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Front line ibrutinib-based regimens gain ground against CLL
Key clinical point: Compared with fludarabine, cyclophosphamide, and rituximab, ibrutinib and rituximab provided a significant progression-free survival (PFS) benefit in treatment-naive patients with chronic lymphocytic leukemia (CLL).
Major finding: After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib and rituximab and was 67 months (95% CI 63-not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (hazard ratio 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib and rituximab group.
Study details: This interim analysis of the multicenter phase 3 FLAIR trial included 771 treatment-naive adult patients with CLL or small lymphocytic lymphoma who were randomly assigned to receive ibrutinib and rituximab (n = 386) or fludarabine, cyclophosphamide, and rituximab (n = 385).
Disclosures: This study was funded by Cancer Research UK, Janssen, and others. Some authors declared participating on data safety monitoring or advisory boards and receiving grants, personal consulting or speaker fees, lecture honoraria, or travel support from the study funders and others.
Source: Hillmen P et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): Interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(5):535-552 (May). Doi: 10.1016/S1470-2045(23)00144-4
Key clinical point: Compared with fludarabine, cyclophosphamide, and rituximab, ibrutinib and rituximab provided a significant progression-free survival (PFS) benefit in treatment-naive patients with chronic lymphocytic leukemia (CLL).
Major finding: After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib and rituximab and was 67 months (95% CI 63-not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (hazard ratio 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib and rituximab group.
Study details: This interim analysis of the multicenter phase 3 FLAIR trial included 771 treatment-naive adult patients with CLL or small lymphocytic lymphoma who were randomly assigned to receive ibrutinib and rituximab (n = 386) or fludarabine, cyclophosphamide, and rituximab (n = 385).
Disclosures: This study was funded by Cancer Research UK, Janssen, and others. Some authors declared participating on data safety monitoring or advisory boards and receiving grants, personal consulting or speaker fees, lecture honoraria, or travel support from the study funders and others.
Source: Hillmen P et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): Interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(5):535-552 (May). Doi: 10.1016/S1470-2045(23)00144-4
Key clinical point: Compared with fludarabine, cyclophosphamide, and rituximab, ibrutinib and rituximab provided a significant progression-free survival (PFS) benefit in treatment-naive patients with chronic lymphocytic leukemia (CLL).
Major finding: After a median follow-up of 53 months, the median PFS was not reached in patients receiving ibrutinib and rituximab and was 67 months (95% CI 63-not reached) in those receiving fludarabine, cyclophosphamide, and rituximab (hazard ratio 0.44; P < .0001). A substantial number of sudden cardiac or unexplained deaths occurred, which were more frequent in the ibrutinib and rituximab group.
Study details: This interim analysis of the multicenter phase 3 FLAIR trial included 771 treatment-naive adult patients with CLL or small lymphocytic lymphoma who were randomly assigned to receive ibrutinib and rituximab (n = 386) or fludarabine, cyclophosphamide, and rituximab (n = 385).
Disclosures: This study was funded by Cancer Research UK, Janssen, and others. Some authors declared participating on data safety monitoring or advisory boards and receiving grants, personal consulting or speaker fees, lecture honoraria, or travel support from the study funders and others.
Source: Hillmen P et al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): Interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(5):535-552 (May). Doi: 10.1016/S1470-2045(23)00144-4
First-line venetoclax-obinutuzumab +/− ibrutinib tops chemoimmunotherapy in advanced CLL
Key clinical point: Compared with the current standard chemoimmunotherapy, venetoclax-obinutuzumab with or without ibrutinib as first line treatment improved outcomes in fit patients with advanced chronic lymphocytic leukemia (CLL).
Major finding: The venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib groups vs the chemoimmunotherapy group had significantly higher undetectable minimal residual disease rates at 15 months (86.5% and 92.2% vs 52.0%, respectively; both P < .001) and 3-year progression-free survival (hazard ratio for disease progression or death 0.42 and 0.32, respectively; both P < .001) and numerically lower fatal adverse event rate (3.9% and 3.9% vs 4.6%, respectively).
Study details: This phase 3 trial, GAIA-CLL13, included 926 fit adult patients with previously untreated, advanced CLL and no del(17p) or TP53 mutations who were randomly assigned to receive standard chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib.
Disclosures: This study was supported by AbbVie, Janssen, and Roche. Some authors declared serving as consultants, advisory board members, or speakers and receiving research grants, speaker honoraria, or travel support from the study funders and others.
Source: Eichhorst B et al for the GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754 (May 11). Doi: 10.1056/NEJMoa2213093
Key clinical point: Compared with the current standard chemoimmunotherapy, venetoclax-obinutuzumab with or without ibrutinib as first line treatment improved outcomes in fit patients with advanced chronic lymphocytic leukemia (CLL).
Major finding: The venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib groups vs the chemoimmunotherapy group had significantly higher undetectable minimal residual disease rates at 15 months (86.5% and 92.2% vs 52.0%, respectively; both P < .001) and 3-year progression-free survival (hazard ratio for disease progression or death 0.42 and 0.32, respectively; both P < .001) and numerically lower fatal adverse event rate (3.9% and 3.9% vs 4.6%, respectively).
Study details: This phase 3 trial, GAIA-CLL13, included 926 fit adult patients with previously untreated, advanced CLL and no del(17p) or TP53 mutations who were randomly assigned to receive standard chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib.
Disclosures: This study was supported by AbbVie, Janssen, and Roche. Some authors declared serving as consultants, advisory board members, or speakers and receiving research grants, speaker honoraria, or travel support from the study funders and others.
Source: Eichhorst B et al for the GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754 (May 11). Doi: 10.1056/NEJMoa2213093
Key clinical point: Compared with the current standard chemoimmunotherapy, venetoclax-obinutuzumab with or without ibrutinib as first line treatment improved outcomes in fit patients with advanced chronic lymphocytic leukemia (CLL).
Major finding: The venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib groups vs the chemoimmunotherapy group had significantly higher undetectable minimal residual disease rates at 15 months (86.5% and 92.2% vs 52.0%, respectively; both P < .001) and 3-year progression-free survival (hazard ratio for disease progression or death 0.42 and 0.32, respectively; both P < .001) and numerically lower fatal adverse event rate (3.9% and 3.9% vs 4.6%, respectively).
Study details: This phase 3 trial, GAIA-CLL13, included 926 fit adult patients with previously untreated, advanced CLL and no del(17p) or TP53 mutations who were randomly assigned to receive standard chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab), venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib.
Disclosures: This study was supported by AbbVie, Janssen, and Roche. Some authors declared serving as consultants, advisory board members, or speakers and receiving research grants, speaker honoraria, or travel support from the study funders and others.
Source: Eichhorst B et al for the GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754 (May 11). Doi: 10.1056/NEJMoa2213093
DLBCL: Major new treatment breakthroughs
Significant breakthroughs have come in just the past few weeks and months, through the use of CAR T-cell and immunotherapies and with the approval in April by the Food and Drug Administration of polatuzumab for frontline DLBCL.
“Until the publishing of data from the POLARIX study (NCT03274492), which led to the approval of polatuzumab vedotin plus rituximab-cyclophosphamide, doxorubicin, and prednisone (pola + R-CHP), we had not had a breakthrough in frontline DLBCL therapies since the addition of rituximab 22 years ago,” said Dr. Charalambos Andreadis, MD, of the University of California at San Francisco’s Helen Diller Family Comprehensive Cancer Center.
“Pola + R-CHP is an improvement over the standard-of-care treatment, R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone), giving treatment naive patients an increase in PFS without an increase in side effects,” Dr. Andreadis said.
R-CHP-polatuzumab was approved only for patients with an International Prognostic Indices score between 2 and 5, leaving patients with IPI scores of 0 or 1 with the frontline standard of care (SoC) treatment of R-CHOP, which has a cure rate of between 60% and 70%.
“The highest likelihood of relapse is in the first year following treatment. After 2 years in remission, patients’ chance of relapsing is the same as the general populations’ chance of getting DLBCL for the first time. This is why even a slight increase in the progression-free survival rate with the addition of pola is so significant,” Dr. Andreadis noted.
Historically, patients with relapsed or refractory (RR) DLBCL who did not respond to R-CHOP or who experienced disease relapse less than a year after primary intervention were treated with alternative chemotherapy regimens, often followed by autologous stem cell transplants (ASCT). Randomized control studies have shown that CAR T-cell therapies yield higher success rates than chemotherapy and ASCT, leading to the SoC in RR patients being CAR-T cell therapy directly following failed primary treatment.
“There are many new CAR T-cell platforms in development, as well as novel combination strategies that aim to target critical genetic pathways,” Kieron Dunleavy, MD, professor of medicine at the Lombardi Comprehensive Cancer Center at Georgetown University Hospital, said in an interview. “While access to CAR T-cell therapies is becoming easier and more feasible in many centers, fast access continues to be an issue for many patients, often depending on geography and socioeconomic factors.”
Asked about the latest breakthroughs in treating DLBCL, Dr. Dunleavy said, “A significant proportion of patients with relapsed or refractory DLBCL do not have easy access to CAR T-cell therapies, so this needs to be addressed and improved. Sometimes the rapidity of clinical progression in DLBCL can make these therapies challenging to deliver, considering logistical issues like apheresis and insurance approvals, which are frequently complex. This highlights the need for alternative and ‘easier to deliver’ CAR-T cells and our continued prioritization of developing alternative effective agents for DLBCL.
“Currently, commercially approved CAR T-cells in DLBCL target the CD-19 marker on lymphoma cells but CAR T-cells targeting other and more than one antigen as well as alternative anti CD19 agents like loncastuximab and tafasitamab are similarly FDA approved and available for patients,” Dr. Dunleavy concluded.
Dr. Dunleavy is affiliated with the MedStar Georgetown Lymphoma group, where Rep. Raskin publicly announced that he had completed 4 months of chemotherapy treatment for DLBCL. On April 27, in an open letter to the U.S. public, he wrote that he rang the bell at MedStar to mark his preliminary diagnosis of being “in remission,” with a “90% prognosis of no relapse.”
Interviewed about the latest advances in treating DLBCL, Jason Westin, MD, associate professor of lymphoma and myeloma at the MD Anderson Cancer Center in Houston, said that even with improvements in overall survival possible with CAR T-cell therapies, “usually, a clinical trial should be considered strongly, as it is often the best option for patients, both in a newly diagnosed or in a relapsed setting, as they allow access to tomorrow’s breakthrough therapies today.”
Dr. Westin cited the example of bispecific T-cell engagers (BITE) as a promising therapy that is available to patients in clinical trials. These agents bind to one side to the lymphoma cell, but they also have a binding arm for T-cells, so they activate a patient’s own immune cells to kill lymphoma cells, in some cases offering a cure when CAR T-cell therapy has failed.
The first BITE to be approved, mosunetuzumab, is authorized only for the treatment of follicular lymphoma. However, data from a recent clinical study indicated that the agent yields complete responses in 24% of heavily pretreated patients with RR DLBCL.
Another BITE, glofitamab, was approved in Canada in March 2023 for use in RR DLBCL. Based on its high efficacy, it soon may be approved elsewhere.
Dr. Andreadis noted, “We are finally at a point where for both treatment naive and RR DLBCL patients, there are several promising options on the horizon that don’t involve ASCT. Furthermore, these breakthroughs reinforce each other, as there are studies in which therapies like BITE are being brought to the front line and pola to RR cases.”
The growing field of new frontline and RR DLBCL therapies lend credence to the optimism of specialists who treat DLBCL – and to the sanguine note that Congressman Raskin struck in published comments about his treatment for DLBCL.
Dr. Andreadis reported ties with BMS, Novartis, Roche, Genmab, Merck, Gilead, AbbVie, and J&J. Dr. Dunleavy disclosed relationships with ONO Pharmaceuticals, Kymera, Merck, Genentech, AstraZeneca, Amgen, ADC Therapeutics, MorphoSys and Incyte, Kite/Gilead, Cellectar. Dr. Westin reported ties with Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Nurix, and MonteRosa.
Significant breakthroughs have come in just the past few weeks and months, through the use of CAR T-cell and immunotherapies and with the approval in April by the Food and Drug Administration of polatuzumab for frontline DLBCL.
“Until the publishing of data from the POLARIX study (NCT03274492), which led to the approval of polatuzumab vedotin plus rituximab-cyclophosphamide, doxorubicin, and prednisone (pola + R-CHP), we had not had a breakthrough in frontline DLBCL therapies since the addition of rituximab 22 years ago,” said Dr. Charalambos Andreadis, MD, of the University of California at San Francisco’s Helen Diller Family Comprehensive Cancer Center.
“Pola + R-CHP is an improvement over the standard-of-care treatment, R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone), giving treatment naive patients an increase in PFS without an increase in side effects,” Dr. Andreadis said.
R-CHP-polatuzumab was approved only for patients with an International Prognostic Indices score between 2 and 5, leaving patients with IPI scores of 0 or 1 with the frontline standard of care (SoC) treatment of R-CHOP, which has a cure rate of between 60% and 70%.
“The highest likelihood of relapse is in the first year following treatment. After 2 years in remission, patients’ chance of relapsing is the same as the general populations’ chance of getting DLBCL for the first time. This is why even a slight increase in the progression-free survival rate with the addition of pola is so significant,” Dr. Andreadis noted.
Historically, patients with relapsed or refractory (RR) DLBCL who did not respond to R-CHOP or who experienced disease relapse less than a year after primary intervention were treated with alternative chemotherapy regimens, often followed by autologous stem cell transplants (ASCT). Randomized control studies have shown that CAR T-cell therapies yield higher success rates than chemotherapy and ASCT, leading to the SoC in RR patients being CAR-T cell therapy directly following failed primary treatment.
“There are many new CAR T-cell platforms in development, as well as novel combination strategies that aim to target critical genetic pathways,” Kieron Dunleavy, MD, professor of medicine at the Lombardi Comprehensive Cancer Center at Georgetown University Hospital, said in an interview. “While access to CAR T-cell therapies is becoming easier and more feasible in many centers, fast access continues to be an issue for many patients, often depending on geography and socioeconomic factors.”
Asked about the latest breakthroughs in treating DLBCL, Dr. Dunleavy said, “A significant proportion of patients with relapsed or refractory DLBCL do not have easy access to CAR T-cell therapies, so this needs to be addressed and improved. Sometimes the rapidity of clinical progression in DLBCL can make these therapies challenging to deliver, considering logistical issues like apheresis and insurance approvals, which are frequently complex. This highlights the need for alternative and ‘easier to deliver’ CAR-T cells and our continued prioritization of developing alternative effective agents for DLBCL.
“Currently, commercially approved CAR T-cells in DLBCL target the CD-19 marker on lymphoma cells but CAR T-cells targeting other and more than one antigen as well as alternative anti CD19 agents like loncastuximab and tafasitamab are similarly FDA approved and available for patients,” Dr. Dunleavy concluded.
Dr. Dunleavy is affiliated with the MedStar Georgetown Lymphoma group, where Rep. Raskin publicly announced that he had completed 4 months of chemotherapy treatment for DLBCL. On April 27, in an open letter to the U.S. public, he wrote that he rang the bell at MedStar to mark his preliminary diagnosis of being “in remission,” with a “90% prognosis of no relapse.”
Interviewed about the latest advances in treating DLBCL, Jason Westin, MD, associate professor of lymphoma and myeloma at the MD Anderson Cancer Center in Houston, said that even with improvements in overall survival possible with CAR T-cell therapies, “usually, a clinical trial should be considered strongly, as it is often the best option for patients, both in a newly diagnosed or in a relapsed setting, as they allow access to tomorrow’s breakthrough therapies today.”
Dr. Westin cited the example of bispecific T-cell engagers (BITE) as a promising therapy that is available to patients in clinical trials. These agents bind to one side to the lymphoma cell, but they also have a binding arm for T-cells, so they activate a patient’s own immune cells to kill lymphoma cells, in some cases offering a cure when CAR T-cell therapy has failed.
The first BITE to be approved, mosunetuzumab, is authorized only for the treatment of follicular lymphoma. However, data from a recent clinical study indicated that the agent yields complete responses in 24% of heavily pretreated patients with RR DLBCL.
Another BITE, glofitamab, was approved in Canada in March 2023 for use in RR DLBCL. Based on its high efficacy, it soon may be approved elsewhere.
Dr. Andreadis noted, “We are finally at a point where for both treatment naive and RR DLBCL patients, there are several promising options on the horizon that don’t involve ASCT. Furthermore, these breakthroughs reinforce each other, as there are studies in which therapies like BITE are being brought to the front line and pola to RR cases.”
The growing field of new frontline and RR DLBCL therapies lend credence to the optimism of specialists who treat DLBCL – and to the sanguine note that Congressman Raskin struck in published comments about his treatment for DLBCL.
Dr. Andreadis reported ties with BMS, Novartis, Roche, Genmab, Merck, Gilead, AbbVie, and J&J. Dr. Dunleavy disclosed relationships with ONO Pharmaceuticals, Kymera, Merck, Genentech, AstraZeneca, Amgen, ADC Therapeutics, MorphoSys and Incyte, Kite/Gilead, Cellectar. Dr. Westin reported ties with Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Nurix, and MonteRosa.
Significant breakthroughs have come in just the past few weeks and months, through the use of CAR T-cell and immunotherapies and with the approval in April by the Food and Drug Administration of polatuzumab for frontline DLBCL.
“Until the publishing of data from the POLARIX study (NCT03274492), which led to the approval of polatuzumab vedotin plus rituximab-cyclophosphamide, doxorubicin, and prednisone (pola + R-CHP), we had not had a breakthrough in frontline DLBCL therapies since the addition of rituximab 22 years ago,” said Dr. Charalambos Andreadis, MD, of the University of California at San Francisco’s Helen Diller Family Comprehensive Cancer Center.
“Pola + R-CHP is an improvement over the standard-of-care treatment, R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone), giving treatment naive patients an increase in PFS without an increase in side effects,” Dr. Andreadis said.
R-CHP-polatuzumab was approved only for patients with an International Prognostic Indices score between 2 and 5, leaving patients with IPI scores of 0 or 1 with the frontline standard of care (SoC) treatment of R-CHOP, which has a cure rate of between 60% and 70%.
“The highest likelihood of relapse is in the first year following treatment. After 2 years in remission, patients’ chance of relapsing is the same as the general populations’ chance of getting DLBCL for the first time. This is why even a slight increase in the progression-free survival rate with the addition of pola is so significant,” Dr. Andreadis noted.
Historically, patients with relapsed or refractory (RR) DLBCL who did not respond to R-CHOP or who experienced disease relapse less than a year after primary intervention were treated with alternative chemotherapy regimens, often followed by autologous stem cell transplants (ASCT). Randomized control studies have shown that CAR T-cell therapies yield higher success rates than chemotherapy and ASCT, leading to the SoC in RR patients being CAR-T cell therapy directly following failed primary treatment.
“There are many new CAR T-cell platforms in development, as well as novel combination strategies that aim to target critical genetic pathways,” Kieron Dunleavy, MD, professor of medicine at the Lombardi Comprehensive Cancer Center at Georgetown University Hospital, said in an interview. “While access to CAR T-cell therapies is becoming easier and more feasible in many centers, fast access continues to be an issue for many patients, often depending on geography and socioeconomic factors.”
Asked about the latest breakthroughs in treating DLBCL, Dr. Dunleavy said, “A significant proportion of patients with relapsed or refractory DLBCL do not have easy access to CAR T-cell therapies, so this needs to be addressed and improved. Sometimes the rapidity of clinical progression in DLBCL can make these therapies challenging to deliver, considering logistical issues like apheresis and insurance approvals, which are frequently complex. This highlights the need for alternative and ‘easier to deliver’ CAR-T cells and our continued prioritization of developing alternative effective agents for DLBCL.
“Currently, commercially approved CAR T-cells in DLBCL target the CD-19 marker on lymphoma cells but CAR T-cells targeting other and more than one antigen as well as alternative anti CD19 agents like loncastuximab and tafasitamab are similarly FDA approved and available for patients,” Dr. Dunleavy concluded.
Dr. Dunleavy is affiliated with the MedStar Georgetown Lymphoma group, where Rep. Raskin publicly announced that he had completed 4 months of chemotherapy treatment for DLBCL. On April 27, in an open letter to the U.S. public, he wrote that he rang the bell at MedStar to mark his preliminary diagnosis of being “in remission,” with a “90% prognosis of no relapse.”
Interviewed about the latest advances in treating DLBCL, Jason Westin, MD, associate professor of lymphoma and myeloma at the MD Anderson Cancer Center in Houston, said that even with improvements in overall survival possible with CAR T-cell therapies, “usually, a clinical trial should be considered strongly, as it is often the best option for patients, both in a newly diagnosed or in a relapsed setting, as they allow access to tomorrow’s breakthrough therapies today.”
Dr. Westin cited the example of bispecific T-cell engagers (BITE) as a promising therapy that is available to patients in clinical trials. These agents bind to one side to the lymphoma cell, but they also have a binding arm for T-cells, so they activate a patient’s own immune cells to kill lymphoma cells, in some cases offering a cure when CAR T-cell therapy has failed.
The first BITE to be approved, mosunetuzumab, is authorized only for the treatment of follicular lymphoma. However, data from a recent clinical study indicated that the agent yields complete responses in 24% of heavily pretreated patients with RR DLBCL.
Another BITE, glofitamab, was approved in Canada in March 2023 for use in RR DLBCL. Based on its high efficacy, it soon may be approved elsewhere.
Dr. Andreadis noted, “We are finally at a point where for both treatment naive and RR DLBCL patients, there are several promising options on the horizon that don’t involve ASCT. Furthermore, these breakthroughs reinforce each other, as there are studies in which therapies like BITE are being brought to the front line and pola to RR cases.”
The growing field of new frontline and RR DLBCL therapies lend credence to the optimism of specialists who treat DLBCL – and to the sanguine note that Congressman Raskin struck in published comments about his treatment for DLBCL.
Dr. Andreadis reported ties with BMS, Novartis, Roche, Genmab, Merck, Gilead, AbbVie, and J&J. Dr. Dunleavy disclosed relationships with ONO Pharmaceuticals, Kymera, Merck, Genentech, AstraZeneca, Amgen, ADC Therapeutics, MorphoSys and Incyte, Kite/Gilead, Cellectar. Dr. Westin reported ties with Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Nurix, and MonteRosa.
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
CLL: Black patients die sooner than Whites
The findings, published in the American Journal of Hematology, hint that the racial disparity has shrunk over time, especially within the first few years of the targeted-therapy era. Still, “Black patients had a shorter median overall survival of 7 years compared to 9 years for White patients,” study coauthor Deborah Stephens, DO, of the University of Utah Huntsman Cancer Institute, said in an interview. “Clearly, more research is needed to tease out the biologic or economic barriers to achieving prolonged survival.”
As the researchers noted, CLL is far more common among White patients (5.1 cases per 100,000) than other races (Black patients: 3.2 cases per 100,000; Hispanic patients: 2.1 cases per 100,000; Asian American patients: 1.1 per 100,000). In total, non-White patients make up just 11%-13% of CLL cases in the United States.
According to Dr. Stephens, “little is known or published” about Black patients with CLL, “and it is still a mystery why fewer patients that are Black develop CLL and why this group would have shorter survival.”
Dr. Stephens and colleagues launched the new study – the largest of its kind to date – to understand disparities between White and Black patients over most of the past 20 years. The researchers especially wanted to analyze trends during the last decade, when targeted therapies revolutionized treatment of the disease.
The study authors analyzed data in the National Cancer Database for 97,804 patients diagnosed from 2004 to 2018 (90.7% White, 7.6% Black, 0.6% Asian, 1.1% other). Of patients who reported ethnicity (n = 93,555), 2.6% were Hispanic.
Black patients were more likely to have begun CLL therapy at diagnosis (35.9%) than were White patients (23.6%), a sign that Black patients had more advanced disease. Black patients also had shorter overall survival (7.0 years, 95% confidence interval [CI], 6.7–7.3 years) vs. White patients (9.1 years, 95% CI, 9.0–9.3 years, P < .001).
“This finding could be due to underlying biologic differences in the pathology of CLL, when comparing patients across racial groups,” Dr. Stephens said. “Additionally, there could be differences in access to care. Notably, there are fewer racial minorities enrolled in clinical trials, and perhaps we are not individualizing therapy for unique biologic factors seen in CLL affecting racial minorities.”
Other factors also could be at play. Black patients were more likely than were White patients to have one or more comorbidities (27.9% vs. 21.3%, P < .001), lack insurance (6.6% vs. 2.1%, P < .001) and live in lower-income neighborhoods (47.7% vs. 13.1%, P < .001).
What explains the gap in outcomes? In an interview, study lead author Victoria Vardell, MD, of the University of Utah, Salt Lake City, noted that researchers often attribute worse medical outcomes in Black patients to economic and social disparities.
“However, when we adjusted for a number of surrogate markers of health care access, including income, comorbidities, and location, among others, this disparity remained. That indicates that this may be a more complex problem in CLL in particular. Certainly, we cannot adjust for all the socioeconomic strain placed on Black Americans, including those with CLL, but there may be molecular features related to ancestry or environmental exposures that also play a role,” Dr. Vardell said.
She added that “the high cost and difficulty obtaining many novel therapies, particularly in the clinical trial setting, places significantly higher burdens on already disadvantaged populations.”
There is some good news in the new report. “Promisingly, our data suggest that the survival disparity between White and Black patients with CLL may be improving, particularly within the last 5 years, though longer follow-up is needed to confirm significance,” the researchers reported.
Alessandra Ferrajoli, MD, of M.D. Anderson Cancer Center, Houston, who has studied racial disparities in CLL, praised the study in an interview. As she noted, it examines an impressively large population.
The explanations for the disparities are still elusive, she said, although it seems clear there are multiple factors at play. “We don’t know if the disease has the same characteristics in African-Americans as in Whites,” Dr. Ferrajoli said. However, she noted, there’s “no indication that the response to treatment is different according to race.”
Moving forward, she said, the study findings “reinforce the fact that we need to pay attention to this population and be quite attentive to their characteristics.”
No study funding was reported. The authors and Dr. Ferrajoli have no disclosures.
The findings, published in the American Journal of Hematology, hint that the racial disparity has shrunk over time, especially within the first few years of the targeted-therapy era. Still, “Black patients had a shorter median overall survival of 7 years compared to 9 years for White patients,” study coauthor Deborah Stephens, DO, of the University of Utah Huntsman Cancer Institute, said in an interview. “Clearly, more research is needed to tease out the biologic or economic barriers to achieving prolonged survival.”
As the researchers noted, CLL is far more common among White patients (5.1 cases per 100,000) than other races (Black patients: 3.2 cases per 100,000; Hispanic patients: 2.1 cases per 100,000; Asian American patients: 1.1 per 100,000). In total, non-White patients make up just 11%-13% of CLL cases in the United States.
According to Dr. Stephens, “little is known or published” about Black patients with CLL, “and it is still a mystery why fewer patients that are Black develop CLL and why this group would have shorter survival.”
Dr. Stephens and colleagues launched the new study – the largest of its kind to date – to understand disparities between White and Black patients over most of the past 20 years. The researchers especially wanted to analyze trends during the last decade, when targeted therapies revolutionized treatment of the disease.
The study authors analyzed data in the National Cancer Database for 97,804 patients diagnosed from 2004 to 2018 (90.7% White, 7.6% Black, 0.6% Asian, 1.1% other). Of patients who reported ethnicity (n = 93,555), 2.6% were Hispanic.
Black patients were more likely to have begun CLL therapy at diagnosis (35.9%) than were White patients (23.6%), a sign that Black patients had more advanced disease. Black patients also had shorter overall survival (7.0 years, 95% confidence interval [CI], 6.7–7.3 years) vs. White patients (9.1 years, 95% CI, 9.0–9.3 years, P < .001).
“This finding could be due to underlying biologic differences in the pathology of CLL, when comparing patients across racial groups,” Dr. Stephens said. “Additionally, there could be differences in access to care. Notably, there are fewer racial minorities enrolled in clinical trials, and perhaps we are not individualizing therapy for unique biologic factors seen in CLL affecting racial minorities.”
Other factors also could be at play. Black patients were more likely than were White patients to have one or more comorbidities (27.9% vs. 21.3%, P < .001), lack insurance (6.6% vs. 2.1%, P < .001) and live in lower-income neighborhoods (47.7% vs. 13.1%, P < .001).
What explains the gap in outcomes? In an interview, study lead author Victoria Vardell, MD, of the University of Utah, Salt Lake City, noted that researchers often attribute worse medical outcomes in Black patients to economic and social disparities.
“However, when we adjusted for a number of surrogate markers of health care access, including income, comorbidities, and location, among others, this disparity remained. That indicates that this may be a more complex problem in CLL in particular. Certainly, we cannot adjust for all the socioeconomic strain placed on Black Americans, including those with CLL, but there may be molecular features related to ancestry or environmental exposures that also play a role,” Dr. Vardell said.
She added that “the high cost and difficulty obtaining many novel therapies, particularly in the clinical trial setting, places significantly higher burdens on already disadvantaged populations.”
There is some good news in the new report. “Promisingly, our data suggest that the survival disparity between White and Black patients with CLL may be improving, particularly within the last 5 years, though longer follow-up is needed to confirm significance,” the researchers reported.
Alessandra Ferrajoli, MD, of M.D. Anderson Cancer Center, Houston, who has studied racial disparities in CLL, praised the study in an interview. As she noted, it examines an impressively large population.
The explanations for the disparities are still elusive, she said, although it seems clear there are multiple factors at play. “We don’t know if the disease has the same characteristics in African-Americans as in Whites,” Dr. Ferrajoli said. However, she noted, there’s “no indication that the response to treatment is different according to race.”
Moving forward, she said, the study findings “reinforce the fact that we need to pay attention to this population and be quite attentive to their characteristics.”
No study funding was reported. The authors and Dr. Ferrajoli have no disclosures.
The findings, published in the American Journal of Hematology, hint that the racial disparity has shrunk over time, especially within the first few years of the targeted-therapy era. Still, “Black patients had a shorter median overall survival of 7 years compared to 9 years for White patients,” study coauthor Deborah Stephens, DO, of the University of Utah Huntsman Cancer Institute, said in an interview. “Clearly, more research is needed to tease out the biologic or economic barriers to achieving prolonged survival.”
As the researchers noted, CLL is far more common among White patients (5.1 cases per 100,000) than other races (Black patients: 3.2 cases per 100,000; Hispanic patients: 2.1 cases per 100,000; Asian American patients: 1.1 per 100,000). In total, non-White patients make up just 11%-13% of CLL cases in the United States.
According to Dr. Stephens, “little is known or published” about Black patients with CLL, “and it is still a mystery why fewer patients that are Black develop CLL and why this group would have shorter survival.”
Dr. Stephens and colleagues launched the new study – the largest of its kind to date – to understand disparities between White and Black patients over most of the past 20 years. The researchers especially wanted to analyze trends during the last decade, when targeted therapies revolutionized treatment of the disease.
The study authors analyzed data in the National Cancer Database for 97,804 patients diagnosed from 2004 to 2018 (90.7% White, 7.6% Black, 0.6% Asian, 1.1% other). Of patients who reported ethnicity (n = 93,555), 2.6% were Hispanic.
Black patients were more likely to have begun CLL therapy at diagnosis (35.9%) than were White patients (23.6%), a sign that Black patients had more advanced disease. Black patients also had shorter overall survival (7.0 years, 95% confidence interval [CI], 6.7–7.3 years) vs. White patients (9.1 years, 95% CI, 9.0–9.3 years, P < .001).
“This finding could be due to underlying biologic differences in the pathology of CLL, when comparing patients across racial groups,” Dr. Stephens said. “Additionally, there could be differences in access to care. Notably, there are fewer racial minorities enrolled in clinical trials, and perhaps we are not individualizing therapy for unique biologic factors seen in CLL affecting racial minorities.”
Other factors also could be at play. Black patients were more likely than were White patients to have one or more comorbidities (27.9% vs. 21.3%, P < .001), lack insurance (6.6% vs. 2.1%, P < .001) and live in lower-income neighborhoods (47.7% vs. 13.1%, P < .001).
What explains the gap in outcomes? In an interview, study lead author Victoria Vardell, MD, of the University of Utah, Salt Lake City, noted that researchers often attribute worse medical outcomes in Black patients to economic and social disparities.
“However, when we adjusted for a number of surrogate markers of health care access, including income, comorbidities, and location, among others, this disparity remained. That indicates that this may be a more complex problem in CLL in particular. Certainly, we cannot adjust for all the socioeconomic strain placed on Black Americans, including those with CLL, but there may be molecular features related to ancestry or environmental exposures that also play a role,” Dr. Vardell said.
She added that “the high cost and difficulty obtaining many novel therapies, particularly in the clinical trial setting, places significantly higher burdens on already disadvantaged populations.”
There is some good news in the new report. “Promisingly, our data suggest that the survival disparity between White and Black patients with CLL may be improving, particularly within the last 5 years, though longer follow-up is needed to confirm significance,” the researchers reported.
Alessandra Ferrajoli, MD, of M.D. Anderson Cancer Center, Houston, who has studied racial disparities in CLL, praised the study in an interview. As she noted, it examines an impressively large population.
The explanations for the disparities are still elusive, she said, although it seems clear there are multiple factors at play. “We don’t know if the disease has the same characteristics in African-Americans as in Whites,” Dr. Ferrajoli said. However, she noted, there’s “no indication that the response to treatment is different according to race.”
Moving forward, she said, the study findings “reinforce the fact that we need to pay attention to this population and be quite attentive to their characteristics.”
No study funding was reported. The authors and Dr. Ferrajoli have no disclosures.
FROM AMERICAN JOURNAL OF HEMATOLOGY
Commentary: New genetic information and treatments for DLBCL, May 2023
Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.1 COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.
Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.4 More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.
Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.
Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.5
In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.8 More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.
Additional References
1. Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914
2. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403
3. Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366
4. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5
5. Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501
6. Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
7. Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730
8. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4
Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.1 COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.
Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.4 More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.
Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.
Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.5
In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.8 More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.
Additional References
1. Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914
2. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403
3. Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366
4. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5
5. Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501
6. Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
7. Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730
8. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4
Diffuse large B-cell lymphoma (DLBCL) is both a clinically and molecularly heterogenous disease. The International Prognostic Index (IPI), which is based on clinical and laboratory variables, is still currently used to delineate risk at the time of diagnosis. Diffuse large B-cell lymphoma can also further be classified into either germinal center B-cell (GCB) or activated B-cell (ABC) subtype, also known as the cell-of-origin classification (COO), which has been prognostic in prior studies.1 COO is based on gene expression profiling (GEP), though it can be estimated by immunohistochemistry.
Although these classifications are available, treatment of DLBCL has largely remained uniform over the past few decades. Despite encouraging preclinical data and early trials, large randomized studies had not demonstrated an advantage of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) plus X over R-CHOP alone.2,3 The REMoDL-B trial, which included 801 adult patients with DLBCL, including patients with ABC, GCB, or molecular high grade (MHG) classification by GEP. Patients received one cycle of R-CHOP and were randomly assigned to R-CHOP (n = 407) alone or bortezomib–R-CHOP (n = 394) for cycles 2-6. Initial reports did not demonstrate any clear benefit of the addition of bortezomib.4 More recently, however, 5-year follow-up data demonstrate that the addition of bortezomib confers an advantage over R-CHOP in patients with ABC and MHG DLBCL (Davies et al). Bortezomib–R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The GCB group showed no significant difference in PFS or OS.
Despite the results of REMoDL-B, it is unlikely that this study will change practice. GEP is not readily available and with the approval of polatuzumab (pola)–R-CHP, based on the results of POLARIX trial, there is new option available for patients with newly diagnosed DLBCL with a high IPI. A recent meta-analysis of 12 randomized controlled trials (Sheng et al) involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received pola–R-CHP or other regimens was also recently performed. This study showed that pola–R-CHP prolonged PFS in patients with ABC-type DLBCL compared with bortezomib–R-CHOP (hazard ratio [HR] 0.52; P = .02); ibrutinib–R-CHOP (HR 0.43; P = .001); lenalidomide–R-CHOP (HR 0.51; P = .009); Obinutuzumab–CHOP (HR 0.46; P = .008); R-CHOP (HR 0.40; P < .001); and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola–R-CHP had no PFS benefit in patients with GCB-type DLBCL. Although it is difficult to directly compare trials, these data suggest that pola–R-CHP is active in ABC subtype DLBCL.
Together, these trials suggest that there still may be a role for more personalized therapy in DLBCL, though there may be room for improvement. Recent studies have suggested more complex genomic underpinnings in DLBCL beyond COO, which will hopefully be studied in the context of DLBCL trials.5
In the second line, patients with primary refractory or early relapse of DLBCL now have the option of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, based on the results of the ZUMA-7 and TRANSFORM studies.6,7 Lisocabtagene maraleucel (liso-cel) was also found to have a manageable safety profile in older patients with large B-cell lymphoma who were not transplant candidates in the PILOT study, leading to approval in this setting.8 More recently, axicabtagene ciloleucel (axi-cel) was found to be an effective second-line therapy with a manageable safety profile for patients aged ≥ 65 years as well (Westin et al). These findings are from a preplanned analysis of 109 patients aged ≥ 65 years from ZUMA-7 who were randomly assigned to receive second-line axi-cel (n = 51) or standard of care (SOC) (n = 58; two or three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation). At a median follow-up of 24.3 months, the median event-free survival was significantly longer with axi-cel vs SOC; 21.5 vs 2.5 months; HR, 0.276; descriptive P < .0001). Rates of grade 3 or higher treatment-emergent adverse events were 94% and 82% with axi-cel and SOC, respectively. Although these patients were considered transplant eligible, this study demonstrates that axi-cel can be safely administered to older patients.
Additional References
1. Rosenwald A, Wright G, Chan WC, et al; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937-1947. doi: 10.1056/NEJMoa012914
2. Younes A, Sehn LH, Johnson P, et al; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37:1285-1295. doi: 10.1200/JCO.18.02403
3. Nowakowski GS, Chiappella A, Gascoyne RD, et al; ROBUST Trial Investigators. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39:1317-1328. doi: 10.1200/JCO.20.01366
4. Davies A, Cummin TE, Barrans S, et al. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019;20:649-662. doi: 10.1016/S1470-2045(18)30935-5
5. Crombie JL, Armand P. Diffuse large B-cell lymphoma's new genomics: the bridge and the chasm. J Clin Oncol. 2020;38:3565-3574. doi: 10.1200/JCO.20.01501
6. Locke FL, Miklos DB, Jacobson CA, et al for All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386:640-654. doi: 10.1056/NEJMoa2116133
7. Abramson JS, Solomon SR, Arnason JE, et al; TRANSFORM Investigators. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2023:141:1675-1684. doi: 10.1182/blood.2022018730
8. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066-1077. doi: 10.1016/S1470-2045(22)00339-4
Frontline CLL treatment: Avoiding adverse events
NEW YORK – The Food and Drug Administration’s 2016 approval of the Bruton’s tyrosine kinase inhibitor ibrutinib (IB) as a frontline therapy for chronic lymphocytic leukemia (CLL) dramatically improved overall survival rates for patients with this condition. Follow-up data from 8 years after the RESONATE-2 trial indicated that patients with CLL (65 years or older) who remain on IB therapy can expect to live as long as someone in the general population.
Physicians now face two challenges in frontline CLL treatment: finding safe and effective drugs with fewer side effects, allowing patients to maintain therapy; and offering young or genomically high-risk patients treatments that reduce the risk of relapse.
said John N. Allan, associate professor at Weill Cornell Medicine, New York, in his presentation on frontline CLL treatments at the Great Debates and Updates Hematologic Malignancies Conference. “This is true even of older patients or those with comorbidities because this class of drug allows us to keep patients on treatment with excellent long-term outcomes.”
Results from the Alpine trial (NCT03734016), which included patients with and without high genomic risk, confirmed the superiority of the second generation Bruton’s tyrosine kinase inhibitor zanubrutinib (ZB) versus ibrutinib in terms of overall response rate 86.2% versus 75.5%, progression free survival 2-years after treatment 79.5% versus 67.3%, and adverse events (AEs) leading to discontinuation 15.4% versus 22.2% respectively.
The SEQUOIA trial (NCT03336333) demonstrated the effectiveness of ZB versus bendamustine + rituximab combination (BR) therapy in treatment-naive CLL / small lymphocytic leukemia patients with normal and high genomic risk. Overall 24-month progression free survival (PFS) was 85% in the ZB cohort vs. 69% in the BR cohort. This trend held true among high-risk subgroups like patients with an unmutated IgVH gene or 11q22.3 gene deletion.
Therapies known as “doublets” and “triplets” (which include a Bruton’s tyrosine kinase inhibitor in addition to other drugs) are not FDA approved for frontline CLL treatment. Yet studies suggest that young patients who are better able to tolerate AEs or high-risk patients with a greater risk of relapse (even on monotherapy maintenance), may derive benefits from multidrug frontline treatment.
“With doublets and triplets, doctors add treatment intensity up front so that patients can have a fixed duration of therapy versus continuous indefinite therapy,” said Vu Nguyen MD, a hematologist at Oakland (Calif.) Medical Center. “This is encouraging because if you can have a fixed duration of treatment, patients can come off treatment agents and hopefully have a prolonged remission and normal lifespan without chronic therapy and side effects.”
The CAPTIVATE study confirmed this approach with 3 cycles of IB followed by 12 cycles of IB + venetoclax leading to a 24-month PFS rate of 94% in patients with high risk or relapse. “Furthermore, 95% of study participants patients less than 70 years old completed 12 months of combination treatment without major problems,” said Dr. Allan. He concluded his remarks by noting that “we need longer term data on the use of combination therapy for frontline CLL treatment to confirm if and when it should be used.”
Dr. Allan disclosed relationships with Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Genentech, Janssen, Lilly, Pharmacyclics, and TG Therapeutics. Dr. Nguyen reported no disclosures.
NEW YORK – The Food and Drug Administration’s 2016 approval of the Bruton’s tyrosine kinase inhibitor ibrutinib (IB) as a frontline therapy for chronic lymphocytic leukemia (CLL) dramatically improved overall survival rates for patients with this condition. Follow-up data from 8 years after the RESONATE-2 trial indicated that patients with CLL (65 years or older) who remain on IB therapy can expect to live as long as someone in the general population.
Physicians now face two challenges in frontline CLL treatment: finding safe and effective drugs with fewer side effects, allowing patients to maintain therapy; and offering young or genomically high-risk patients treatments that reduce the risk of relapse.
said John N. Allan, associate professor at Weill Cornell Medicine, New York, in his presentation on frontline CLL treatments at the Great Debates and Updates Hematologic Malignancies Conference. “This is true even of older patients or those with comorbidities because this class of drug allows us to keep patients on treatment with excellent long-term outcomes.”
Results from the Alpine trial (NCT03734016), which included patients with and without high genomic risk, confirmed the superiority of the second generation Bruton’s tyrosine kinase inhibitor zanubrutinib (ZB) versus ibrutinib in terms of overall response rate 86.2% versus 75.5%, progression free survival 2-years after treatment 79.5% versus 67.3%, and adverse events (AEs) leading to discontinuation 15.4% versus 22.2% respectively.
The SEQUOIA trial (NCT03336333) demonstrated the effectiveness of ZB versus bendamustine + rituximab combination (BR) therapy in treatment-naive CLL / small lymphocytic leukemia patients with normal and high genomic risk. Overall 24-month progression free survival (PFS) was 85% in the ZB cohort vs. 69% in the BR cohort. This trend held true among high-risk subgroups like patients with an unmutated IgVH gene or 11q22.3 gene deletion.
Therapies known as “doublets” and “triplets” (which include a Bruton’s tyrosine kinase inhibitor in addition to other drugs) are not FDA approved for frontline CLL treatment. Yet studies suggest that young patients who are better able to tolerate AEs or high-risk patients with a greater risk of relapse (even on monotherapy maintenance), may derive benefits from multidrug frontline treatment.
“With doublets and triplets, doctors add treatment intensity up front so that patients can have a fixed duration of therapy versus continuous indefinite therapy,” said Vu Nguyen MD, a hematologist at Oakland (Calif.) Medical Center. “This is encouraging because if you can have a fixed duration of treatment, patients can come off treatment agents and hopefully have a prolonged remission and normal lifespan without chronic therapy and side effects.”
The CAPTIVATE study confirmed this approach with 3 cycles of IB followed by 12 cycles of IB + venetoclax leading to a 24-month PFS rate of 94% in patients with high risk or relapse. “Furthermore, 95% of study participants patients less than 70 years old completed 12 months of combination treatment without major problems,” said Dr. Allan. He concluded his remarks by noting that “we need longer term data on the use of combination therapy for frontline CLL treatment to confirm if and when it should be used.”
Dr. Allan disclosed relationships with Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Genentech, Janssen, Lilly, Pharmacyclics, and TG Therapeutics. Dr. Nguyen reported no disclosures.
NEW YORK – The Food and Drug Administration’s 2016 approval of the Bruton’s tyrosine kinase inhibitor ibrutinib (IB) as a frontline therapy for chronic lymphocytic leukemia (CLL) dramatically improved overall survival rates for patients with this condition. Follow-up data from 8 years after the RESONATE-2 trial indicated that patients with CLL (65 years or older) who remain on IB therapy can expect to live as long as someone in the general population.
Physicians now face two challenges in frontline CLL treatment: finding safe and effective drugs with fewer side effects, allowing patients to maintain therapy; and offering young or genomically high-risk patients treatments that reduce the risk of relapse.
said John N. Allan, associate professor at Weill Cornell Medicine, New York, in his presentation on frontline CLL treatments at the Great Debates and Updates Hematologic Malignancies Conference. “This is true even of older patients or those with comorbidities because this class of drug allows us to keep patients on treatment with excellent long-term outcomes.”
Results from the Alpine trial (NCT03734016), which included patients with and without high genomic risk, confirmed the superiority of the second generation Bruton’s tyrosine kinase inhibitor zanubrutinib (ZB) versus ibrutinib in terms of overall response rate 86.2% versus 75.5%, progression free survival 2-years after treatment 79.5% versus 67.3%, and adverse events (AEs) leading to discontinuation 15.4% versus 22.2% respectively.
The SEQUOIA trial (NCT03336333) demonstrated the effectiveness of ZB versus bendamustine + rituximab combination (BR) therapy in treatment-naive CLL / small lymphocytic leukemia patients with normal and high genomic risk. Overall 24-month progression free survival (PFS) was 85% in the ZB cohort vs. 69% in the BR cohort. This trend held true among high-risk subgroups like patients with an unmutated IgVH gene or 11q22.3 gene deletion.
Therapies known as “doublets” and “triplets” (which include a Bruton’s tyrosine kinase inhibitor in addition to other drugs) are not FDA approved for frontline CLL treatment. Yet studies suggest that young patients who are better able to tolerate AEs or high-risk patients with a greater risk of relapse (even on monotherapy maintenance), may derive benefits from multidrug frontline treatment.
“With doublets and triplets, doctors add treatment intensity up front so that patients can have a fixed duration of therapy versus continuous indefinite therapy,” said Vu Nguyen MD, a hematologist at Oakland (Calif.) Medical Center. “This is encouraging because if you can have a fixed duration of treatment, patients can come off treatment agents and hopefully have a prolonged remission and normal lifespan without chronic therapy and side effects.”
The CAPTIVATE study confirmed this approach with 3 cycles of IB followed by 12 cycles of IB + venetoclax leading to a 24-month PFS rate of 94% in patients with high risk or relapse. “Furthermore, 95% of study participants patients less than 70 years old completed 12 months of combination treatment without major problems,” said Dr. Allan. He concluded his remarks by noting that “we need longer term data on the use of combination therapy for frontline CLL treatment to confirm if and when it should be used.”
Dr. Allan disclosed relationships with Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Genentech, Janssen, Lilly, Pharmacyclics, and TG Therapeutics. Dr. Nguyen reported no disclosures.
AT 2023 GREAT DEBATES AND UPDATES HEMATOLOGIC MALIGNANCIES CONFERENCE
Benefits of Pola-R-CHP over other novel agents against newly diagnosed DLBCL
Key clinical point: Polatuzumab vedotin (Pola)-rituximab-cyclophosphamide, doxorubicin, and prednisone (R-CHP) compared with other novel regimens prolongs progression-free survival (PFS) in patients with previously untreated activated B-cell (ABC)-type diffuse large B-cell lymphoma (DLBCL).
Major finding: Pola-R-CHP prolonged PFS in patients with ABC-type DLBCL compared with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)+bortezomib (hazard ratio [HR] 0.52; P = .02); R-CHOP+ibrutinib (HR 0.43; P = .001), R-CHOP+lenalidomide (HR 0.51; P = .009), obinutuzumab-CHOP (HR 0.46; P = .008), R-CHOP (HR 0.40; P < .001), and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola-R-CHP had no PFS benefit in patients with germinal center B-cell (GCB)-type DLBCL.
Study details: This was a network meta-analysis of 12 randomized controlled trials involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received Pola-R-CHP or other regimens.
Disclosures: This study did not report the funding source. The authors declared no conflicts of interest.
Source: Sheng Z et al. Superiority of polatuzumab vedotin over other novel agents in previously untreated ABC‑type diffuse large B‑cell lymphoma: A network meta‑analysis of 20 RCTs. Ann Hematol. 2023;102:1011-1017 (Mar 22). Doi: 10.1007/s00277-023-05161-1
Key clinical point: Polatuzumab vedotin (Pola)-rituximab-cyclophosphamide, doxorubicin, and prednisone (R-CHP) compared with other novel regimens prolongs progression-free survival (PFS) in patients with previously untreated activated B-cell (ABC)-type diffuse large B-cell lymphoma (DLBCL).
Major finding: Pola-R-CHP prolonged PFS in patients with ABC-type DLBCL compared with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)+bortezomib (hazard ratio [HR] 0.52; P = .02); R-CHOP+ibrutinib (HR 0.43; P = .001), R-CHOP+lenalidomide (HR 0.51; P = .009), obinutuzumab-CHOP (HR 0.46; P = .008), R-CHOP (HR 0.40; P < .001), and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola-R-CHP had no PFS benefit in patients with germinal center B-cell (GCB)-type DLBCL.
Study details: This was a network meta-analysis of 12 randomized controlled trials involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received Pola-R-CHP or other regimens.
Disclosures: This study did not report the funding source. The authors declared no conflicts of interest.
Source: Sheng Z et al. Superiority of polatuzumab vedotin over other novel agents in previously untreated ABC‑type diffuse large B‑cell lymphoma: A network meta‑analysis of 20 RCTs. Ann Hematol. 2023;102:1011-1017 (Mar 22). Doi: 10.1007/s00277-023-05161-1
Key clinical point: Polatuzumab vedotin (Pola)-rituximab-cyclophosphamide, doxorubicin, and prednisone (R-CHP) compared with other novel regimens prolongs progression-free survival (PFS) in patients with previously untreated activated B-cell (ABC)-type diffuse large B-cell lymphoma (DLBCL).
Major finding: Pola-R-CHP prolonged PFS in patients with ABC-type DLBCL compared with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)+bortezomib (hazard ratio [HR] 0.52; P = .02); R-CHOP+ibrutinib (HR 0.43; P = .001), R-CHOP+lenalidomide (HR 0.51; P = .009), obinutuzumab-CHOP (HR 0.46; P = .008), R-CHOP (HR 0.40; P < .001), and bortezomib, rituximab, and cyclophosphamide (HR 0.44; P = .07). Pola-R-CHP had no PFS benefit in patients with germinal center B-cell (GCB)-type DLBCL.
Study details: This was a network meta-analysis of 12 randomized controlled trials involving 8376 patients with previously untreated ABC- or GCB-type DLBCL who received Pola-R-CHP or other regimens.
Disclosures: This study did not report the funding source. The authors declared no conflicts of interest.
Source: Sheng Z et al. Superiority of polatuzumab vedotin over other novel agents in previously untreated ABC‑type diffuse large B‑cell lymphoma: A network meta‑analysis of 20 RCTs. Ann Hematol. 2023;102:1011-1017 (Mar 22). Doi: 10.1007/s00277-023-05161-1
Addition of bortezomib to R-CHOP improves survival in DLBCL molecular subgroups
Key clinical point: The addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) confers a survival advantage over R-CHOP in patients with activated B-cell (ABC)- and molecular high grade (MHG)-type diffuse large B-cell lymphoma (DLBCL).
Major finding: Bortezomib-R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups, and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The germinal center B-cell (GCB) group showed no significant difference in PFS or OS.
Study details: This updated retrospective analysis of the phase 3 REMoDL-B study included 801 adult patients with DLBCL (ABC, MHG, or GCB subtype) who were randomly assigned to receive 2-6 cycles of R-CHOP (n = 407) or bortezomib-R-CHOP (n = 394) after one cycle of R-CHOP.
Disclosures: This study was supported by a grant from Janssen-Cilag and Cancer Research UK. Some authors reported ties with various organizations, including Janssen.
Source: Davies AJ et al. Differential efficacy from the addition of bortezomib to r-chop in diffuse large B-cell lymphoma according to the molecular subgroup in the REMoDL-B study with a 5-year follow-up. J Clin Oncol. 2023 (Mar 27). Doi: 10.1200/JCO.23.00033
Key clinical point: The addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) confers a survival advantage over R-CHOP in patients with activated B-cell (ABC)- and molecular high grade (MHG)-type diffuse large B-cell lymphoma (DLBCL).
Major finding: Bortezomib-R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups, and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The germinal center B-cell (GCB) group showed no significant difference in PFS or OS.
Study details: This updated retrospective analysis of the phase 3 REMoDL-B study included 801 adult patients with DLBCL (ABC, MHG, or GCB subtype) who were randomly assigned to receive 2-6 cycles of R-CHOP (n = 407) or bortezomib-R-CHOP (n = 394) after one cycle of R-CHOP.
Disclosures: This study was supported by a grant from Janssen-Cilag and Cancer Research UK. Some authors reported ties with various organizations, including Janssen.
Source: Davies AJ et al. Differential efficacy from the addition of bortezomib to r-chop in diffuse large B-cell lymphoma according to the molecular subgroup in the REMoDL-B study with a 5-year follow-up. J Clin Oncol. 2023 (Mar 27). Doi: 10.1200/JCO.23.00033
Key clinical point: The addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) confers a survival advantage over R-CHOP in patients with activated B-cell (ABC)- and molecular high grade (MHG)-type diffuse large B-cell lymphoma (DLBCL).
Major finding: Bortezomib-R-CHOP vs R-CHOP significantly improved 60-month progression-free survival (PFS) in the ABC (adjusted hazard ratio [aHR] 0.65; P = .041) and MHG (aHR 0.46; P = .011) groups, and overall survival (OS) in the ABC group (aHR 0.58; P = .032). The germinal center B-cell (GCB) group showed no significant difference in PFS or OS.
Study details: This updated retrospective analysis of the phase 3 REMoDL-B study included 801 adult patients with DLBCL (ABC, MHG, or GCB subtype) who were randomly assigned to receive 2-6 cycles of R-CHOP (n = 407) or bortezomib-R-CHOP (n = 394) after one cycle of R-CHOP.
Disclosures: This study was supported by a grant from Janssen-Cilag and Cancer Research UK. Some authors reported ties with various organizations, including Janssen.
Source: Davies AJ et al. Differential efficacy from the addition of bortezomib to r-chop in diffuse large B-cell lymphoma according to the molecular subgroup in the REMoDL-B study with a 5-year follow-up. J Clin Oncol. 2023 (Mar 27). Doi: 10.1200/JCO.23.00033
Ibrutinib offers better efficacy and tolerability over idelalisib+rituximab in relapsed/refractory CLL
Key clinical point: Compared with idelalisib+rituximab (R-idela), ibrutinib significantly prolonged survival and was associated with lower treatment discontinuation rates in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) in routine practice.
Major finding: The ibrutinib vs R-idela group had significantly longer median progression-free survival (40.5 vs 22.0 months; hazard ratio [HR] 0.55; P < .001) and overall survival (54.4 vs 37.7 months; HR 0.73; P = .040) and lower rates of treatment discontinuation due to toxicity (22.5% vs 39.8%) and CLL progression (11.1% vs 27.5%).
Study details: This real-world retrospective study included 415 patients with relapsed or refractory CLL from the Chronic Lymphocytic Leukemia Patients Registry who received R-idela (n = 171) or ibrutinib (n = 244).
Disclosures: This study was funded by grants from the Ministry of Health, Czech Republic, and Programme Cooperation, Research Area ONCO. Some authors reported ties with various organizations.
Source: Spacek M et al for the Czech CLL Study Group. Idelalisib plus rituximab versus ibrutinib in the treatment of relapsed/refractory chronic lymphocytic leukaemia: A real-world analysis from the Chronic Lymphocytic Leukemia Patients Registry (CLLEAR). Br J Haematol. 2023 (Mar 27). Doi: 10.1111/bjh.18736
Key clinical point: Compared with idelalisib+rituximab (R-idela), ibrutinib significantly prolonged survival and was associated with lower treatment discontinuation rates in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) in routine practice.
Major finding: The ibrutinib vs R-idela group had significantly longer median progression-free survival (40.5 vs 22.0 months; hazard ratio [HR] 0.55; P < .001) and overall survival (54.4 vs 37.7 months; HR 0.73; P = .040) and lower rates of treatment discontinuation due to toxicity (22.5% vs 39.8%) and CLL progression (11.1% vs 27.5%).
Study details: This real-world retrospective study included 415 patients with relapsed or refractory CLL from the Chronic Lymphocytic Leukemia Patients Registry who received R-idela (n = 171) or ibrutinib (n = 244).
Disclosures: This study was funded by grants from the Ministry of Health, Czech Republic, and Programme Cooperation, Research Area ONCO. Some authors reported ties with various organizations.
Source: Spacek M et al for the Czech CLL Study Group. Idelalisib plus rituximab versus ibrutinib in the treatment of relapsed/refractory chronic lymphocytic leukaemia: A real-world analysis from the Chronic Lymphocytic Leukemia Patients Registry (CLLEAR). Br J Haematol. 2023 (Mar 27). Doi: 10.1111/bjh.18736
Key clinical point: Compared with idelalisib+rituximab (R-idela), ibrutinib significantly prolonged survival and was associated with lower treatment discontinuation rates in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) in routine practice.
Major finding: The ibrutinib vs R-idela group had significantly longer median progression-free survival (40.5 vs 22.0 months; hazard ratio [HR] 0.55; P < .001) and overall survival (54.4 vs 37.7 months; HR 0.73; P = .040) and lower rates of treatment discontinuation due to toxicity (22.5% vs 39.8%) and CLL progression (11.1% vs 27.5%).
Study details: This real-world retrospective study included 415 patients with relapsed or refractory CLL from the Chronic Lymphocytic Leukemia Patients Registry who received R-idela (n = 171) or ibrutinib (n = 244).
Disclosures: This study was funded by grants from the Ministry of Health, Czech Republic, and Programme Cooperation, Research Area ONCO. Some authors reported ties with various organizations.
Source: Spacek M et al for the Czech CLL Study Group. Idelalisib plus rituximab versus ibrutinib in the treatment of relapsed/refractory chronic lymphocytic leukaemia: A real-world analysis from the Chronic Lymphocytic Leukemia Patients Registry (CLLEAR). Br J Haematol. 2023 (Mar 27). Doi: 10.1111/bjh.18736