, investigators compared outcomes in 66 adults without genetic risk factors to 129 with deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain, all of which are associated with poor outcomes and poor responses to chemoimmunotherapy.
Over 95% of patients responded regardless of risk factors, with complete response in 61% of patients with and 53% of subjects without high-risk features. Progression free-survival (PFS) lasted at least 3 years in 88% of the high-risk group and 92% of low-risk patients, with over 95% of patients in both groups alive at 3 years
“Since high-risk genetic features inform treatment selection, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk CLL is important to determine how this regimen fits in the first-line treatment algorithm for the disease,” hematologic oncologist John Allan, MD, a CLL specialist at Weill Cornell Medical Center in New York and the lead investigator, said in a press release from American Association for Cancer Research, publisher of CCR.
Although the analysis was not powered to perform statistical comparisons between the two groups, Dr. Allan said the results “support fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population.”
The press release also noted that the outcomes “compare favorably” to other upfront targeted therapy approaches for CLL.
Experts respond
Asked for comment, Thomas LeBlanc, MD, a hematologic oncologist at Duke University in Durham, N.C., said “the advent of some fixed duration regimens with novel therapies has been an exciting thing for patients especially, recognizing that at the start of treatment one already knows the completion date, and one can also thus forgo much of the potentially cumulative physical, psychological, and financial toxicity of an indefinite oral therapy.”
As for the new findings, he said they show “that even in this high-risk population ... we can achieve remarkable remission rates and levels of [minimal residual disease] negativity by combining the two best drug classes to date in CLL: BTK inhibitors and venetoclax.”
Another expert, hematologic oncologist John Byrd, MD, a leukemia specialist at the University of Cincinnati, was more cautious.
“These findings confirm the results of many other prior studies of targeted therapies where high complete response rates with absence of detectable disease is observed,” he said.
However, while “such therapeutic combinations for sure enable treatment discontinuation,” Dr. Byrd noted, they “lack long-term follow-up. Given the added toxicities associated with these combinations and lack of long-term follow up, use of treatments such as those brought forth in the CAPTIVATE trial should be considered only in the context of a well-designed clinical trial.”
Study details
The new findings follow previous reports of CAPTIVATE, which found strong first-line response across CLL patients but did not focus as specifically on patients with high-risk genetic features.
Subjects received three 28-day cycles of ibrutinib 420 mg/day followed by twelve 28-day cycles of ibrutinib plus venetoclax, with a 5-week venetoclax ramp-up to 400 mg/day.
Side effects were similar regardless of high-risk features and included, most commonly, diarrhea, neutropenia, nausea, and arthralgia. The most common grade 3/4 treatment-emergent adverse events were neutropenia in 36% of patients in both groups and hypertension in 9% of patients with and 3% of patients without high-risk features.
The study was funded by Pharmacyclics/AbbVie, maker/marketer of both ibrutinib and venetoclax. Investigators had numerous ties to the companies, including Dr. Allan, who reported grants and/or personal fees. Dr. LeBlanc reported speaker/consulting honoraria from AbbVie as well as institutional research funding. Dr. Byrd did not have any connections to the companies.
In the new analysis, published in Clinical Cancer Research, investigators compared outcomes in 66 adults without genetic risk factors to 129 with deletion of 17p, mutated TP53, and/or unmutated immunoglobulin heavy chain, all of which are associated with poor outcomes and poor responses to chemoimmunotherapy.
Over 95% of patients responded regardless of risk factors, with complete response in 61% of patients with and 53% of subjects without high-risk features. Progression free-survival (PFS) lasted at least 3 years in 88% of the high-risk group and 92% of low-risk patients, with over 95% of patients in both groups alive at 3 years
“Since high-risk genetic features inform treatment selection, understanding the efficacy of fixed-duration ibrutinib plus venetoclax in patients with high-risk CLL is important to determine how this regimen fits in the first-line treatment algorithm for the disease,” hematologic oncologist John Allan, MD, a CLL specialist at Weill Cornell Medical Center in New York and the lead investigator, said in a press release from American Association for Cancer Research, publisher of CCR.
Although the analysis was not powered to perform statistical comparisons between the two groups, Dr. Allan said the results “support fixed-duration ibrutinib plus venetoclax as a treatment approach for this patient population.”
The press release also noted that the outcomes “compare favorably” to other upfront targeted therapy approaches for CLL.
Experts respond
Asked for comment, Thomas LeBlanc, MD, a hematologic oncologist at Duke University in Durham, N.C., said “the advent of some fixed duration regimens with novel therapies has been an exciting thing for patients especially, recognizing that at the start of treatment one already knows the completion date, and one can also thus forgo much of the potentially cumulative physical, psychological, and financial toxicity of an indefinite oral therapy.”
As for the new findings, he said they show “that even in this high-risk population ... we can achieve remarkable remission rates and levels of [minimal residual disease] negativity by combining the two best drug classes to date in CLL: BTK inhibitors and venetoclax.”
Another expert, hematologic oncologist John Byrd, MD, a leukemia specialist at the University of Cincinnati, was more cautious.
“These findings confirm the results of many other prior studies of targeted therapies where high complete response rates with absence of detectable disease is observed,” he said.
However, while “such therapeutic combinations for sure enable treatment discontinuation,” Dr. Byrd noted, they “lack long-term follow-up. Given the added toxicities associated with these combinations and lack of long-term follow up, use of treatments such as those brought forth in the CAPTIVATE trial should be considered only in the context of a well-designed clinical trial.”
Study details
The new findings follow previous reports of CAPTIVATE, which found strong first-line response across CLL patients but did not focus as specifically on patients with high-risk genetic features.
Subjects received three 28-day cycles of ibrutinib 420 mg/day followed by twelve 28-day cycles of ibrutinib plus venetoclax, with a 5-week venetoclax ramp-up to 400 mg/day.
Side effects were similar regardless of high-risk features and included, most commonly, diarrhea, neutropenia, nausea, and arthralgia. The most common grade 3/4 treatment-emergent adverse events were neutropenia in 36% of patients in both groups and hypertension in 9% of patients with and 3% of patients without high-risk features.
The study was funded by Pharmacyclics/AbbVie, maker/marketer of both ibrutinib and venetoclax. Investigators had numerous ties to the companies, including Dr. Allan, who reported grants and/or personal fees. Dr. LeBlanc reported speaker/consulting honoraria from AbbVie as well as institutional research funding. Dr. Byrd did not have any connections to the companies.
FROM CLINICAL CANCER RESEARCH
Widespread carboplatin, cisplatin shortages: NCCN survey
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
`Remarkable’: CAR T therapy for CLL/SLL
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
The phase 1/2 TRANSCEND CLL 004 trial represents “the first pivotal multicenter trial to evaluate a CAR T-cell therapy in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma,” first author Tanya Siddiqi, MD, associate professor in the division of lymphoma, City of Hope National Medical Center, Duarte, Calif., said in a press statement in connection with her presentation at the annual meeting of the American Society of Clinical Oncology.
“The durable complete responses observed with liso-cel in the TRANSCEND CLL 004 trial are remarkable and represent a major step in bringing a personalized, T cell–based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” she said.
Real-world evidence shows that patients with CLL or SLL who have relapsed or are refractory to treatment with BTKi therapy can have progressively worse outcomes. Moreover, with few other treatment options, research shows that the median time from dual discontinuation of BTKi and venetoclax to subsequent treatment failure or death is just 5.6 months.
“We are seeing a subset of patients now who are progressing on BTK inhibitors and venetoclax, and there is a high, unmet medical need for new, more effective treatments in this patient population,” Dr. Siddiqi said.
With liso-cel showing efficacy in the treatment of large B-cell lymphoma and receiving approval from the Food and Drug Administration for the indication, the multicenter TRANSCEND CLL 004 trial was launched to investigate the therapy’s effects in r/r CLL/SLL.
In a safety set of 117 patients with r/r CLL or SLL who received at least two prior lines of therapy, including a BTKi, patients received a single target dose of either 50 (n=9) or 100 × 106 (n = 87) CAR-positive T cells.
The primary efficacy analysis set included 49 patients who were treated with the target dose of 100 x 106 CAR-positive viable T cells of liso-cel.
With a median on-study follow-up of 21.1 months, the primary endpoint of a complete response (CR) and complete response was achieved among 18.4% (n = 9; P = .0006).
Among patients achieving a complete response, no disease progression or deaths were reported, with a median duration of response that was not reached.
The undetectable minimal residual disease (MRD) rate was 63.3% in blood and 59.2% in bone marrow, which was associated with progression-free survival.
The overall response rate was 42.9%, which was not statistically significant, and the median duration of an objective response was 35.3 months (95% confidence interval, 11.01 to not reached).
The median time to first response was 1.2 months, and the median time to first complete response was 3.0 months.
The results were consistent in the broader safety set of 117 patients, including those who were heavily pretreated with a median of five prior lines of therapy (range, 2-12) and high-risk disease, with a CR rate of 18.4%.
In terms of safety, no new safety signals were observed, and the treatment’s safety profile was manageable, the authors noted.
Cytokine release syndrome (CRS), common with CAR T-cell therapy, occurred in 85% of patients; however, most cases were low grade; 9% of cases were grade 3, and there were no grade 4 or 5 cases.
Neurologic events occurred among 45%, including grade 3 in 17.9% and grade 4 in 0.9%, with no cases of grade 5.
For treatment of the CRS, 69.2% of patients received tocilizumab and/or corticosteroids for the cases of CRS and neurological events.
Of 51 deaths that occurred while on the study, 43 occurred following liso-cel infusion, including 5 caused by treatment-emergent adverse events occurring within 90 days of liso-cel infusion.
One death was determined to be related to liso-cel, involving macrophage activation syndrome–hemophagocytic lymphohistiocytosis.
“The safety profile was manageable, with low rates of grade 3 or higher CRS and neurotoxicity,” Dr. Siddiqi said.
She noted that, as encouraging as the results are, work should continue regarding further improving survival for patients.
“We need to look at this population more closely to see how we can make it even better for them,” she said in her talk.
For instance, “do we need to add maintenance, or do we need to do something else with CAR T therapy? Because one shot of CAR T is buying them a lot of time – 6 or 12 months of progression-free survival, but maybe we can make it even better.”
Dr. Siddiqi noted that she has “a lot of patients” who received CAR T-cell therapy who have not progressed or relapsed after as long as 4 years.
“I also have some patients who did relapse at 3 or 3 and 1/2 years, but everybody is so thankful for having that time of several years without any treatment; without the need for continuous therapy or continuous doctors’ visits. It is actually priceless,” she said.
Largest data set to date
Commenting on the study, Jakub Svoboda, MD, agreed that the findings suggest an important role of liso-cel among the growing numbers of patients who progress despite standard therapies.
“This is an important study and the [results] are very relevant as there is a growing population of patients with CLL/SLL who stopped responding to both BTKi and venetoclax and have limited options,” Dr. Svoboda, a medical oncologist at Penn Medicine, and associate professor of medicine at the Hospital of the University of Pennsylvania, both in Philadelphia, said in an interview.
“Many of my CLL/SLL patients benefited from BTK inhibitors and venetoclax for years, but it is clear that these are not curative agents, and ultimately our patients need other effective therapeutic options,” he said. “We have seen reports of smaller single-site studies with different anti-CD19 CAR T-cell products used in CLL/SLL in the past, but this multisite study using liso-cel represents the largest data set in over 100 patients with median follow-up of 21 months.”
Liso-cel, like other CAR T-cell treatments – which are derived from patients’ own cells that are then reengineered and delivered via a one-time infusion – has a 4-1BB costimulatory domain. This has the effect of enhancing the expansion and persistence of the CAR T cells.
Significantly, the study establishes that CAR T-cell manufacturing in CLL/SLL patients is feasible on a large scale, “which is important, considering the unique T-lymphocyte biology in CLL/SLL,” Dr. Svoboda remarked.
In terms of efficacy, “I have been mostly impressed by the high degree of undetectable minimal residual disease and the duration of response in the cohort of patients who previously failed both BTKi and venetoclax,” he added. “While there are a few agents used or being developed for patients failing both BTKi and venetoclax, it appears that CAR T-cell therapy has the unique potential to achieve long-term remissions in a subset of these patients.”
Discussant Carolyn Owen, MD, an associate professor in the division of hematology and hematological malignancies, University of Calgary (Alta.), and hematologist at the Tom Baker Cancer Centre, also in Calgary, also expressed enthusiasm over the encouraging results.
“The results of this study are very exciting,” she said during her discussion in the session.
“What is really important is that, even though this may be a small proportion of all of the patients, if we start offering this therapy a little bit earlier, and don’t wait for people to become completely refractory, we could increase the proportion of patients who are [not relapsing].”
Furthermore, “what’s most groundbreaking about this study is that patients could indeed have a really durable remission,” Dr. Owen added. “Hopefully not relapsing even beyond this 20-month follow up, which we haven’t seen with any of our other therapies.”
The results were also published in The Lancet.
The study was sponsored by Juno Therapeutics. Dr. Siddiqi disclosed relationships with Acerta Pharma, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb/Sanofi, Celgene, Juno Therapeutics, Kite, Oncternal Therapeutics, Pharmacyclics, and TG Therapeutics. Dr. Svoboda reported ties with Bristol-Myers Squibb. Dr. Owen disclosed relationships with Janssen, AstraZeneca, Roche Canada, AbbVie, Novartis Canada Pharmaceuticals, BeiGene, Merck, Incyte, and Seagen.
FROM ASCO 2023
PMBCL: Postremission, patients may safely skip radiation
“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).
The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.
While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.
However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.
In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.
Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.
With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.
The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.
Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.
With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).
After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.
The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.
“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.
Overall survival after 3 years was excellent and identical in both arms, at about 99%.
To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.
Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.
“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.
“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”
Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.
“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.
In further comments, he added that “these results will inform and likely change clinical practice.”
Dr. Speers said the study is notable for being the first of its kind.
“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.
“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.
“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.
The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.
“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”
Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.
“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.
The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.
“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).
The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.
While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.
However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.
In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.
Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.
With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.
The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.
Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.
With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).
After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.
The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.
“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.
Overall survival after 3 years was excellent and identical in both arms, at about 99%.
To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.
Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.
“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.
“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”
Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.
“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.
In further comments, he added that “these results will inform and likely change clinical practice.”
Dr. Speers said the study is notable for being the first of its kind.
“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.
“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.
“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.
The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.
“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”
Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.
“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.
The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.
“This study is the largest prospective study of PMBCL ever conducted,” said first author Emanuele Zucca, MD, consultant and head of the lymphoma unit at the Oncology Institute of Southern Switzerland in Bellinzona. Dr. Zucca presented the findings at the annual meeting of the American Society of Clinical Oncology (ASCO).
The results of the research underscore that “mediastinal radiation therapy in patients with complete remission after frontline immunochemotherapy can be safely omitted,” he said.
While PMBCL has a relatively low incidence, representing fewer than 5% of cases of non-Hodgkin lymphoma, the cancer is over-represented in young White women between approximately 30 and 40 years of age, and is a notably aggressive form of diffuse large B-cell lymphoma.
However, in patients who rapidly achieve remission with dose-intensive immunochemotherapy, the prognosis is good.
In such cases, the use of mediastinal radiation therapy has been seen as a measure to further consolidate the immunochemotherapy response, but the additional treatment comes at the cost of an increased risk of second malignancies, as well as coronary or valvular heart disease.
Meanwhile, in recent decades promising data has shown that aggressive chemoimmunotherapy regimens alone, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) can be enough for patients achieving a complete remission, while novel approaches such as checkpoint inhibitors and CAR T-cell therapy further show benefits in patients with lymphoma that relapses after treatment.
With ongoing controversy over whether to include the added radiation therapy among patients with a complete metabolic response, Dr. Zucca and his colleagues conducted the IELSG37 international study, enrolling 545 patients from 74 centers in 13 countries, including 336 women, with newly diagnosed PMBCL.
The patients were treated with induction chemoimmunotherapy with rituximab and anthracycline-based therapy based on local practice, and response assessed among of 530 of the 545 patients showed that 268 (50.6%) achieved a complete metabolic response.
Those patients were then randomized to either observation (n = 132) or consolidation radiation therapy (30 Gy; n = 136). The characteristics between the two groups were similar, with a mean age of 35.5, and about 65% female.
With a median follow-up of 63 months (range, 48-60 months), the primary endpoint of progression-free survival at 30 months was not significantly different between the observation arm (98.5%) and radiation therapy arm (96.2%; P = .278).
After adjustment for factors including sex, chemotherapy, country, and positron emission tomography (PET) response score, the estimated relative effect of radiotherapy versus observation was a hazard ratio of 0.68, and the absolute risk reduction associated with radiotherapy at 30 months was 1.2% after adjustment.
The number needed to treat is high, at 126.3 after stratification, and the 5-year overall survival was excellent in both arms, at 99%.
“What this tells us is that treatment with radiation therapy in well over 100 patients is needed just to avoid a single recurrence,” Dr. Zucca explained.
Overall survival after 3 years was excellent and identical in both arms, at about 99%.
To date, three severe cardiac events and three second cancers have been recorded in the study, all occurring among patients randomized to receive radiation therapy.
Dr. Zucca noted that longer follow-up is needed to better examine late toxicities.
“The long-term toxicities of mediastinal radiotherapy are well documented, particularly second breast, thyroid, and lung cancers and increased risk of coronary or valvular heart disease, in a patient group dominated by young adults,” Dr. Zucca said in a press statement.
“This study shows chemoimmunotherapy alone is an effective treatment for primary mediastinal B-cell lymphoma and strongly supports omitting radiotherapy without impacting chances of cure.”
Commenting on the study, Corey W. Speers, MD, PhD, assistant professor, radiation oncology, department of surgery, University of Michigan Hospital, Ann Arbor, said the findings have important clinical implications.
“We all should be encouraged by the low rates in this trial, which are lower than expected,” Dr. Speers said in a press briefing.
In further comments, he added that “these results will inform and likely change clinical practice.”
Dr. Speers said the study is notable for being the first of its kind.
“This clinical question has not previously been directly addressed, and this is the first study to do so,” he said.
“With more effective systemic therapies, many patients have their lymphoma disappear with early aggressive treatment, and although radiation is very effective at treating lymphoma, it has not been clear if it is needed in these patients that have an early rapid response to systemic therapy before starting radiation,” Dr. Speers explained.
“We have struggled as oncologists to know whether omitting this effective radiotherapy would compromise outcomes, and thus many were inclined to continue offering it to patients, even with the great early response. This study helps answer this critical question,” he said.
The results add reassuring evidence, buttressing efforts to avoid unnecessary interventions that may provide little or no benefit, Dr. Speers added.
“We are now in an era of ‘less being more’ as we seek ways to provide optimal quality and quantity of life to patients with cancer and their families, and this is just another example of the tremendous progress being made.”
Further commenting on the study at the press briefing, Julie R. Gralow, MD, ASCO chief medical officer and executive vice president, said the research supports ASCO’s ongoing efforts to reduce the toxicities of cancer treatment.
“Our ASCO vision is a world where cancer is either prevented or cured, and every patient is cured – and every survivor is healthy, and that part about every survivor being healthy is what we’re working on here [in this study],” Dr. Gralow said.
The study was funded by the Swiss Cancer League and Cancer Research UK, with partial support from the Swiss National Science Foundation. Dr. Zucca reported relationships with AstraZeneca, Beigene, Celgene, Incyte, Janssen, Merck, Roche, Celltrion Healthcare, Kite, and Abbvie. Dr. Speers disclosed his coinvention of technology that assesses radiosensitivity and predicts benefits from adjutant radiotherapy.
FROM ASCO 2023
New CLL meds: Improved survival rates, 1990-2018
“The clinical take-away from our study is that population-based statistics show a decline in mortality and an increase in survival that is concurrent with the introduction of new therapies for treating CLL,” said lead study author Nadia Howlader, PhD, of the Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Md. This research was published in Cancer Epidemiology, Biomarkers & Prevention.
From 1992 to 2011, CLL mortality decreased 1.1% annually, then the pace of the decline hastened to 3.6% per year from 2011 to 2021 among adults aged ≥ 20 years. Furthermore, 5-year survival rates among patients with CLL increased 0.7% per year on average from 1992 to 2016. To account for yearly random fluctuations in the number of cases detected, incidence data was fit to a model to determine the trend.
Although the study was not designed to specify which treatments were disseminated among patients or to estimate the impact of a specific drug, there were only six new drugs approved for CLL from 1991 to 2010. In contrast, between 2011 and 2018, 11 new CLL drugs (in particular the approval of new tyrosine kinase inhibitors (TKIs)) ushered in a period of more rapid annual decreases in mortality.
“The approval of ibrutinib [2014] was a sea change in decreasing CLL mortality. Earlier therapies like chemoimmunotherapies were not as effective in patients with TP53 mutation and/or 17P deletions,” said Binsah George, MD, of McGovern Medical School at UTHealth, Houston, who was not associated with the study.
New TKIs not only decrease mortality, but also have fewer side effects than earlier cytotoxic therapies, do not require inpatient treatment, and are available to all patients on Medicare and Medicaid.
Although patients with relapsed CLL may benefit from bone marrow transplants or CAR T-cell therapy, these treatments are not available at many community oncology practices. Furthermore, some patients are too sick to receive them or don’t have the economic and social resources to get them.
Even though TKIs increase overall survival in patients with CLL, they are not curative and require lifelong treatment.
“The estimated cost for CLL treatment is around $600,000 in a lifetime per patient, possibly placing significant burden on patients and the health care system,” said Dr. George.
“Certain trials are looking at stopping TKI treatment after a fixed period of time. This will let us learn more about the disease and could possibly lead to a decrease in cost and side effects of therapy,” concluded Dr. George.
Due to the study’s retrospective nature and data being sourced from state cancer registries and federal statistics, authors posited that rates of CLL could be underestimated, due to miscoding and missing information, particularly from those who get treatment outside of hospital settings. Additionally, some of the improvement in mortality could be attributed to better supportive care and less toxicity in medications, rather than then efficacy of novel agents.
Dr. Howlader and Dr. Binsah reported no conflicts of interest.
“The clinical take-away from our study is that population-based statistics show a decline in mortality and an increase in survival that is concurrent with the introduction of new therapies for treating CLL,” said lead study author Nadia Howlader, PhD, of the Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Md. This research was published in Cancer Epidemiology, Biomarkers & Prevention.
From 1992 to 2011, CLL mortality decreased 1.1% annually, then the pace of the decline hastened to 3.6% per year from 2011 to 2021 among adults aged ≥ 20 years. Furthermore, 5-year survival rates among patients with CLL increased 0.7% per year on average from 1992 to 2016. To account for yearly random fluctuations in the number of cases detected, incidence data was fit to a model to determine the trend.
Although the study was not designed to specify which treatments were disseminated among patients or to estimate the impact of a specific drug, there were only six new drugs approved for CLL from 1991 to 2010. In contrast, between 2011 and 2018, 11 new CLL drugs (in particular the approval of new tyrosine kinase inhibitors (TKIs)) ushered in a period of more rapid annual decreases in mortality.
“The approval of ibrutinib [2014] was a sea change in decreasing CLL mortality. Earlier therapies like chemoimmunotherapies were not as effective in patients with TP53 mutation and/or 17P deletions,” said Binsah George, MD, of McGovern Medical School at UTHealth, Houston, who was not associated with the study.
New TKIs not only decrease mortality, but also have fewer side effects than earlier cytotoxic therapies, do not require inpatient treatment, and are available to all patients on Medicare and Medicaid.
Although patients with relapsed CLL may benefit from bone marrow transplants or CAR T-cell therapy, these treatments are not available at many community oncology practices. Furthermore, some patients are too sick to receive them or don’t have the economic and social resources to get them.
Even though TKIs increase overall survival in patients with CLL, they are not curative and require lifelong treatment.
“The estimated cost for CLL treatment is around $600,000 in a lifetime per patient, possibly placing significant burden on patients and the health care system,” said Dr. George.
“Certain trials are looking at stopping TKI treatment after a fixed period of time. This will let us learn more about the disease and could possibly lead to a decrease in cost and side effects of therapy,” concluded Dr. George.
Due to the study’s retrospective nature and data being sourced from state cancer registries and federal statistics, authors posited that rates of CLL could be underestimated, due to miscoding and missing information, particularly from those who get treatment outside of hospital settings. Additionally, some of the improvement in mortality could be attributed to better supportive care and less toxicity in medications, rather than then efficacy of novel agents.
Dr. Howlader and Dr. Binsah reported no conflicts of interest.
“The clinical take-away from our study is that population-based statistics show a decline in mortality and an increase in survival that is concurrent with the introduction of new therapies for treating CLL,” said lead study author Nadia Howlader, PhD, of the Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Md. This research was published in Cancer Epidemiology, Biomarkers & Prevention.
From 1992 to 2011, CLL mortality decreased 1.1% annually, then the pace of the decline hastened to 3.6% per year from 2011 to 2021 among adults aged ≥ 20 years. Furthermore, 5-year survival rates among patients with CLL increased 0.7% per year on average from 1992 to 2016. To account for yearly random fluctuations in the number of cases detected, incidence data was fit to a model to determine the trend.
Although the study was not designed to specify which treatments were disseminated among patients or to estimate the impact of a specific drug, there were only six new drugs approved for CLL from 1991 to 2010. In contrast, between 2011 and 2018, 11 new CLL drugs (in particular the approval of new tyrosine kinase inhibitors (TKIs)) ushered in a period of more rapid annual decreases in mortality.
“The approval of ibrutinib [2014] was a sea change in decreasing CLL mortality. Earlier therapies like chemoimmunotherapies were not as effective in patients with TP53 mutation and/or 17P deletions,” said Binsah George, MD, of McGovern Medical School at UTHealth, Houston, who was not associated with the study.
New TKIs not only decrease mortality, but also have fewer side effects than earlier cytotoxic therapies, do not require inpatient treatment, and are available to all patients on Medicare and Medicaid.
Although patients with relapsed CLL may benefit from bone marrow transplants or CAR T-cell therapy, these treatments are not available at many community oncology practices. Furthermore, some patients are too sick to receive them or don’t have the economic and social resources to get them.
Even though TKIs increase overall survival in patients with CLL, they are not curative and require lifelong treatment.
“The estimated cost for CLL treatment is around $600,000 in a lifetime per patient, possibly placing significant burden on patients and the health care system,” said Dr. George.
“Certain trials are looking at stopping TKI treatment after a fixed period of time. This will let us learn more about the disease and could possibly lead to a decrease in cost and side effects of therapy,” concluded Dr. George.
Due to the study’s retrospective nature and data being sourced from state cancer registries and federal statistics, authors posited that rates of CLL could be underestimated, due to miscoding and missing information, particularly from those who get treatment outside of hospital settings. Additionally, some of the improvement in mortality could be attributed to better supportive care and less toxicity in medications, rather than then efficacy of novel agents.
Dr. Howlader and Dr. Binsah reported no conflicts of interest.
FROM CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION
Cross-border U.S.-Mexican collaboration drives up ALL survival
A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.
Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.
For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.
“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.
The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.
Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.
“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
‘Huge survival gap’
“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.
This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.
“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.
Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”
She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”
Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”
Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.
However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.
“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
Study details
Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.
In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.
The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.
“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.
This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.
Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.
Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.
Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
Impact of the collaboration
To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.
The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.
Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”
Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.
“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.
The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.
A version of this article first appeared on Medscape.com.
A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.
Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.
For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.
“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.
The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.
Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.
“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
‘Huge survival gap’
“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.
This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.
“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.
Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”
She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”
Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”
Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.
However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.
“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
Study details
Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.
In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.
The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.
“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.
This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.
Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.
Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.
Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
Impact of the collaboration
To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.
The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.
Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”
Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.
“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.
The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.
A version of this article first appeared on Medscape.com.
A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.
Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.
For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.
“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.
The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.
Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.
“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
‘Huge survival gap’
“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.
This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.
“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.
Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”
She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”
Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”
Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.
However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.
“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
Study details
Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.
In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.
The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.
“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.
This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.
Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.
Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.
Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
Impact of the collaboration
To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.
The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.
Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”
Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.
“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.
The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.
A version of this article first appeared on Medscape.com.
FROM ASCO 2023
FDA approves epcoritamab for r/r DLBCL
Epcoritamab is the first subcutaneous bispecific antibody approved for the indication. The biologic simultaneously binds CD3 on cytotoxic T cells to CD20 on lymphomic B cells, inducing T-cell mediated destruction.
“Together with our partner, AbbVie, we recognize the unmet need for safe, effective, and accessible treatments for patients with B-cell malignancies and we believe that epcoritamab has the potential to become a core therapy in this patient population,” Jan van de Winkel, PhD, CEO of Genmab, said in a press release announcing the FDA’s acceptance of its biologic licensing application in November 2022.
A potential competitor, Roche’s bispecific antibody mosunetuzumab (Lunsumio), was approved in December 2022. Mosunetuzumab has the same mechanism of action as epcoritamab but is indicated for relapsed or refractory follicular lymphoma after at least two lines of systemic therapy. A phase 3 trial is currently underway exploring epcoritamab for relapsed or refractory follicular lymphoma as part of combination therapy.
The current approval was based on the open-label phase 2 EPCORE NHL-1 trial conducted by AbbVie and Genmab. The trial’s efficacy population included 148 adults with relapsed or refractory CD20+ large B-cell lymphoma who had received at least two prior lines of therapy, including anti-CD20 therapies. Almost 40% had undergone CAR-T cell therapy.
Epcoritamab was administered initially once weekly, then every 2 weeks, and then every 4 weeks until disease progression or unacceptable toxicity. The trial had no comparator arm.
At a median follow-up of 10.7 months, the overall response rate was 61% and the complete response rate was 38%. At a median follow-up of 9.8 months among responders, the median duration of response was 15.6 months.
The prescribing information comes with a boxed warning for serious or life-threatening cytokine release syndrome and life-threatening or fatal immune effector cell–associated neurotoxicity syndrome. Warnings and precautions include infections and cytopenias.
Among the 157 patients who received epcoritamab in the trial at the recommended dose, grade 1-3 cytokine release syndrome occurred in 51%, immune effector cell–associated neurotoxicity syndrome occurred in 6% (with one fatal case), and 15% experienced serious infections.
The most common grade 3 or 4 events included neutropenia (14.6%), anemia (10.2%), and thrombocytopenia (5.7%).
The FDA recommends epcoritamab be administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity.
The FDA also noted that “this indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”
A version of this article first appeared on Medscape.com.
Epcoritamab is the first subcutaneous bispecific antibody approved for the indication. The biologic simultaneously binds CD3 on cytotoxic T cells to CD20 on lymphomic B cells, inducing T-cell mediated destruction.
“Together with our partner, AbbVie, we recognize the unmet need for safe, effective, and accessible treatments for patients with B-cell malignancies and we believe that epcoritamab has the potential to become a core therapy in this patient population,” Jan van de Winkel, PhD, CEO of Genmab, said in a press release announcing the FDA’s acceptance of its biologic licensing application in November 2022.
A potential competitor, Roche’s bispecific antibody mosunetuzumab (Lunsumio), was approved in December 2022. Mosunetuzumab has the same mechanism of action as epcoritamab but is indicated for relapsed or refractory follicular lymphoma after at least two lines of systemic therapy. A phase 3 trial is currently underway exploring epcoritamab for relapsed or refractory follicular lymphoma as part of combination therapy.
The current approval was based on the open-label phase 2 EPCORE NHL-1 trial conducted by AbbVie and Genmab. The trial’s efficacy population included 148 adults with relapsed or refractory CD20+ large B-cell lymphoma who had received at least two prior lines of therapy, including anti-CD20 therapies. Almost 40% had undergone CAR-T cell therapy.
Epcoritamab was administered initially once weekly, then every 2 weeks, and then every 4 weeks until disease progression or unacceptable toxicity. The trial had no comparator arm.
At a median follow-up of 10.7 months, the overall response rate was 61% and the complete response rate was 38%. At a median follow-up of 9.8 months among responders, the median duration of response was 15.6 months.
The prescribing information comes with a boxed warning for serious or life-threatening cytokine release syndrome and life-threatening or fatal immune effector cell–associated neurotoxicity syndrome. Warnings and precautions include infections and cytopenias.
Among the 157 patients who received epcoritamab in the trial at the recommended dose, grade 1-3 cytokine release syndrome occurred in 51%, immune effector cell–associated neurotoxicity syndrome occurred in 6% (with one fatal case), and 15% experienced serious infections.
The most common grade 3 or 4 events included neutropenia (14.6%), anemia (10.2%), and thrombocytopenia (5.7%).
The FDA recommends epcoritamab be administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity.
The FDA also noted that “this indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”
A version of this article first appeared on Medscape.com.
Epcoritamab is the first subcutaneous bispecific antibody approved for the indication. The biologic simultaneously binds CD3 on cytotoxic T cells to CD20 on lymphomic B cells, inducing T-cell mediated destruction.
“Together with our partner, AbbVie, we recognize the unmet need for safe, effective, and accessible treatments for patients with B-cell malignancies and we believe that epcoritamab has the potential to become a core therapy in this patient population,” Jan van de Winkel, PhD, CEO of Genmab, said in a press release announcing the FDA’s acceptance of its biologic licensing application in November 2022.
A potential competitor, Roche’s bispecific antibody mosunetuzumab (Lunsumio), was approved in December 2022. Mosunetuzumab has the same mechanism of action as epcoritamab but is indicated for relapsed or refractory follicular lymphoma after at least two lines of systemic therapy. A phase 3 trial is currently underway exploring epcoritamab for relapsed or refractory follicular lymphoma as part of combination therapy.
The current approval was based on the open-label phase 2 EPCORE NHL-1 trial conducted by AbbVie and Genmab. The trial’s efficacy population included 148 adults with relapsed or refractory CD20+ large B-cell lymphoma who had received at least two prior lines of therapy, including anti-CD20 therapies. Almost 40% had undergone CAR-T cell therapy.
Epcoritamab was administered initially once weekly, then every 2 weeks, and then every 4 weeks until disease progression or unacceptable toxicity. The trial had no comparator arm.
At a median follow-up of 10.7 months, the overall response rate was 61% and the complete response rate was 38%. At a median follow-up of 9.8 months among responders, the median duration of response was 15.6 months.
The prescribing information comes with a boxed warning for serious or life-threatening cytokine release syndrome and life-threatening or fatal immune effector cell–associated neurotoxicity syndrome. Warnings and precautions include infections and cytopenias.
Among the 157 patients who received epcoritamab in the trial at the recommended dose, grade 1-3 cytokine release syndrome occurred in 51%, immune effector cell–associated neurotoxicity syndrome occurred in 6% (with one fatal case), and 15% experienced serious infections.
The most common grade 3 or 4 events included neutropenia (14.6%), anemia (10.2%), and thrombocytopenia (5.7%).
The FDA recommends epcoritamab be administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity.
The FDA also noted that “this indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”
A version of this article first appeared on Medscape.com.
ASCO honors Hagop Kantarjian, MD, for leukemia research
This award is the society’s “highest scientific honor, and I am extremely happy and honored to receive it,” Dr. Kantarjian commented in an interview with this news organization.
Dr. Kantarjian serves as the chair of the department of leukemia and currently holds the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston.
“No doubt that this is not an individual award. It represents an award for the accomplishments of all the leukemia faculty at MD Anderson across 4 decades. It’s really a teamwork effort that led to so many discoveries and improvements in treatment and care of patients with leukemia,” he commented.
The David A. Karnofsky Memorial Award has been presented annually since 1970 to recognize oncologists who have made outstanding contributions to cancer research, diagnosis, or treatment, ASCO noted.
From Lebanon to Texas
Dr. Kantarjian received his medical degree from the American University of Beirut, in Lebanon, in 1979 and completed his residency in internal medicine at the same institution in 1981.
It was his experience at MD Anderson as a young medical student and later as a fellow that fueled his interest and career in leukemia, he said.
“In 1978, I took a 4-month elective at MD Anderson, and I soon realized how different and innovative the atmosphere at MD Anderson was, compared to where I was training in Lebanon,” Dr. Kantarjian told this news organization.
Working with mentors that included MD Anderson heavyweights Emil Freireich, MD, Kenneth McCredie, MD, and Michael Keating, MD, helped shape his career and guide his leukemia research, he said.
Transformative impact on leukemia outcomes
The award citation notes that over the past 4 decades, Dr. Kantarjian’s research has transformed some standards of care and has dramatically improved survival in several leukemia subtypes, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphocytic leukemia (ALL).
“Four decades ago, most of the leukemias were incurable. Today, most of the leukemias are potentially curable with targeted therapies. That’s what I am most proud of,” Dr. Kantarjian told this news organization.
Among Dr. Kantarjian’s contributions to the field of leukemia:
- Developing the HYPER-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) as a standard-of-care, frontline therapy for adults with ALL.
- Establishing clinical biology parameters of CML, including definitions of CML phases and cytogenetic responses, and establishing new prognostic factors that were subsequently adopted in studies of tyrosine kinase inhibitors.
- Leading the development of decitabine and epigenetic hypomethylation therapy for MDS and for older/unfit patients with AML.
- Pioneering research with hypomethylating agents (HMAs) in combination with venetoclax, which led to FDA approval of HMA-venetoclax combinations for older/unfit patients with AML.
- Championing the development of clofarabine, conducting animal toxicology studies, and leading subsequent phase 1 and 2 trials and pivotal phase 3 and 4 trials that led to FDA approval of clofarabine for pediatric ALL.
- Developing several FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and venetoclax, which all received FDA approval for the treatment of AML and its subsets.
- Developing regimens for inotuzumab and blinatumomab combined with chemotherapy for adults with pre-B ALL.
- Working on the development of imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and omacetaxine, which all received FDA approval for CML therapy.
“Dr. Kantarjian’s long list of accomplishments and groundbreaking discoveries are a testament to his lifelong commitment to impactful cancer research and patient care,” Giulio Draetta, MD, PhD, chief scientific officer at MD Anderson, said in a statement.
Giving back
Dr. Kantarjian has written more than 2,200 peer-reviewed articles and more than 100 book chapters. In 2012, he cofounded the Society of Hematologic Oncology, which has now expanded worldwide.
He has served on multiple ASCO committees throughout the years and served on the ASCO board of directors from 2010 to 2015.
Dr. Kantarjian is passionately involved in mentoring and education. In 2000 he created the MD Anderson Leukemia Fellowship, which now trains about 10 fellows in leukemia annually.
He is a nonresident fellow in health care at the Rice Baker Institute and has written extensively on important health care issues in cancer, including the importance of universal equitable health care, health care safety nets, health care as a human right, and the problem of drug shortages.
Dr. Kantarjian is a strong advocate for more affordable drug therapies. For years he has been outspoken about the high price of leukemia drugs and has written high-profile articles in medical journals. He has even appeared on a popular television program to publicize the issue.
“Drug costs have been increasing over time. If you think about it, even if you discover a drug that cures cancer, but the drug is affordable for the 1% of the patients, then you have no cure for cancer,” Dr. Kantarjian told this news organization.
“I started speaking about the issue of the cancer drug costs in 2012. Unfortunately, we have not made progress simply because of the for-profit nature of health care and the strong lobbying by drug companies,” he added. Dr. Kantarjian hopes new legislation will eventually turn the tide.
Dr. Kantarjian has received many other honors throughout his distinguished career, including the American Lebanese Medical Association’s Lifetime Achievement Award, the American Association for Cancer Research’s Joseph H. Burchenal Memorial Award, and the Leukemia Society of America’s Outstanding Service to Mankind Award. He also was named an ASCO Fellow and a Leukemia Society of America Special Fellow and Scholar.
Dr. Kantarjian will be presented with the 2023 David A. Karnofsky Memorial Award, which includes a $25,000 honorarium, and will give a scientific lecture about his research at the ASCO annual meeting in Chicago in early June.
A version of this article originally appeared on Medscape.com.
This award is the society’s “highest scientific honor, and I am extremely happy and honored to receive it,” Dr. Kantarjian commented in an interview with this news organization.
Dr. Kantarjian serves as the chair of the department of leukemia and currently holds the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston.
“No doubt that this is not an individual award. It represents an award for the accomplishments of all the leukemia faculty at MD Anderson across 4 decades. It’s really a teamwork effort that led to so many discoveries and improvements in treatment and care of patients with leukemia,” he commented.
The David A. Karnofsky Memorial Award has been presented annually since 1970 to recognize oncologists who have made outstanding contributions to cancer research, diagnosis, or treatment, ASCO noted.
From Lebanon to Texas
Dr. Kantarjian received his medical degree from the American University of Beirut, in Lebanon, in 1979 and completed his residency in internal medicine at the same institution in 1981.
It was his experience at MD Anderson as a young medical student and later as a fellow that fueled his interest and career in leukemia, he said.
“In 1978, I took a 4-month elective at MD Anderson, and I soon realized how different and innovative the atmosphere at MD Anderson was, compared to where I was training in Lebanon,” Dr. Kantarjian told this news organization.
Working with mentors that included MD Anderson heavyweights Emil Freireich, MD, Kenneth McCredie, MD, and Michael Keating, MD, helped shape his career and guide his leukemia research, he said.
Transformative impact on leukemia outcomes
The award citation notes that over the past 4 decades, Dr. Kantarjian’s research has transformed some standards of care and has dramatically improved survival in several leukemia subtypes, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphocytic leukemia (ALL).
“Four decades ago, most of the leukemias were incurable. Today, most of the leukemias are potentially curable with targeted therapies. That’s what I am most proud of,” Dr. Kantarjian told this news organization.
Among Dr. Kantarjian’s contributions to the field of leukemia:
- Developing the HYPER-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) as a standard-of-care, frontline therapy for adults with ALL.
- Establishing clinical biology parameters of CML, including definitions of CML phases and cytogenetic responses, and establishing new prognostic factors that were subsequently adopted in studies of tyrosine kinase inhibitors.
- Leading the development of decitabine and epigenetic hypomethylation therapy for MDS and for older/unfit patients with AML.
- Pioneering research with hypomethylating agents (HMAs) in combination with venetoclax, which led to FDA approval of HMA-venetoclax combinations for older/unfit patients with AML.
- Championing the development of clofarabine, conducting animal toxicology studies, and leading subsequent phase 1 and 2 trials and pivotal phase 3 and 4 trials that led to FDA approval of clofarabine for pediatric ALL.
- Developing several FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and venetoclax, which all received FDA approval for the treatment of AML and its subsets.
- Developing regimens for inotuzumab and blinatumomab combined with chemotherapy for adults with pre-B ALL.
- Working on the development of imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and omacetaxine, which all received FDA approval for CML therapy.
“Dr. Kantarjian’s long list of accomplishments and groundbreaking discoveries are a testament to his lifelong commitment to impactful cancer research and patient care,” Giulio Draetta, MD, PhD, chief scientific officer at MD Anderson, said in a statement.
Giving back
Dr. Kantarjian has written more than 2,200 peer-reviewed articles and more than 100 book chapters. In 2012, he cofounded the Society of Hematologic Oncology, which has now expanded worldwide.
He has served on multiple ASCO committees throughout the years and served on the ASCO board of directors from 2010 to 2015.
Dr. Kantarjian is passionately involved in mentoring and education. In 2000 he created the MD Anderson Leukemia Fellowship, which now trains about 10 fellows in leukemia annually.
He is a nonresident fellow in health care at the Rice Baker Institute and has written extensively on important health care issues in cancer, including the importance of universal equitable health care, health care safety nets, health care as a human right, and the problem of drug shortages.
Dr. Kantarjian is a strong advocate for more affordable drug therapies. For years he has been outspoken about the high price of leukemia drugs and has written high-profile articles in medical journals. He has even appeared on a popular television program to publicize the issue.
“Drug costs have been increasing over time. If you think about it, even if you discover a drug that cures cancer, but the drug is affordable for the 1% of the patients, then you have no cure for cancer,” Dr. Kantarjian told this news organization.
“I started speaking about the issue of the cancer drug costs in 2012. Unfortunately, we have not made progress simply because of the for-profit nature of health care and the strong lobbying by drug companies,” he added. Dr. Kantarjian hopes new legislation will eventually turn the tide.
Dr. Kantarjian has received many other honors throughout his distinguished career, including the American Lebanese Medical Association’s Lifetime Achievement Award, the American Association for Cancer Research’s Joseph H. Burchenal Memorial Award, and the Leukemia Society of America’s Outstanding Service to Mankind Award. He also was named an ASCO Fellow and a Leukemia Society of America Special Fellow and Scholar.
Dr. Kantarjian will be presented with the 2023 David A. Karnofsky Memorial Award, which includes a $25,000 honorarium, and will give a scientific lecture about his research at the ASCO annual meeting in Chicago in early June.
A version of this article originally appeared on Medscape.com.
This award is the society’s “highest scientific honor, and I am extremely happy and honored to receive it,” Dr. Kantarjian commented in an interview with this news organization.
Dr. Kantarjian serves as the chair of the department of leukemia and currently holds the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston.
“No doubt that this is not an individual award. It represents an award for the accomplishments of all the leukemia faculty at MD Anderson across 4 decades. It’s really a teamwork effort that led to so many discoveries and improvements in treatment and care of patients with leukemia,” he commented.
The David A. Karnofsky Memorial Award has been presented annually since 1970 to recognize oncologists who have made outstanding contributions to cancer research, diagnosis, or treatment, ASCO noted.
From Lebanon to Texas
Dr. Kantarjian received his medical degree from the American University of Beirut, in Lebanon, in 1979 and completed his residency in internal medicine at the same institution in 1981.
It was his experience at MD Anderson as a young medical student and later as a fellow that fueled his interest and career in leukemia, he said.
“In 1978, I took a 4-month elective at MD Anderson, and I soon realized how different and innovative the atmosphere at MD Anderson was, compared to where I was training in Lebanon,” Dr. Kantarjian told this news organization.
Working with mentors that included MD Anderson heavyweights Emil Freireich, MD, Kenneth McCredie, MD, and Michael Keating, MD, helped shape his career and guide his leukemia research, he said.
Transformative impact on leukemia outcomes
The award citation notes that over the past 4 decades, Dr. Kantarjian’s research has transformed some standards of care and has dramatically improved survival in several leukemia subtypes, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphocytic leukemia (ALL).
“Four decades ago, most of the leukemias were incurable. Today, most of the leukemias are potentially curable with targeted therapies. That’s what I am most proud of,” Dr. Kantarjian told this news organization.
Among Dr. Kantarjian’s contributions to the field of leukemia:
- Developing the HYPER-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) as a standard-of-care, frontline therapy for adults with ALL.
- Establishing clinical biology parameters of CML, including definitions of CML phases and cytogenetic responses, and establishing new prognostic factors that were subsequently adopted in studies of tyrosine kinase inhibitors.
- Leading the development of decitabine and epigenetic hypomethylation therapy for MDS and for older/unfit patients with AML.
- Pioneering research with hypomethylating agents (HMAs) in combination with venetoclax, which led to FDA approval of HMA-venetoclax combinations for older/unfit patients with AML.
- Championing the development of clofarabine, conducting animal toxicology studies, and leading subsequent phase 1 and 2 trials and pivotal phase 3 and 4 trials that led to FDA approval of clofarabine for pediatric ALL.
- Developing several FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and venetoclax, which all received FDA approval for the treatment of AML and its subsets.
- Developing regimens for inotuzumab and blinatumomab combined with chemotherapy for adults with pre-B ALL.
- Working on the development of imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and omacetaxine, which all received FDA approval for CML therapy.
“Dr. Kantarjian’s long list of accomplishments and groundbreaking discoveries are a testament to his lifelong commitment to impactful cancer research and patient care,” Giulio Draetta, MD, PhD, chief scientific officer at MD Anderson, said in a statement.
Giving back
Dr. Kantarjian has written more than 2,200 peer-reviewed articles and more than 100 book chapters. In 2012, he cofounded the Society of Hematologic Oncology, which has now expanded worldwide.
He has served on multiple ASCO committees throughout the years and served on the ASCO board of directors from 2010 to 2015.
Dr. Kantarjian is passionately involved in mentoring and education. In 2000 he created the MD Anderson Leukemia Fellowship, which now trains about 10 fellows in leukemia annually.
He is a nonresident fellow in health care at the Rice Baker Institute and has written extensively on important health care issues in cancer, including the importance of universal equitable health care, health care safety nets, health care as a human right, and the problem of drug shortages.
Dr. Kantarjian is a strong advocate for more affordable drug therapies. For years he has been outspoken about the high price of leukemia drugs and has written high-profile articles in medical journals. He has even appeared on a popular television program to publicize the issue.
“Drug costs have been increasing over time. If you think about it, even if you discover a drug that cures cancer, but the drug is affordable for the 1% of the patients, then you have no cure for cancer,” Dr. Kantarjian told this news organization.
“I started speaking about the issue of the cancer drug costs in 2012. Unfortunately, we have not made progress simply because of the for-profit nature of health care and the strong lobbying by drug companies,” he added. Dr. Kantarjian hopes new legislation will eventually turn the tide.
Dr. Kantarjian has received many other honors throughout his distinguished career, including the American Lebanese Medical Association’s Lifetime Achievement Award, the American Association for Cancer Research’s Joseph H. Burchenal Memorial Award, and the Leukemia Society of America’s Outstanding Service to Mankind Award. He also was named an ASCO Fellow and a Leukemia Society of America Special Fellow and Scholar.
Dr. Kantarjian will be presented with the 2023 David A. Karnofsky Memorial Award, which includes a $25,000 honorarium, and will give a scientific lecture about his research at the ASCO annual meeting in Chicago in early June.
A version of this article originally appeared on Medscape.com.
What’s Causing Cancers at Air Force Bases?
It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).
In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.
So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.
In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.
Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.
The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711th Human Performance Wing, obtained by the Associated Press.
This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.
In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”
On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.
The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.
Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”
The USAF has also established a website to address the missileer community’s concerns.
It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).
In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.
So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.
In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.
Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.
The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711th Human Performance Wing, obtained by the Associated Press.
This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.
In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”
On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.
The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.
Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”
The USAF has also established a website to address the missileer community’s concerns.
It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).
In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.
So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.
In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.
Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.
The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711th Human Performance Wing, obtained by the Associated Press.
This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.
In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”
On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.
The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.
Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”
The USAF has also established a website to address the missileer community’s concerns.
CLL: Venetoclax combos top first-line chemoimmunotherapy
according to a phase 3 trial published in the New England Journal of Medicine.
The trial, dubbed GAIA–CLL13, “is a remarkable demonstration of the quality of fixed-duration therapies for younger, fit patients, and it challenges us to continue to work to develop therapeutic strategies that will ultimately cure patients with CLL,” two hematologic cancer specialists said in an accompanying editorial.
In short, “venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib were superior to chemoimmunotherapy with respect to both the minimal residual disease end point and progression-free survival, but venetoclax-rituximab was not,” Jennifer Woyach, MD, of Ohio State University, Columbus, and John Byrd, MD, University of Cincinnati, said in their commentary.
Noting that randomized trials involving venetoclax combinations in fit CLL patients “have been lacking,” the investigators compared 6 cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) with 12 cycles of venetoclax plus the anti-CD20 antibody rituximab, venetoclax plus the third generation anti-CD20 antibody obinutuzumab, and venetoclax combined with both obinutuzumab and the Bruton’s tyrosine kinase inhibitor ibrutinib in a novel triple-therapy regimen.
The 926 patients in the study were a mean of 61 years old and split about evenly among the four treatment arms. Ibrutinib was discontinued after two consecutive measurements if patients had undetectable minimal residual disease (uMRD). Subjects did not have TP53 aberrations, a marker of poor prognosis in CLL.
At 15 months, the percentage of patients with uMRD was significantly higher in the triple-therapy arm (92.2%) and the venetoclax-obinutuzumab group (86.5%) than in the chemoimmunotherapy group (52.0%), but there was no statistical difference with venetoclax-rituximab (57%, P = .32).
The three-year progression-free survival (PFS) was 90.5% in the triple-therapy arm versus 87.7% with venetoclax-obinutuzumab. The 3-year PFS with venetoclax-rituximab (80.8%) was again not statistically different than the 75.5% with chemoimmunotherapy (P = .18).
Not ready for prime time
The benefits of triple therapy and venetoclax-obinutuzumab held only in patients with unmutated IgVH. “The high efficacy of the fludarabine, cyclophosphamide, and rituximab regimen in young, fit patients with mutated IgVH may be difficult to improve on,” noted the investigators, led by Barbara Eichhorst, MD, a hematologic malignancy specialist at the University of Cologne (Germany).
Also, although triple-therapy results were impressive, some of the benefits “are neutralized by the need for dose reductions and early treatment discontinuation owing to adverse events,” they said.
For instance, triple therapy had the highest incidence of both grade 3 and 4 infections (21.2%) and atrial fibrillation (7.8%).
The editorialists noted that there has been “a flurry of interest” in trials combining ibrutinib and venetoclax – as was done in the triple-therapy arm – since both emerged as powerful tools against CLL in recent years. However, even with the study results, they said “the use of triplet therapy should be viewed as investigational.”
For one thing, rates of uMRD were not “dramatically different” between triple therapy and venetoclax-obinutuzumab, and longer follow-up is better gauge differences in PFS and long-term toxicities.
Also, ibrutinib is being eclipsed by the second-generation Bruton’s tyrosine kinase inhibitors acalabrutinib and zanubrutinib, because they have better safety profiles, and they are being assessed in CLL combination trials. For now, there are too many unknowns for routine use of triple therapy in fit CLL patients, they said.
The investigators and editorialists both noted that improved uMRD in the study translated into superior PFS, raising the possibility that uMRD might be a valid alternative endpoint to PFS in CLL trials.
With “median remissions in CLL lasting far in excess of 5 years, designing studies that take 8-10 years” to reach a PFS endpoint is simply too slow. Moving to an alternative endpoint such a uMRD would preserve “the momentum that has been generated” with recent advances, Dr. Woyach and Dr. Byrd said.
The work was funded by the companies that market venetoclax, ibrutinib, and obinutuzumab: AbbVie, Janssen, and Roche. Dr. Eichhorst is a consultant and/or speaker for the companies and also reported grants from them. Dr. Byrd is a consultant/adviser for Eilean Therapeutics, Kurome Therapeutics, Newave, and Orbimed. Dr. Woyach disclosed ties with AbbVie, AstraZeneca, Lilly, and other companies.
according to a phase 3 trial published in the New England Journal of Medicine.
The trial, dubbed GAIA–CLL13, “is a remarkable demonstration of the quality of fixed-duration therapies for younger, fit patients, and it challenges us to continue to work to develop therapeutic strategies that will ultimately cure patients with CLL,” two hematologic cancer specialists said in an accompanying editorial.
In short, “venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib were superior to chemoimmunotherapy with respect to both the minimal residual disease end point and progression-free survival, but venetoclax-rituximab was not,” Jennifer Woyach, MD, of Ohio State University, Columbus, and John Byrd, MD, University of Cincinnati, said in their commentary.
Noting that randomized trials involving venetoclax combinations in fit CLL patients “have been lacking,” the investigators compared 6 cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) with 12 cycles of venetoclax plus the anti-CD20 antibody rituximab, venetoclax plus the third generation anti-CD20 antibody obinutuzumab, and venetoclax combined with both obinutuzumab and the Bruton’s tyrosine kinase inhibitor ibrutinib in a novel triple-therapy regimen.
The 926 patients in the study were a mean of 61 years old and split about evenly among the four treatment arms. Ibrutinib was discontinued after two consecutive measurements if patients had undetectable minimal residual disease (uMRD). Subjects did not have TP53 aberrations, a marker of poor prognosis in CLL.
At 15 months, the percentage of patients with uMRD was significantly higher in the triple-therapy arm (92.2%) and the venetoclax-obinutuzumab group (86.5%) than in the chemoimmunotherapy group (52.0%), but there was no statistical difference with venetoclax-rituximab (57%, P = .32).
The three-year progression-free survival (PFS) was 90.5% in the triple-therapy arm versus 87.7% with venetoclax-obinutuzumab. The 3-year PFS with venetoclax-rituximab (80.8%) was again not statistically different than the 75.5% with chemoimmunotherapy (P = .18).
Not ready for prime time
The benefits of triple therapy and venetoclax-obinutuzumab held only in patients with unmutated IgVH. “The high efficacy of the fludarabine, cyclophosphamide, and rituximab regimen in young, fit patients with mutated IgVH may be difficult to improve on,” noted the investigators, led by Barbara Eichhorst, MD, a hematologic malignancy specialist at the University of Cologne (Germany).
Also, although triple-therapy results were impressive, some of the benefits “are neutralized by the need for dose reductions and early treatment discontinuation owing to adverse events,” they said.
For instance, triple therapy had the highest incidence of both grade 3 and 4 infections (21.2%) and atrial fibrillation (7.8%).
The editorialists noted that there has been “a flurry of interest” in trials combining ibrutinib and venetoclax – as was done in the triple-therapy arm – since both emerged as powerful tools against CLL in recent years. However, even with the study results, they said “the use of triplet therapy should be viewed as investigational.”
For one thing, rates of uMRD were not “dramatically different” between triple therapy and venetoclax-obinutuzumab, and longer follow-up is better gauge differences in PFS and long-term toxicities.
Also, ibrutinib is being eclipsed by the second-generation Bruton’s tyrosine kinase inhibitors acalabrutinib and zanubrutinib, because they have better safety profiles, and they are being assessed in CLL combination trials. For now, there are too many unknowns for routine use of triple therapy in fit CLL patients, they said.
The investigators and editorialists both noted that improved uMRD in the study translated into superior PFS, raising the possibility that uMRD might be a valid alternative endpoint to PFS in CLL trials.
With “median remissions in CLL lasting far in excess of 5 years, designing studies that take 8-10 years” to reach a PFS endpoint is simply too slow. Moving to an alternative endpoint such a uMRD would preserve “the momentum that has been generated” with recent advances, Dr. Woyach and Dr. Byrd said.
The work was funded by the companies that market venetoclax, ibrutinib, and obinutuzumab: AbbVie, Janssen, and Roche. Dr. Eichhorst is a consultant and/or speaker for the companies and also reported grants from them. Dr. Byrd is a consultant/adviser for Eilean Therapeutics, Kurome Therapeutics, Newave, and Orbimed. Dr. Woyach disclosed ties with AbbVie, AstraZeneca, Lilly, and other companies.
according to a phase 3 trial published in the New England Journal of Medicine.
The trial, dubbed GAIA–CLL13, “is a remarkable demonstration of the quality of fixed-duration therapies for younger, fit patients, and it challenges us to continue to work to develop therapeutic strategies that will ultimately cure patients with CLL,” two hematologic cancer specialists said in an accompanying editorial.
In short, “venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib were superior to chemoimmunotherapy with respect to both the minimal residual disease end point and progression-free survival, but venetoclax-rituximab was not,” Jennifer Woyach, MD, of Ohio State University, Columbus, and John Byrd, MD, University of Cincinnati, said in their commentary.
Noting that randomized trials involving venetoclax combinations in fit CLL patients “have been lacking,” the investigators compared 6 cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) with 12 cycles of venetoclax plus the anti-CD20 antibody rituximab, venetoclax plus the third generation anti-CD20 antibody obinutuzumab, and venetoclax combined with both obinutuzumab and the Bruton’s tyrosine kinase inhibitor ibrutinib in a novel triple-therapy regimen.
The 926 patients in the study were a mean of 61 years old and split about evenly among the four treatment arms. Ibrutinib was discontinued after two consecutive measurements if patients had undetectable minimal residual disease (uMRD). Subjects did not have TP53 aberrations, a marker of poor prognosis in CLL.
At 15 months, the percentage of patients with uMRD was significantly higher in the triple-therapy arm (92.2%) and the venetoclax-obinutuzumab group (86.5%) than in the chemoimmunotherapy group (52.0%), but there was no statistical difference with venetoclax-rituximab (57%, P = .32).
The three-year progression-free survival (PFS) was 90.5% in the triple-therapy arm versus 87.7% with venetoclax-obinutuzumab. The 3-year PFS with venetoclax-rituximab (80.8%) was again not statistically different than the 75.5% with chemoimmunotherapy (P = .18).
Not ready for prime time
The benefits of triple therapy and venetoclax-obinutuzumab held only in patients with unmutated IgVH. “The high efficacy of the fludarabine, cyclophosphamide, and rituximab regimen in young, fit patients with mutated IgVH may be difficult to improve on,” noted the investigators, led by Barbara Eichhorst, MD, a hematologic malignancy specialist at the University of Cologne (Germany).
Also, although triple-therapy results were impressive, some of the benefits “are neutralized by the need for dose reductions and early treatment discontinuation owing to adverse events,” they said.
For instance, triple therapy had the highest incidence of both grade 3 and 4 infections (21.2%) and atrial fibrillation (7.8%).
The editorialists noted that there has been “a flurry of interest” in trials combining ibrutinib and venetoclax – as was done in the triple-therapy arm – since both emerged as powerful tools against CLL in recent years. However, even with the study results, they said “the use of triplet therapy should be viewed as investigational.”
For one thing, rates of uMRD were not “dramatically different” between triple therapy and venetoclax-obinutuzumab, and longer follow-up is better gauge differences in PFS and long-term toxicities.
Also, ibrutinib is being eclipsed by the second-generation Bruton’s tyrosine kinase inhibitors acalabrutinib and zanubrutinib, because they have better safety profiles, and they are being assessed in CLL combination trials. For now, there are too many unknowns for routine use of triple therapy in fit CLL patients, they said.
The investigators and editorialists both noted that improved uMRD in the study translated into superior PFS, raising the possibility that uMRD might be a valid alternative endpoint to PFS in CLL trials.
With “median remissions in CLL lasting far in excess of 5 years, designing studies that take 8-10 years” to reach a PFS endpoint is simply too slow. Moving to an alternative endpoint such a uMRD would preserve “the momentum that has been generated” with recent advances, Dr. Woyach and Dr. Byrd said.
The work was funded by the companies that market venetoclax, ibrutinib, and obinutuzumab: AbbVie, Janssen, and Roche. Dr. Eichhorst is a consultant and/or speaker for the companies and also reported grants from them. Dr. Byrd is a consultant/adviser for Eilean Therapeutics, Kurome Therapeutics, Newave, and Orbimed. Dr. Woyach disclosed ties with AbbVie, AstraZeneca, Lilly, and other companies.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE