User login
FDA warns of increased risk of death with CLL, lymphoma drug
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib, following a voluntary request by the drug manufacturer, Secura Bio Inc.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by Medscape, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib, following a voluntary request by the drug manufacturer, Secura Bio Inc.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by Medscape, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib, following a voluntary request by the drug manufacturer, Secura Bio Inc.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by Medscape, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com.
FDA warning: Lymphoma drug heightens risk of death
The U.S. Food and Drug Administration issued a warning today that the cancer drug duvelisib (Copiktra, Verastem), a PI3 kinase inhibitor, may increase the risk of death and serious side effects.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib, compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced that it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib following a voluntary request by the drug manufacturer Secura Bio.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by this news organization, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com
The U.S. Food and Drug Administration issued a warning today that the cancer drug duvelisib (Copiktra, Verastem), a PI3 kinase inhibitor, may increase the risk of death and serious side effects.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib, compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced that it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib following a voluntary request by the drug manufacturer Secura Bio.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by this news organization, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com
The U.S. Food and Drug Administration issued a warning today that the cancer drug duvelisib (Copiktra, Verastem), a PI3 kinase inhibitor, may increase the risk of death and serious side effects.
Duvelisib was approved in 2018 to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received at least two prior therapies that did not work or stopped working.
However, more recent 5-year overall survival results from the randomized phase 3 DUO clinical trial found a possible increased risk of death with duvelisib, compared with another drug used to treat leukemia and lymphoma, according to an FDA Drug Safety Communication.
“The trial also found Copiktra was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood,” states the warning, which advises prescribers to weigh the risks and benefits of continued use versus use of other treatments.
More specifically, median 5-year overall survival among 319 patients with CLL or SLL in the DUO trial was 52.3 months with duvelisib versus 63.3 months with the monoclonal antibody ofatumumab (hazard ratio, 1.09 overall and 1.06 among patients who received at least two prior lines of therapy).
Serious adverse events of grade 3 or higher were also more common in those treated with duvelisib.
Of note, in April, the FDA also announced that it was withdrawing approval of the relapsed or refractory follicular lymphoma indication for duvelisib following a voluntary request by the drug manufacturer Secura Bio.
A public meeting will be scheduled to discuss the findings of the trial and whether the drug should continue to be prescribed.
This FDA warning follows the agency’s June 1 withdrawal of approval for umbralisib (Ukoniq), another PI3 kinase inhibitor, following an investigation into a “possible increased risk of death.”
As reported by this news organization, umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.
“These safety findings were similar for other medicines in the same PI3 kinase inhibitor class, which were discussed at an advisory committee meeting of non-FDA experts in April 2022,” according to the FDA warning.
The FDA urges patients and health care professionals to report side effects involving duvelisib or other medicines to the FDA MedWatch program.
A version of this article first appeared on Medscape.com
‘Superior’ CLL regimen cuts chemo in half
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
FROM EHA 2022
FDA approves liso-cel as second-line therapy for LBCL
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
Venetoclax combos prolong progression-free CLL survival
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding the Bruton tyrosine kinase inhibitor ibrutinib to the two-drug combination pushed the 3-year PFS even higher, but the risk of severe adverse events may outweigh the benefits of the triple combination for some higher-risk patients.
“Time-limited targeted therapy with venetoclax plus obinutuzumab, with or without ibrutinib, is superior to chemoimmunotherapy with respect to progression-free survival,” said first author Barbara Eichhorst, MD, of the University of Cologne (Germany).
However, given higher rates of infection and other adverse events observed when adding ibrutinib, “I would say, based on this data, not to use the triple combination in clinical practice,” Dr. Eichhorst cautioned.
Dr. Eichhorst presented these late-breaking results at the European Hematology Association annual congress.
For patients considered unfit for chemoimmunotherapy, the fixed-duration therapy of venetoclax plus obinutuzumab has become standard treatment for CLL. For those deemed fit to withstand chemoimmunotherapy, this option remains the standard of care.
However, no studies have compared the targeted combination with chemoimmunotherapy for fit patients with CLL.
Dr. Eichhorst and colleagues conducted the GAIA/CLL13 trial to determine how the two- or three-drug targeted combinations stack up against standard chemoimmunotherapy for fit patients.
In the phase 3 study, 920 treatment-naive, fit patients with CLL in which there were no TP53 aberrations were randomly assigned to one of four treatment groups that each had 230 patients – standard chemoimmunotherapy or one of three time-limited venetoclax arms.
The regimen for the chemoimmunotherapy group included fludarabine, cyclophosphamide, and rituximab for those aged 65 and younger, and bendamustine and rituximab for those over 65. The patients who received venetoclax were divided into groups that received either venetoclax plus rituximab, venetoclax plus obinutuzumab, or triple therapy of venetoclax, obinutuzumab, and ibrutinib.
The median age was 61, and follow-up was just over 3 years (38.8 months). Nearly 40% of patients were in advanced Binet stages, and more than half (56%) were of unmutated immunoglobulin heavy chain gene (IgVH) status, which is associated with worse outcomes in CLL.
Compared with chemotherapy, the two-drug combination demonstrated significantly better PFS (hazard ratio, 0.32; P < .000001), as did the triple therapy (HR, 0.42; P < .001), though the venetoclax-rituximab combination did not (HR, 0.79; P = .183).
The 3-year PFS rates were highest in the triple-therapy group (90.5%), followed by the venetoclax and obinutuzumab group (87.7%). The chemoimmunotherapy (75.5%) and venetoclax plus rituximab groups (80.8%) had the lowest 3-year PFS rates.
Overall, 3-year PFS rates for patients with unmutated IgVH were slightly lower, compared with those who had mutated IgVH.
The best PFS rate was among patients who received the 3-drug combination, although one interesting caveat emerged among the under-65 subset of patients in the mutated IgVH group: the chemotherapy arm achieved a slightly better PFS rate (95%) compared with the triple-therapy arm (93.6%).
Notably, overall survival was similar among all groups; about 96% of patients were alive at 3 years.
Several adverse events were more pronounced in the triple-therapy group. The highest rate of grade 3-4 infections was among those who received ibrutinib (22.1% vs. 20.4% for chemotherapy, 11.4% for venetoclax/rituximab, and 14.9% for venetoclax/obinutuzumab). The triple-therapy group also had the highest rate of hypertension (5.6% vs. 1.4% for chemotherapy, 2.1% for venetoclax/rituximab, and 1.8% for venetoclax/obinutuzumab).
Rates of febrile neutropenia and secondary primary malignancies, however, were highest in the chemoimmunotherapy group. More than 11% of patients in the chemoimmunotherapy group had febrile neutropenia, compared with 7.8% of those who received triple therapy, 4.2% in the venetoclax/rituximab group, and 3.1% of those who received venetoclax/obinutuzumab. Almost half of patients in the chemoimmunotherapy group had secondary primary malignancies versus fewer than 30% in the other arms.
EHA President-Elect António Almeida, MD, noted that the research sheds important light on evolving treatment options for CLL.
“The first is that the triple combination appears better than the double combinations, and I think that’s an important message because of longer treatment-free remission and progression-free remissions,” Dr. Almeida, of the Hospital da Luz, Lisbon, said in an interview.
The second important message: Given the time-limited administration of the venetoclax combinations, the data show that “we can stop ibrutinib and that is safe,” he added. “That’s quite important.”
Third, the findings can help guide treatment choices. “We’ve already had an indication that obinutuzumab is better than rituximab in the CLL setting, but this again solidifies that notion,” Dr. Almeida added.
Dr. Eichhorst has relationships with Janssen, Gilead, F. Hoffmann–La Roche, AbbVie, BeiGene, AstraZeneca, MSD, Adaptive Biotechnologies, and Hexal. Dr. Almeida disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EHA 2022
Studies address ibrutinib bleeding risk in patients with CLL receiving Mohs surgery
Patients receiving , new research shows.
“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.
“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).
With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.
While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.
In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.
However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.
The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.
The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).
Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.
In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.
“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.
In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).
Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).
There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).
In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”
Holding treatment
To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”
“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.
Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.
The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.
The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.
“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.
“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.
She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.
“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”
Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients receiving , new research shows.
“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.
“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).
With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.
While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.
In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.
However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.
The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.
The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).
Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.
In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.
“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.
In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).
Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).
There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).
In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”
Holding treatment
To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”
“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.
Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.
The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.
The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.
“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.
“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.
She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.
“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”
Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients receiving , new research shows.
“Our cohort of CLL patients on ibrutinib had a two-times greater risk of bleeding complications relative to those on anticoagulants and a nearly 40-times greater risk of bleeding complications relative to those patients on no anticoagulants or CLL therapy,” Kelsey E. Hirotsu, MD, first author of one of two studies on the issue presented at the American College of Mohs Surgery annual meeting, told this news organization.
“It was definitely surprising to see this doubled risk with ibrutinib relative to anticoagulants, and certainly highlights the clinically relevant increased bleeding risk in patients on ibrutinib,” said Dr. Hirotsu, a Mohs micrographic surgery fellow in the department of dermatology, University of California, San Diego (UCSD).
With CLL associated with an increased risk for aggressive skin cancers, particularly squamous cell carcinoma, Mohs surgeons may commonly find themselves treating patients with these unique considerations. Surgical treatment of those cancers can be complicated not only because of potential underlying thrombocytopenia, which occurs in about 5% of untreated CLL patients, but also because of the increased risk for bleeding that is associated with the use of the Bruton tyrosine kinase inhibitor ibrutinib, commonly used for CLL.
While the nature of the increased bleeding-related complications among patients with CLL undergoing Mohs surgery has been documented in some case reports, evidence from larger studies has been lacking.
In one of the studies presented at the ACMS meeting, Dr. Hirotsu and her colleagues evaluated data on patients with CLL who underwent at least one Mohs surgery procedure at UCSD Dermatologic Surgery over 10 years. Of the 362 Mohs cases among 98 patients with CLL, 32 cases had at least one complication. Patients on anticoagulants, including antiplatelet agents, Coumadin, and direct oral anticoagulants (DOACs), not surprisingly, had higher rates of complications, particularly bleeding.
However, those treated with ibrutinib had the highest rates of complications among all of the patients (40.6%), with all of their complications involving bleeding-related events. In comparison, the complication rates, for instance, of patients treated with antiplatelets were 21.9%; Coumadin, 6.2%; and DOACs, 15.6%.
The incidence of bleeding-related complications among the cases in the ibrutinib-treated patients was 30.2% compared with 13.2% among those on blood thinners and no CLL therapy (relative risk [RR], 2.08; 95% confidence interval [CI], 0.85-5.11; P = .11). “Although not statistically significant, these results could trend toward significance with larger sample sizes,” Dr. Hirotsu said.
The risk for bleeding among patients on ibrutinib compared with patients on no medications, however, was significant, with a relative risk of 39.0 (95% CI, 2.35-646; P = .011).
Of note, among 12 patients on ibrutinib who experienced bleeding complications, 7 had previously undergone Mohs surgeries when they were not taking ibrutinib and no bleeding complications had occurred in those procedures. “This may further implicate ibrutinib as a cause of the bleeding-related complications,” Dr. Hirotsu said.
In investigating the role of thrombocytopenia at the time of Mohs surgery, the authors found that, among ibrutinib-treated patients who had no complications, 30% had thrombocytopenia, compared with 70% of those who did have bleeding while on ibrutinib at the time of surgery.
“It was interesting that thrombocytopenia is more common in ibrutinib patients with bleeding-related complications, but further research needs to be done to determine the clinical relevance and possible management implications,” Dr. Hirotsu said.
In a separate study presented at the meeting, 37 patients treated with ibrutinib for CLL while undergoing cutaneous surgery that included Mohs surgery and excisions had a significantly increased bleeding complication rate compared with a control group of 64 age- and sex-matched patients with CLL undergoing cutaneous surgery: 6 of 75 procedures (8%) versus 1 of 115 procedures (0.9%; P = .02).
Those with bleeding complications while on ibrutinib were all male, older (mean age, 82.7 vs. 73.0; P = .01), and had lower mean platelet counts (104 K/mcL vs. 150.5 K/mcL; P = .03).
There were no significant differences between the case and control groups in terms of anatomic site, type of procedure (Mohs versus excision), tumor diagnosis, lesion size, or type of reconstruction, while the control group was more likely to be on aspirin or other anticoagulants (P < .0001).
In an interview, senior author Nahid Y. Vidal, MD, a Mohs surgeon and dermatologic oncologist at the Mayo Clinic, Rochester, Minn., said that “the take-home message is that patients on ibrutinib should be considered higher risk for bleeding events, regardless of whether they are having a simpler surgery [excision] or more involved skin surgery procedure [Mohs with flap].”
Holding treatment
To offset the bleeding risk, Dr. Vidal notes that holding the treatment is considered safe and that the manufacturer recommends holding ibrutinib for at least 3-7 days pre- and post surgery, “depending on type of surgery and risk of bleeding.”
“In our institution, with the hematologist/oncologist’s input, we hold ibrutinib for 5 days preop and 3 days post op, and have not had bleed complications in these patients,” she said, noting that there were no bleeding events in the patients in the study when ibrutinib was held.
Likewise, Dr. Hirotsu noted that at her center at UCSD, patients on ibrutinib are asked during the preop call to hold treatment for 3 days before and after Mohs surgery – but are advised to discuss the decision with their hematologist/oncologist for approval.
The measure isn’t always successful in preventing bleeding, however, as seen in a case study describing two patients who experienced bleeding complications following Mohs surgery despite being taken off ibrutinib 3 days prior to the procedure.
The senior author of that study, Kira Minkis, MD, PhD, department of dermatology, Weill Cornell/New York Presbyterian, New York, told this news organization that her team concluded that in those cases ibrutinib perhaps should have been held longer than 3 days.
“In some cases, especially if the Mohs surgery is a large procedure with a more advanced reconstruction, such as a large flap, it might be more prudent to continue it longer than 3 days,” Dr. Minkis said. She noted that the high bleeding risk observed in the studies at ACMS was notable – but not unexpected.
“I’m not that surprised because if you look at the hematologic literature, the risk is indeed pretty significant, so it makes sense that it would also occur with Mohs surgeries,” she said.
She underscored that a 3-day hold of ibrutinib should be considered the minimum, “and in some cases, it should be held up to 7 days prior to surgery, depending on the specific surgery,” with the important caveat of consulting with the patient’s hematology team.
“Multidisciplinary decision-making is necessary for these cases, and the interruption of therapy should always be discussed with their hematology team,” she added. That said, Dr. Minkis noted that “I’ve never had a hematologist who had any concerns for withholding ibrutinib even for a week around the time of a surgery.”
Dr. Hirotsu, Dr. Vidal, and Dr. Minkis reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE ACMS ANNUAL MEETING
Phase-3 study: Leukemia patients live longer with ibrutinib
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
“This trial led to the first-line approval of ibrutinib for CLL patients,” lead author Paul M. Barr, MD, of the University of Rochester (N.Y.), said in an interview. “It is important to follow these patients long-term to understand the expected duration of response/disease control and to monitor for late toxicity,” he said “The data are useful in guiding clinicians who treat CLL and patients being treated with single agent BTK inhibitors,” he noted.
In the initial RESONATE-2, a phase 3, open-label study, 269 adults aged 65 years and older who were previously untreated for CLL or small lymphocytic leukemia were randomized to ibrutinib or the standard of care, chlorambucil. Patients received 420 mg of ibrutinib once daily until disease progression or unacceptable toxicity (136 patients) or up to 12 cycles of 0.5-0.8 mg/kg of chlorambucil (133 patients).
The long-term outcome data were published in Blood Advances.
Overall, at a median of 83 months’ follow-up, progression-free survival was significantly higher for ibrutinib patients than for chlorambucil patients (hazard ratio 0.154).
At 7 years, progression-free survival was 59% in the ibrutinib group vs. 9% in the chlorambucil group.
Notably, progression-free survival benefits with ibrutinib also were higher for patients with high-risk genomic features, identified as del(11q) and unmutated immunoglobulin heavy-chain variable region gene (IGHV).
Complete data were available for 54 patients with del(11q) and 118 with unmutated IGHV. In this subset of patients, progression-free survival rates at 7 years were significantly higher for those treated with ibrutinib vs. chlorambucil who had del(11q) or unmutated IGHV (52% vs. 0% and 58% vs. 2%, respectively).
Approximately 42% of patients with chronic lymphocytic leukemia treated with ibrutinib remained on the therapy at up to 8 years, with a median follow-up of 7.4 years. Overall survival at 7 years was 78% for ibrutinib; overall survival data were not collected for chlorambucil for patients with progressive disease after the median of 5 years, as these patients were eligible to switch to ibrutinib in a long-term extension study or exit the study.
Adverse events prompted reduction of ibrutinib in 30 patients and dose holding for at least 7 days in 79 patients. However, dose modification resolved or improved the adverse events in 85% of the patients with held doses and 90% of those with reduced doses.
The overall prevalence of adverse events was similar to previous follow-up data at 5 years. No new safety signals were observed during the longer study period. The rate of treatment discontinuation because of adverse events was highest in the first year.
“We have been surprised at how long the remissions have lasted with ibrutinib,” said Dr. Barr. “Even with up to 8 years of follow-up, we have yet to reach the median progression free-survival,” he noted.
“These data, in combination with other data sets, highlight the impact that ibrutinib and other BTK inhibitors have had in treating CLL,” said Dr. Barr. “Patients are living longer and avoiding the side effects of chemotherapy in the era of novel agent use,” he said.
However, research gaps remain, Dr. Barr noted. “We need to continue following these patients over time given the length of the remissions. Additionally, we need to continue investigating novel combinations,” he said. Such studies will help us understand the benefit of fixed durations regimens compared to single agent BTK inhibitors,” he emphasized.
Safety and efficacy remain promising
“Ibrutinib was approved for the treatment of CLL, but only in the relapsed setting,” Susan M. O’Brien, MD, of the University of California, Irvine, said in an interview. “This trial was important because it led to the approval of ibrutinib in the front-line setting, making it the first, and at the time, only, small molecule that could be used upfront,” said Dr. O’Brien, who was not involved with the study.
“The initial results were certainly not surprising, as given the efficacy of ibrutinib in the relapsed setting, it seemed likely that it would produce a longer PFS than chlorambucil,” said Dr. O’Brien. “What may not have been expected though, is the incredible durability of these responses with ibrutinib,” she noted.
The clinical implications of the long-term data are that ibrutinib is producing “very durable remissions with continuous therapy,” Dr. O’Brien said. “There are no late safety signals and most side effects diminish with time. However, hypertension and atrial fibrillation continue to occur, so continued monitoring of blood pressure in these patients is important,” she emphasized.
Minor, but annoying, side effects are not infrequent early on with ibrutinib and may present a barrier to use for some patients, Dr. O’Brien said. “Some side effects may be overcome with temporary pauses of drug or dose reduction,” she noted. However, “it is important for patients to be aware that most of these side effects will completely abate with time,” she added.
“The main limitation of this trial was that the comparison was to a rather weak chemotherapy agent, albeit it one frequently used in older patients, particularly in Europe,” said Dr. O’Brien. “Nevertheless, two subsequent trials comparing ibrutinib (with or without rituximab) with either BR [bendamustine/rituximab] or FCR [fludarabine/cyclophosphamide/rituximab] showed a longer PFS with ibrutinib, as compared to that seen with either chemoimmunotherapy regimen,” she said.
The study was supported by Pharmacyclics LLC, an AbbVie company. Dr. Barr collaborated with sponsor AbbVie on the study design, and disclosed relationships with companies including AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, Morphosys, Pharmacyclics LLC (an AbbVie company), Seattle Genetics, and TG Therapeutics. Dr. O’Brien had no relevant financial conflicts to disclose.
FROM BLOOD ADVANCES
Third-generation Black woman physician makes cancer research history
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
Ex–hospital porter a neglected giant of cancer research
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
‘Agony of choice’ for clinicians treating leukemia
“Targeted therapies have outnumbered chemoimmunotherapy-based treatment approaches, demonstrating superior efficacy and tolerability profiles across nearly all CLL patient subgroups in the frontline and relapsed disease treatment setting,” author Jan-Paul Bohn, MD, PhD, of the department of internal medicine V, hematology and oncology, at Medical University of Innsbruck (Austria), reported in the review published in Memo, the Magazine of European Medical Oncology.
The options leave clinicians “spoilt for choice when selecting optimal therapy,” he said.
The three major drug classes to emerge – inhibitors of Bruton tyrosine kinase (BTK), antiapoptotic protein B-cell lymphoma 2 (BCL2) and phosphoinositide 3’-kinase (PI3K) – all appear similar in efficacy and tolerability.
Particularly in high-risk patients, the drugs have been so effective that the less desirable previous standard of “chemoimmunotherapy has widely faded into the background in the Western hemisphere,” Dr. Bohn wrote.
However, with caveats of the newer drugs including acquired resistances and potential toxicities, challenges have shifted to determining how to best juggle and/or combine the agents.
Frontline therapy
In terms of frontline options for CLL therapy, the BTK inhibitors, along with the BCL2 inhibitor venetoclax have been key in negating the need for chemotherapy, with some of the latest data showing superiority of venetoclax in combination with obinutuzumab (GVe) over chemotherapy even in the higher-risk subset of patients with mutated IGHV status and without TP53 disruption.
Hence, “chemoimmunotherapy may now even be questioned in the remaining subset of CLL patients with mutated IGHV status and without TP53 disruption,” Dr. Bohn reported.
That being said, the criteria for treatment choices in the frontline setting among the newer drug classes can often come down to the key issues of patients’ comorbidities and treatment preferences.
For example, in terms of patients who have higher risk because of tumor lysis syndrome (TLS), or issues including declining renal function, continuous BTK inhibitor treatment may be the preferred choice over the combination of venetoclax plus obinutuzumab (GVe), Dr. Bohn noted.
Conversely, for patients with cardiac comorbidities or a higher risk of bleeding, the GVe combination may be preferred over ibrutinib, with recent findings showing ibrutinib to be associated with as much as an 18-times higher risk of sudden unexplained death or cardiac death in young and fit patients who had preexisting arterial hypertension and/or a history of cardiac disorders requiring therapy.
For those with cardiac comorbidities, the more selective second-generation BTK inhibitor acalabrutinib is a potentially favorable alternative, as the drug is “at least similarly effective and more favorable in terms of tolerability, compared with ibrutinib, particularly as far as cardiac and bleeding side effects are considered,” Dr. Bohn said.
And in higher-risk cases involving TP53 dysfunction, a BTK inhibitor may be superior to GVe for frontline treatment, Dr. Bohn noted, with data showing progression-free survival in patients with and without deletion 17p to be significantly reduced with GVe versus the BTK inhibitor ibrutinib.
Relapsed and refractory disease
With similarly high efficacy observed with the new drug classes among relapsed and/or refractory patients, chemoimmunotherapy has likewise “become obsolete in nearly all patients naive to novel agents at relapse who typically present with genetically high-risk disease,” Dr. Bohn noted.
He wrote that most of the recommendations for frontline therapy hold true in the relapsed and refractory patients, with comorbidities and personal preferences again key drivers of treatment choices.
While data is currently limited regarding benefits of venetoclax-based regimens over BTK inhibitors in relapsed/refractory patients, there is “growing evidence suggesting similar clinical outcomes achievable with these agents in either order,” Dr. Bohn wrote.
Further recommendations regarding relapsed or refractory patients include:
- Among patients who do experience disease progression while on continuous treatment with BTK inhibitors, venetoclax-based regimes seem most effective. However, with relapse after venetoclax-based regimes, some growing evidence supports retreatment with the drug “depending on depth and duration of response achieved after first venetoclax exposure,” Dr. Bohn noted.
- For patients with deletion 17p, venetoclax shows promising efficacy during relapse when given as monotherapy until disease progression or occurrence of unacceptable toxicity.
- And for patients with TP53 abnormalities, the considerations are the same as for frontline therapy, with venetoclax showing promising efficacy when given in monotherapy until disease progression or occurrence of unacceptable toxicity.
Of note, PI3K inhibitors are generally not used in CLL patients naive to BTK and BCL2 inhibitors because of the higher risk of immune-mediated toxicities and infectious complications associated with the currently approved PI3K inhibitors idelalisib and duvelisib, he reported.
Nevertheless, “PI3K inhibitors remain a valuable therapeutic addition in patients refractory or intolerant to BTK inhibitors and venetoclax-based regimens,” Dr. Bohn said.
Newer agents, fixed duration
Commenting on the review, hematologist Seema A. Bhat, MD, an assistant professor with the Ohio State University Comprehensive Cancer Center, Columbus, said that the advances with targeted therapies in CLL are paying off with improved survival.
“With these recent advances in the treatment of CLL, especially the availability of targeted therapies, there has been an improvement in survival of patients with CLL, as the CLL-related death rate steadily reduced by approximately 3% per year between 2006 and 2015,” she said in an interview.
She added that even-newer agents in development, including the reversibly binding BTK inhibitor–like pirtobrutinib and nemtabrutinib, when approved, will further add to the treatment choices for patients.
Meanwhile, a key area of focus is the combination of BTK inhibitors and BCL2 inhibitors, specifically for a fixed duration of time to obtain a deeper response and hence possibility a time-limited therapy, she noted. “We are also excited about the possibility of having more fixed-duration treatments available for our patients, which will make their treatment journey less troublesome, both physically as well as financially.”
Dr. Bohn reported receiving personal fees from AbbVie, AstraZeneca and Janssen for advisory board participation. Dr. Bhat has served on advisory board for AstraZeneca and received honorarium from them.
“Targeted therapies have outnumbered chemoimmunotherapy-based treatment approaches, demonstrating superior efficacy and tolerability profiles across nearly all CLL patient subgroups in the frontline and relapsed disease treatment setting,” author Jan-Paul Bohn, MD, PhD, of the department of internal medicine V, hematology and oncology, at Medical University of Innsbruck (Austria), reported in the review published in Memo, the Magazine of European Medical Oncology.
The options leave clinicians “spoilt for choice when selecting optimal therapy,” he said.
The three major drug classes to emerge – inhibitors of Bruton tyrosine kinase (BTK), antiapoptotic protein B-cell lymphoma 2 (BCL2) and phosphoinositide 3’-kinase (PI3K) – all appear similar in efficacy and tolerability.
Particularly in high-risk patients, the drugs have been so effective that the less desirable previous standard of “chemoimmunotherapy has widely faded into the background in the Western hemisphere,” Dr. Bohn wrote.
However, with caveats of the newer drugs including acquired resistances and potential toxicities, challenges have shifted to determining how to best juggle and/or combine the agents.
Frontline therapy
In terms of frontline options for CLL therapy, the BTK inhibitors, along with the BCL2 inhibitor venetoclax have been key in negating the need for chemotherapy, with some of the latest data showing superiority of venetoclax in combination with obinutuzumab (GVe) over chemotherapy even in the higher-risk subset of patients with mutated IGHV status and without TP53 disruption.
Hence, “chemoimmunotherapy may now even be questioned in the remaining subset of CLL patients with mutated IGHV status and without TP53 disruption,” Dr. Bohn reported.
That being said, the criteria for treatment choices in the frontline setting among the newer drug classes can often come down to the key issues of patients’ comorbidities and treatment preferences.
For example, in terms of patients who have higher risk because of tumor lysis syndrome (TLS), or issues including declining renal function, continuous BTK inhibitor treatment may be the preferred choice over the combination of venetoclax plus obinutuzumab (GVe), Dr. Bohn noted.
Conversely, for patients with cardiac comorbidities or a higher risk of bleeding, the GVe combination may be preferred over ibrutinib, with recent findings showing ibrutinib to be associated with as much as an 18-times higher risk of sudden unexplained death or cardiac death in young and fit patients who had preexisting arterial hypertension and/or a history of cardiac disorders requiring therapy.
For those with cardiac comorbidities, the more selective second-generation BTK inhibitor acalabrutinib is a potentially favorable alternative, as the drug is “at least similarly effective and more favorable in terms of tolerability, compared with ibrutinib, particularly as far as cardiac and bleeding side effects are considered,” Dr. Bohn said.
And in higher-risk cases involving TP53 dysfunction, a BTK inhibitor may be superior to GVe for frontline treatment, Dr. Bohn noted, with data showing progression-free survival in patients with and without deletion 17p to be significantly reduced with GVe versus the BTK inhibitor ibrutinib.
Relapsed and refractory disease
With similarly high efficacy observed with the new drug classes among relapsed and/or refractory patients, chemoimmunotherapy has likewise “become obsolete in nearly all patients naive to novel agents at relapse who typically present with genetically high-risk disease,” Dr. Bohn noted.
He wrote that most of the recommendations for frontline therapy hold true in the relapsed and refractory patients, with comorbidities and personal preferences again key drivers of treatment choices.
While data is currently limited regarding benefits of venetoclax-based regimens over BTK inhibitors in relapsed/refractory patients, there is “growing evidence suggesting similar clinical outcomes achievable with these agents in either order,” Dr. Bohn wrote.
Further recommendations regarding relapsed or refractory patients include:
- Among patients who do experience disease progression while on continuous treatment with BTK inhibitors, venetoclax-based regimes seem most effective. However, with relapse after venetoclax-based regimes, some growing evidence supports retreatment with the drug “depending on depth and duration of response achieved after first venetoclax exposure,” Dr. Bohn noted.
- For patients with deletion 17p, venetoclax shows promising efficacy during relapse when given as monotherapy until disease progression or occurrence of unacceptable toxicity.
- And for patients with TP53 abnormalities, the considerations are the same as for frontline therapy, with venetoclax showing promising efficacy when given in monotherapy until disease progression or occurrence of unacceptable toxicity.
Of note, PI3K inhibitors are generally not used in CLL patients naive to BTK and BCL2 inhibitors because of the higher risk of immune-mediated toxicities and infectious complications associated with the currently approved PI3K inhibitors idelalisib and duvelisib, he reported.
Nevertheless, “PI3K inhibitors remain a valuable therapeutic addition in patients refractory or intolerant to BTK inhibitors and venetoclax-based regimens,” Dr. Bohn said.
Newer agents, fixed duration
Commenting on the review, hematologist Seema A. Bhat, MD, an assistant professor with the Ohio State University Comprehensive Cancer Center, Columbus, said that the advances with targeted therapies in CLL are paying off with improved survival.
“With these recent advances in the treatment of CLL, especially the availability of targeted therapies, there has been an improvement in survival of patients with CLL, as the CLL-related death rate steadily reduced by approximately 3% per year between 2006 and 2015,” she said in an interview.
She added that even-newer agents in development, including the reversibly binding BTK inhibitor–like pirtobrutinib and nemtabrutinib, when approved, will further add to the treatment choices for patients.
Meanwhile, a key area of focus is the combination of BTK inhibitors and BCL2 inhibitors, specifically for a fixed duration of time to obtain a deeper response and hence possibility a time-limited therapy, she noted. “We are also excited about the possibility of having more fixed-duration treatments available for our patients, which will make their treatment journey less troublesome, both physically as well as financially.”
Dr. Bohn reported receiving personal fees from AbbVie, AstraZeneca and Janssen for advisory board participation. Dr. Bhat has served on advisory board for AstraZeneca and received honorarium from them.
“Targeted therapies have outnumbered chemoimmunotherapy-based treatment approaches, demonstrating superior efficacy and tolerability profiles across nearly all CLL patient subgroups in the frontline and relapsed disease treatment setting,” author Jan-Paul Bohn, MD, PhD, of the department of internal medicine V, hematology and oncology, at Medical University of Innsbruck (Austria), reported in the review published in Memo, the Magazine of European Medical Oncology.
The options leave clinicians “spoilt for choice when selecting optimal therapy,” he said.
The three major drug classes to emerge – inhibitors of Bruton tyrosine kinase (BTK), antiapoptotic protein B-cell lymphoma 2 (BCL2) and phosphoinositide 3’-kinase (PI3K) – all appear similar in efficacy and tolerability.
Particularly in high-risk patients, the drugs have been so effective that the less desirable previous standard of “chemoimmunotherapy has widely faded into the background in the Western hemisphere,” Dr. Bohn wrote.
However, with caveats of the newer drugs including acquired resistances and potential toxicities, challenges have shifted to determining how to best juggle and/or combine the agents.
Frontline therapy
In terms of frontline options for CLL therapy, the BTK inhibitors, along with the BCL2 inhibitor venetoclax have been key in negating the need for chemotherapy, with some of the latest data showing superiority of venetoclax in combination with obinutuzumab (GVe) over chemotherapy even in the higher-risk subset of patients with mutated IGHV status and without TP53 disruption.
Hence, “chemoimmunotherapy may now even be questioned in the remaining subset of CLL patients with mutated IGHV status and without TP53 disruption,” Dr. Bohn reported.
That being said, the criteria for treatment choices in the frontline setting among the newer drug classes can often come down to the key issues of patients’ comorbidities and treatment preferences.
For example, in terms of patients who have higher risk because of tumor lysis syndrome (TLS), or issues including declining renal function, continuous BTK inhibitor treatment may be the preferred choice over the combination of venetoclax plus obinutuzumab (GVe), Dr. Bohn noted.
Conversely, for patients with cardiac comorbidities or a higher risk of bleeding, the GVe combination may be preferred over ibrutinib, with recent findings showing ibrutinib to be associated with as much as an 18-times higher risk of sudden unexplained death or cardiac death in young and fit patients who had preexisting arterial hypertension and/or a history of cardiac disorders requiring therapy.
For those with cardiac comorbidities, the more selective second-generation BTK inhibitor acalabrutinib is a potentially favorable alternative, as the drug is “at least similarly effective and more favorable in terms of tolerability, compared with ibrutinib, particularly as far as cardiac and bleeding side effects are considered,” Dr. Bohn said.
And in higher-risk cases involving TP53 dysfunction, a BTK inhibitor may be superior to GVe for frontline treatment, Dr. Bohn noted, with data showing progression-free survival in patients with and without deletion 17p to be significantly reduced with GVe versus the BTK inhibitor ibrutinib.
Relapsed and refractory disease
With similarly high efficacy observed with the new drug classes among relapsed and/or refractory patients, chemoimmunotherapy has likewise “become obsolete in nearly all patients naive to novel agents at relapse who typically present with genetically high-risk disease,” Dr. Bohn noted.
He wrote that most of the recommendations for frontline therapy hold true in the relapsed and refractory patients, with comorbidities and personal preferences again key drivers of treatment choices.
While data is currently limited regarding benefits of venetoclax-based regimens over BTK inhibitors in relapsed/refractory patients, there is “growing evidence suggesting similar clinical outcomes achievable with these agents in either order,” Dr. Bohn wrote.
Further recommendations regarding relapsed or refractory patients include:
- Among patients who do experience disease progression while on continuous treatment with BTK inhibitors, venetoclax-based regimes seem most effective. However, with relapse after venetoclax-based regimes, some growing evidence supports retreatment with the drug “depending on depth and duration of response achieved after first venetoclax exposure,” Dr. Bohn noted.
- For patients with deletion 17p, venetoclax shows promising efficacy during relapse when given as monotherapy until disease progression or occurrence of unacceptable toxicity.
- And for patients with TP53 abnormalities, the considerations are the same as for frontline therapy, with venetoclax showing promising efficacy when given in monotherapy until disease progression or occurrence of unacceptable toxicity.
Of note, PI3K inhibitors are generally not used in CLL patients naive to BTK and BCL2 inhibitors because of the higher risk of immune-mediated toxicities and infectious complications associated with the currently approved PI3K inhibitors idelalisib and duvelisib, he reported.
Nevertheless, “PI3K inhibitors remain a valuable therapeutic addition in patients refractory or intolerant to BTK inhibitors and venetoclax-based regimens,” Dr. Bohn said.
Newer agents, fixed duration
Commenting on the review, hematologist Seema A. Bhat, MD, an assistant professor with the Ohio State University Comprehensive Cancer Center, Columbus, said that the advances with targeted therapies in CLL are paying off with improved survival.
“With these recent advances in the treatment of CLL, especially the availability of targeted therapies, there has been an improvement in survival of patients with CLL, as the CLL-related death rate steadily reduced by approximately 3% per year between 2006 and 2015,” she said in an interview.
She added that even-newer agents in development, including the reversibly binding BTK inhibitor–like pirtobrutinib and nemtabrutinib, when approved, will further add to the treatment choices for patients.
Meanwhile, a key area of focus is the combination of BTK inhibitors and BCL2 inhibitors, specifically for a fixed duration of time to obtain a deeper response and hence possibility a time-limited therapy, she noted. “We are also excited about the possibility of having more fixed-duration treatments available for our patients, which will make their treatment journey less troublesome, both physically as well as financially.”
Dr. Bohn reported receiving personal fees from AbbVie, AstraZeneca and Janssen for advisory board participation. Dr. Bhat has served on advisory board for AstraZeneca and received honorarium from them.
FROM MEMO – MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY