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Gloom lifting as MCL treatments evolve
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
Traditionally, MCL has had a notoriously poor prognosis and is still impossible to cure. But survival rates are rising thanks to better treatments, the review authors wrote, and even relapsed/refractory patients have a growing number of options that can potentially give them extra years of life.
“Prognosis has certainly changed in past 10 years. We have been able to have an excellent control of disease, and patients are living longer, even past the 8- or 10-year mark,” Moffit Cancer Center/Memorial Healthcare System hematologist-oncologist Jose Sandoval‐Sus, MD, said in an interview. He is corresponding author of the review, which appeared in the October issue of Current Oncology Reports.
MCL – which affects cells in the mantle zone of lymph nodes – is rare. It usually strikes older men, often presents at an advanced stage, and accounts for 6%-8% of non-Hodgkin lymphomas in the United States.
Prognoses are improving. The review highlights a study released earlier this year that found that median 5-year overall survival has increased from 68.8% (2002-2009) to 81.6% (2010-2015).
Now, the review notes, there are several first-line chemotherapy options that combine agents with rituximab such as rituximab/bendamustine, which “has generally been established as an effective treatment for MCL at first relapse in patients who are bendamustine naive when compared to other chemotherapy agents.”
Other treatments include rituximab, bortezomib, cyclophosphamide, doxorubicin, vincristine, and prednisolone; rituximab, bendamustine and cytarabine; and rituximab, gemcitabine, and oxaliplatin.
“I think of rituximab as a medication of maintenance, either after autologous stem cell transplant or even in patients who have not been through transplant,” Dr. Sandoval‐Sus said. “As maintenance, it really has improved outcomes for these patients.”
But the first step before treatment, he said, is to explore prognostic factors such as alterations on the TP53 gene that “really dictate a lot in terms of the prognosis of patients.” As the review notes, these alterations – either bi-allelic del17p or TP53 mutations – “are associated with poor outcomes after frontline and salvage regimens, including targeted agents such as Burton’s tyrosine kinase inhibitors (BTKis).”
These patients, who make up about 20% of those with MCL, also are most unlikely to benefit from autologous stem cell transplantation, Dr. Sandoval‐Sus said.
What about refracted/relapsed (R/R) cases? BTKis have been a major advance for these patients, he said. However, choosing the best drug can be a challenge. As the review notes, “all approved BTKis for R/R MCL seem to have similar clinical outcomes based on identical mechanism of action, and there are no prospective trials comparing these agents in a head-to-head fashion.”
The authors added that “we wonder if AEs [adverse events] could be decreased by using combinations based on new generation BTKi, but it is still a question that needs to be resolved in the clinical trial arena.”
Stem cell transplants may be an option, the review said, but “in practice the clinical benefit ... is limited to single-center series or small multi-institutional registries with few prospective studies.”
Then there’s CAR-T cell therapy, the game-changer. A type called brexucabtagene autoleucel (Brexu-cel) is now approved in MCL, the review authors wrote, and real-world data “serve as a platform to expand CAR-T therapy to more R/R MCL patients that do not fit the strict inclusion criteria of the studies (e.g., controlled comorbidities and worse performance status)... We strongly recommend early referral of these patients to accredited institutions with ample cellular therapy experience, including high-risk MCL patients (e.g., blastoid/pleomorphic morphology, biallelic del17p, TP53 mutations) so an appropriate bridging strategy and a CAR-T cell roadmap is planned with the patient and caretakers.”
Some researchers are exploring combination treatment with both BTKis and CAR T-cell therapy, “which may be considered for patients with R/R MCL who are naive to both CAR T-cell and BTKi therapy, because combination therapy may increase treatment efficacy,” wrote the authors of another review that appeared in the October issue of Current Oncology Reports. “Based on limited data in patients with CLL, BTKi therapy may be initiated as bridging therapy and continued during lymphodepletion prior to CAR T-cell infusion”
What’s next? Multiple treatments are in the research stage, Dr. Sandoval‐Sus said. “There are a lot of things in development that are really incredible.”
Reversible BTKis, for example, appear to be effective at controlling disease and are well-tolerated, he said. “And we are awaiting the results of clinical trials of targeted therapies.”
For now, he said, the best advice for hematologists is to gain a full understanding of a patient’s MCL, in order to provide the most appropriate treatment. Community oncologists should get at least one second opinion from an academic center or other clinic that treats these kinds of lymphomas, he said, and molecular tests are crucial. A discussion about stem cell transplantation after remission is a good idea, he said, and so is an exploration of clinical trials “from the get-go.”
“In patients who relapse and have high-risk features, they should be started on a BTKi inhibitor for the most part,” he said, “although we need to weigh risks and benefits between the side effects of different BTKi inhibitors. And they should be referred earlier to a CAR T cell therapy center, so they can discuss the benefits and see if they’re an appropriate patient. I think patients are being referred a little bit too late in the second- or third-line setting.”
What about CAR T therapy as a first-line therapy? It’s not FDA-approved, Dr. Sandoval‐Sus said, and “definitely not a standard of care.” But clinical trials are exploring the idea, he said. As for messages to patients, Dr. Sandoval-Sus said he would tell them that MCL is not yet curable, “but the future is very bright.”
Dr. Sandoval-Sus declared advisory board relationships with Seagen, Incyte, Janssen, ADC Therapeutics, TG therapeutics, and Genmab. The other review authors had no disclosures.
FDA approved acalabrutinib tablet for MCL, CLL, SLL
These include adult patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, and relapsed or refractory mantle cell lymphoma.
Approval of the tablet formulation of the selective Bruton tyrosine kinase inhibitor was based on the ELEVATE-PLUS trials, which showed bioequivalence with the capsule. The tablet had the same efficacy and safety profile with the same dosing strength and schedule, AstraZeneca said in a press release.
The benefit of the tablet formulation is that patients with acid reflux and other problems can take it with proton pump inhibitors, antacids, and H2-receptor antagonists, the company noted.
A version of this article first appeared on Medscape.com.
These include adult patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, and relapsed or refractory mantle cell lymphoma.
Approval of the tablet formulation of the selective Bruton tyrosine kinase inhibitor was based on the ELEVATE-PLUS trials, which showed bioequivalence with the capsule. The tablet had the same efficacy and safety profile with the same dosing strength and schedule, AstraZeneca said in a press release.
The benefit of the tablet formulation is that patients with acid reflux and other problems can take it with proton pump inhibitors, antacids, and H2-receptor antagonists, the company noted.
A version of this article first appeared on Medscape.com.
These include adult patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, and relapsed or refractory mantle cell lymphoma.
Approval of the tablet formulation of the selective Bruton tyrosine kinase inhibitor was based on the ELEVATE-PLUS trials, which showed bioequivalence with the capsule. The tablet had the same efficacy and safety profile with the same dosing strength and schedule, AstraZeneca said in a press release.
The benefit of the tablet formulation is that patients with acid reflux and other problems can take it with proton pump inhibitors, antacids, and H2-receptor antagonists, the company noted.
A version of this article first appeared on Medscape.com.
‘Plethora’ of new MCL treatment options
Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.
The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.
“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.
Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.
“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.
Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”
Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.
These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.
Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.
Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.
For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).
Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:
“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”
For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.
“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”
Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.
“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.
For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.
Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.
The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.
“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.
Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.
“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.
Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”
Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.
These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.
Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.
Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.
For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).
Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:
“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”
For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.
“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”
Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.
“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.
For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.
Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.
The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.
“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.
Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.
“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.
Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”
Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.
These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.
Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.
Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.
For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).
Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:
“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”
For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.
“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”
Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.
“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.
For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Noted oncologist ponders death, life, care inequities
In 2020, he published a book aimed at cancer specialists and their patients on how to die “with hope and dignity,” titled “Between Life and Death” (Penguin Random House India).
When Dr. Patel, the CEO of Carolina Blood and Cancer Care Associates in Rock Hill, S.C., became president of the Washington-based Community Oncology Alliance 2 years ago, he stepped into a leadership role in community oncology. As an advocate for health care payment reform on Capitol Hill, the South Carolina legislature, and within his own practice, Dr. Patel has long worked to eliminate disparities in U.S. cancer care.
This news organization spoke with Dr. Patel about his unusual career path.
Question: Your father had a great influence on you. Can you tell us more about him?
Answer: My dad was a hermit and a saint. He lost his dad when he was 4 years old and moved to the big city with his cousins. When he was 9 or so, he got a message saying that his mum was very ill. So, he and his cousin raised some money, got a doctor and one of those old, rugged jeeps, and they started driving to the village, but rains had destroyed the road. So, without penicillin, his mum died of pneumonia.
He felt that roads and doctor access were the two big factors that could have saved her life. He eventually became the Superintending Engineer for four districts in Gujarat State, building roads connecting every village, but he never gave up his simplistic, minimalist life.
When I was in elementary school, every other weekend my dad would literally dump me at the Mahatma Gandhi Ashram and come back in 2 hours. So, I’m looking at Gandhi’s cabinets, his pictures, reading about his life. So, my formative years were born in that.
Q: I read that you were intending to become an engineer and join the space race. How did your father nudge you toward medicine?
A: When I was 9 years old, my favorite movie hero died of cancer. To comfort me, my father inserted the idea into my brain: When you grow up, you can become a doctor to cure cancer. So, when I finished high school, I was 24th in the state and had an option to go to the space school in India. On the day when I was going for the interview, I could see tears in my father’s eyes, and he said, You know what, boy? I thought you’re going to become a doctor and cure cancer. So, to honor him, I went to med school instead.
Q: I understand that your father also triggered your interest in photography?
A: I started photographing Kutchi tribal people in 1977, after I bought a camera from a famous architect [Hasmukh Patel], while traveling with my dad. And then my dad bought me a motorcycle, so I started riding myself. From the time I entered med school in 1978 until I finished my residency in 1987, I made several trips following Kutchi migrant families and livestock. They leave their homeland in Kutch [district] during summer in search of grass and water to keep their livestock alive and walk across the state from the desert of Kutch all the way to central Gujarat until monsoon begins. Then they return, only to resume the journey next year. I would catch them along their journey, would talk to them, drink tea and eat millet crepes with them.
In 1984, between Dr. Patel’s medical school and residency, the Lions Club in his hometown, Ahmedabad, India, sponsored him and three buddies to document people and wildlife in Gujarat state. Traveling by motorcycle, the four friends stayed for free with local families by knocking on doors and explaining that they were medical students. Dr. Patel’s photographs were exhibited by the Lions Club of Ahmedabad and at India’s top art institution, the Lalit Kala gallery.
In the 3rd year of his internal-medicine residency in Bombay (now Mumbai), Dr. Patel approached a national newspaper, The Indian Express, for work. He was immediately sent on assignment to cover a cholera epidemic and filed his story and photographs the following day. He worked as a photojournalist and subeditor for a year.
Q: Among all your thousands of pictures, do you have a favorite?
A: There were two photos of Kutchi people that touched me. There was one photo of a lady. All of her worldly belongings were in the picture and a smile on her face showed that we don’t need so many things to be happy. The second photo is of an elderly lady shifting her water pan on her head to a younger family member. And a little girl looks up with a look of curiosity: Will I be doing this when I grow up? We seek so much materialistic happiness. But when you look at the curiosity, smiles, and happiness [in these photos], you realize we could have a lot of happiness in minimalism, as well.
Q: After you finished your residency in Ahmedabad, how did you get started in oncology?
A: In 1986, Ahmedabad City and Gujarat State did not have structured training programs in oncology, so I went to Bombay [Mumbai], where Dr. B.C. Mehta, a true legend and pioneer in India, had started hematology-oncology training. I was a post-doc research fellow with him for a little over a year but when I started seeing patients, I had to answer to myself, Am I doing everything I can to help these people? I saw that the U.K. had one of the best training programs in hem malignancy, so I started applying. Then something happened that was almost like a miracle.
In April 1992, Dr. Patel was working at the Institute of Kidney Diseases in Ahmedabad. One afternoon, just as the clinic was closing for siesta, a family brought in a young girl. She had drug-induced thrombocytopenia and needed an immediate transfusion. The father offered to sell his wedding ring to pay Dr. Patel if he would supervise the treatment and stay by the girl’s side. Dr. Patel told the man to keep his ring, then he remained in the office with the child. At 4 p.m., the office phone rang. It was Dr. H.K. Parikh, an eminent British physician who was wintering in India and needed to make a medical appointment for his wife. On a normal day, Dr. Patel would have missed the call.
“This is how I got to meet Dr. Parikh, out of the blue,” said Dr. Patel. “His wife came to the office for 6 weeks and after 6 weeks, he said, You’re a smart guy; you should come to England. That was in April. I sent a resume and all the usual paperwork. On July 16, 1992, at 2 in the morning, I got a call from the U.K. saying, Your job is confirmed. I’m going to fax your appointment through the Royal College of Physicians, and you’re coming to Manchester to work with us. I’d been sponsored by the Overseas Doctors Training Program.
“So, it turns out that if I’d declined to see that patient and declined to stay in my clinic that afternoon, if I’d declined to see this doctor’s wife, I would never have been in the U.K. And that opened up the doors for me. I like that story because I’ve found that standing up for people who do not have a voice, who do not have hope, always leads to what is destined for me.”
Q: After working as a registrar in the United Kingdom 4 years, you found yourself in the United States and, once again, had to train as an internist. What was new about U.S. oncology?
A: I took 3 years to get recertified in Jamaica Hospital in Queens, then became a fellow in hematology-oncology at the Thomas Jefferson in Philadelphia. My U.K. training was all based on hematological malignancy. In the United States, I shifted into solid tumors.
Q: You have a long history of advocating for affordable oncology at the community, state, and federal level, and you recently launched a disparities initiative in your center called NOLA (No One Left Alone). What was the trigger for NOLA?
A: In the spring of 2020, when we started seeing the COVID surge and the difference in mortality rate between the multiple races, at the same time I saw the AACR [American Association for Cancer Research] 2020 disparity report showing that 34% of cancer deaths are preventable – one in three – if we took care of disparities. The same year, the Community Oncology Alliance asked me to become the president. So, I felt that there is something herding me, leading me, to this position. Eighty percent of cancer patients are treated in community clinics like ours. It put the onus on me to do something.
I learned from Gandhi that I cannot depend on government, I cannot depend on the policy, I have to act myself.
I said, I would not worry about making money, I would rather lose funding on this. So, we started. I read 400+ papers; I spent over 1,000 hours reading about disparities. And I realized that it’s not complicated. There are five pillars to eliminate disparity: access to care for financial reasons, access to biomarker testing or precision medicine, access to social determinants of health, access to cancer screening, and trials. If we focus on these five, we can at least bring that number from 34% to 20%, if not lower.
So, we put that plan in place. I dedicated three employees whose only role is to ensure that not a single patient has to take financial burden from my practice. And we showed it’s doable.
This has now become my mission for the last quarter of my life.
In 2020, Dr. Patel published a book on dying well titled “Between Life and Death.” It’s framed as a series of his conversations with a former patient, Harry Falls. Harry wanted to understand death better, so Dr. Patel narrated five patient stories, drawing the threads together to help Harry face the inevitable. Dr. Patel now uses a similar approach to train clinicians on having meaningful end-of-life conversations with patients.
Q: Why did you feel the need to write a book about dying?
A: The more I’ve witnessed, the more I’m convinced that there are things that we don’t know about this process, which needs to be explored much more. However, I do feel that there’s a power within all of us to steer the process of leaving this world.
Before I sat down with Harry, I loved to counsel patients, but I didn’t have any structural ideas. It was Harry himself who told me that I now had a simple way to explain dying to a much larger audience.
Q: What is your secret for fitting everything into your life?
A: I’ll tell you, it’s very simple. If I put my soul, heart, mind, actions, and language on the one plane and don’t let my brain and conditioning influence my choices, then I live in the moment. Whenever I let my conditioned mind take all the decisions, those are crooked, because you know, we’re selfish creatures – we can use what we call the convenient lie to hide inconvenient truth. And I try not to do that. I mean, it’s been a journey. It didn’t come overnight. I learned. And I feel that over all these years, the only thing that rewarded me, that opened the door of where I am today, was pure, selfless process, whether it’s the act of talking, speaking, or doing.
In 2020, he published a book aimed at cancer specialists and their patients on how to die “with hope and dignity,” titled “Between Life and Death” (Penguin Random House India).
When Dr. Patel, the CEO of Carolina Blood and Cancer Care Associates in Rock Hill, S.C., became president of the Washington-based Community Oncology Alliance 2 years ago, he stepped into a leadership role in community oncology. As an advocate for health care payment reform on Capitol Hill, the South Carolina legislature, and within his own practice, Dr. Patel has long worked to eliminate disparities in U.S. cancer care.
This news organization spoke with Dr. Patel about his unusual career path.
Question: Your father had a great influence on you. Can you tell us more about him?
Answer: My dad was a hermit and a saint. He lost his dad when he was 4 years old and moved to the big city with his cousins. When he was 9 or so, he got a message saying that his mum was very ill. So, he and his cousin raised some money, got a doctor and one of those old, rugged jeeps, and they started driving to the village, but rains had destroyed the road. So, without penicillin, his mum died of pneumonia.
He felt that roads and doctor access were the two big factors that could have saved her life. He eventually became the Superintending Engineer for four districts in Gujarat State, building roads connecting every village, but he never gave up his simplistic, minimalist life.
When I was in elementary school, every other weekend my dad would literally dump me at the Mahatma Gandhi Ashram and come back in 2 hours. So, I’m looking at Gandhi’s cabinets, his pictures, reading about his life. So, my formative years were born in that.
Q: I read that you were intending to become an engineer and join the space race. How did your father nudge you toward medicine?
A: When I was 9 years old, my favorite movie hero died of cancer. To comfort me, my father inserted the idea into my brain: When you grow up, you can become a doctor to cure cancer. So, when I finished high school, I was 24th in the state and had an option to go to the space school in India. On the day when I was going for the interview, I could see tears in my father’s eyes, and he said, You know what, boy? I thought you’re going to become a doctor and cure cancer. So, to honor him, I went to med school instead.
Q: I understand that your father also triggered your interest in photography?
A: I started photographing Kutchi tribal people in 1977, after I bought a camera from a famous architect [Hasmukh Patel], while traveling with my dad. And then my dad bought me a motorcycle, so I started riding myself. From the time I entered med school in 1978 until I finished my residency in 1987, I made several trips following Kutchi migrant families and livestock. They leave their homeland in Kutch [district] during summer in search of grass and water to keep their livestock alive and walk across the state from the desert of Kutch all the way to central Gujarat until monsoon begins. Then they return, only to resume the journey next year. I would catch them along their journey, would talk to them, drink tea and eat millet crepes with them.
In 1984, between Dr. Patel’s medical school and residency, the Lions Club in his hometown, Ahmedabad, India, sponsored him and three buddies to document people and wildlife in Gujarat state. Traveling by motorcycle, the four friends stayed for free with local families by knocking on doors and explaining that they were medical students. Dr. Patel’s photographs were exhibited by the Lions Club of Ahmedabad and at India’s top art institution, the Lalit Kala gallery.
In the 3rd year of his internal-medicine residency in Bombay (now Mumbai), Dr. Patel approached a national newspaper, The Indian Express, for work. He was immediately sent on assignment to cover a cholera epidemic and filed his story and photographs the following day. He worked as a photojournalist and subeditor for a year.
Q: Among all your thousands of pictures, do you have a favorite?
A: There were two photos of Kutchi people that touched me. There was one photo of a lady. All of her worldly belongings were in the picture and a smile on her face showed that we don’t need so many things to be happy. The second photo is of an elderly lady shifting her water pan on her head to a younger family member. And a little girl looks up with a look of curiosity: Will I be doing this when I grow up? We seek so much materialistic happiness. But when you look at the curiosity, smiles, and happiness [in these photos], you realize we could have a lot of happiness in minimalism, as well.
Q: After you finished your residency in Ahmedabad, how did you get started in oncology?
A: In 1986, Ahmedabad City and Gujarat State did not have structured training programs in oncology, so I went to Bombay [Mumbai], where Dr. B.C. Mehta, a true legend and pioneer in India, had started hematology-oncology training. I was a post-doc research fellow with him for a little over a year but when I started seeing patients, I had to answer to myself, Am I doing everything I can to help these people? I saw that the U.K. had one of the best training programs in hem malignancy, so I started applying. Then something happened that was almost like a miracle.
In April 1992, Dr. Patel was working at the Institute of Kidney Diseases in Ahmedabad. One afternoon, just as the clinic was closing for siesta, a family brought in a young girl. She had drug-induced thrombocytopenia and needed an immediate transfusion. The father offered to sell his wedding ring to pay Dr. Patel if he would supervise the treatment and stay by the girl’s side. Dr. Patel told the man to keep his ring, then he remained in the office with the child. At 4 p.m., the office phone rang. It was Dr. H.K. Parikh, an eminent British physician who was wintering in India and needed to make a medical appointment for his wife. On a normal day, Dr. Patel would have missed the call.
“This is how I got to meet Dr. Parikh, out of the blue,” said Dr. Patel. “His wife came to the office for 6 weeks and after 6 weeks, he said, You’re a smart guy; you should come to England. That was in April. I sent a resume and all the usual paperwork. On July 16, 1992, at 2 in the morning, I got a call from the U.K. saying, Your job is confirmed. I’m going to fax your appointment through the Royal College of Physicians, and you’re coming to Manchester to work with us. I’d been sponsored by the Overseas Doctors Training Program.
“So, it turns out that if I’d declined to see that patient and declined to stay in my clinic that afternoon, if I’d declined to see this doctor’s wife, I would never have been in the U.K. And that opened up the doors for me. I like that story because I’ve found that standing up for people who do not have a voice, who do not have hope, always leads to what is destined for me.”
Q: After working as a registrar in the United Kingdom 4 years, you found yourself in the United States and, once again, had to train as an internist. What was new about U.S. oncology?
A: I took 3 years to get recertified in Jamaica Hospital in Queens, then became a fellow in hematology-oncology at the Thomas Jefferson in Philadelphia. My U.K. training was all based on hematological malignancy. In the United States, I shifted into solid tumors.
Q: You have a long history of advocating for affordable oncology at the community, state, and federal level, and you recently launched a disparities initiative in your center called NOLA (No One Left Alone). What was the trigger for NOLA?
A: In the spring of 2020, when we started seeing the COVID surge and the difference in mortality rate between the multiple races, at the same time I saw the AACR [American Association for Cancer Research] 2020 disparity report showing that 34% of cancer deaths are preventable – one in three – if we took care of disparities. The same year, the Community Oncology Alliance asked me to become the president. So, I felt that there is something herding me, leading me, to this position. Eighty percent of cancer patients are treated in community clinics like ours. It put the onus on me to do something.
I learned from Gandhi that I cannot depend on government, I cannot depend on the policy, I have to act myself.
I said, I would not worry about making money, I would rather lose funding on this. So, we started. I read 400+ papers; I spent over 1,000 hours reading about disparities. And I realized that it’s not complicated. There are five pillars to eliminate disparity: access to care for financial reasons, access to biomarker testing or precision medicine, access to social determinants of health, access to cancer screening, and trials. If we focus on these five, we can at least bring that number from 34% to 20%, if not lower.
So, we put that plan in place. I dedicated three employees whose only role is to ensure that not a single patient has to take financial burden from my practice. And we showed it’s doable.
This has now become my mission for the last quarter of my life.
In 2020, Dr. Patel published a book on dying well titled “Between Life and Death.” It’s framed as a series of his conversations with a former patient, Harry Falls. Harry wanted to understand death better, so Dr. Patel narrated five patient stories, drawing the threads together to help Harry face the inevitable. Dr. Patel now uses a similar approach to train clinicians on having meaningful end-of-life conversations with patients.
Q: Why did you feel the need to write a book about dying?
A: The more I’ve witnessed, the more I’m convinced that there are things that we don’t know about this process, which needs to be explored much more. However, I do feel that there’s a power within all of us to steer the process of leaving this world.
Before I sat down with Harry, I loved to counsel patients, but I didn’t have any structural ideas. It was Harry himself who told me that I now had a simple way to explain dying to a much larger audience.
Q: What is your secret for fitting everything into your life?
A: I’ll tell you, it’s very simple. If I put my soul, heart, mind, actions, and language on the one plane and don’t let my brain and conditioning influence my choices, then I live in the moment. Whenever I let my conditioned mind take all the decisions, those are crooked, because you know, we’re selfish creatures – we can use what we call the convenient lie to hide inconvenient truth. And I try not to do that. I mean, it’s been a journey. It didn’t come overnight. I learned. And I feel that over all these years, the only thing that rewarded me, that opened the door of where I am today, was pure, selfless process, whether it’s the act of talking, speaking, or doing.
In 2020, he published a book aimed at cancer specialists and their patients on how to die “with hope and dignity,” titled “Between Life and Death” (Penguin Random House India).
When Dr. Patel, the CEO of Carolina Blood and Cancer Care Associates in Rock Hill, S.C., became president of the Washington-based Community Oncology Alliance 2 years ago, he stepped into a leadership role in community oncology. As an advocate for health care payment reform on Capitol Hill, the South Carolina legislature, and within his own practice, Dr. Patel has long worked to eliminate disparities in U.S. cancer care.
This news organization spoke with Dr. Patel about his unusual career path.
Question: Your father had a great influence on you. Can you tell us more about him?
Answer: My dad was a hermit and a saint. He lost his dad when he was 4 years old and moved to the big city with his cousins. When he was 9 or so, he got a message saying that his mum was very ill. So, he and his cousin raised some money, got a doctor and one of those old, rugged jeeps, and they started driving to the village, but rains had destroyed the road. So, without penicillin, his mum died of pneumonia.
He felt that roads and doctor access were the two big factors that could have saved her life. He eventually became the Superintending Engineer for four districts in Gujarat State, building roads connecting every village, but he never gave up his simplistic, minimalist life.
When I was in elementary school, every other weekend my dad would literally dump me at the Mahatma Gandhi Ashram and come back in 2 hours. So, I’m looking at Gandhi’s cabinets, his pictures, reading about his life. So, my formative years were born in that.
Q: I read that you were intending to become an engineer and join the space race. How did your father nudge you toward medicine?
A: When I was 9 years old, my favorite movie hero died of cancer. To comfort me, my father inserted the idea into my brain: When you grow up, you can become a doctor to cure cancer. So, when I finished high school, I was 24th in the state and had an option to go to the space school in India. On the day when I was going for the interview, I could see tears in my father’s eyes, and he said, You know what, boy? I thought you’re going to become a doctor and cure cancer. So, to honor him, I went to med school instead.
Q: I understand that your father also triggered your interest in photography?
A: I started photographing Kutchi tribal people in 1977, after I bought a camera from a famous architect [Hasmukh Patel], while traveling with my dad. And then my dad bought me a motorcycle, so I started riding myself. From the time I entered med school in 1978 until I finished my residency in 1987, I made several trips following Kutchi migrant families and livestock. They leave their homeland in Kutch [district] during summer in search of grass and water to keep their livestock alive and walk across the state from the desert of Kutch all the way to central Gujarat until monsoon begins. Then they return, only to resume the journey next year. I would catch them along their journey, would talk to them, drink tea and eat millet crepes with them.
In 1984, between Dr. Patel’s medical school and residency, the Lions Club in his hometown, Ahmedabad, India, sponsored him and three buddies to document people and wildlife in Gujarat state. Traveling by motorcycle, the four friends stayed for free with local families by knocking on doors and explaining that they were medical students. Dr. Patel’s photographs were exhibited by the Lions Club of Ahmedabad and at India’s top art institution, the Lalit Kala gallery.
In the 3rd year of his internal-medicine residency in Bombay (now Mumbai), Dr. Patel approached a national newspaper, The Indian Express, for work. He was immediately sent on assignment to cover a cholera epidemic and filed his story and photographs the following day. He worked as a photojournalist and subeditor for a year.
Q: Among all your thousands of pictures, do you have a favorite?
A: There were two photos of Kutchi people that touched me. There was one photo of a lady. All of her worldly belongings were in the picture and a smile on her face showed that we don’t need so many things to be happy. The second photo is of an elderly lady shifting her water pan on her head to a younger family member. And a little girl looks up with a look of curiosity: Will I be doing this when I grow up? We seek so much materialistic happiness. But when you look at the curiosity, smiles, and happiness [in these photos], you realize we could have a lot of happiness in minimalism, as well.
Q: After you finished your residency in Ahmedabad, how did you get started in oncology?
A: In 1986, Ahmedabad City and Gujarat State did not have structured training programs in oncology, so I went to Bombay [Mumbai], where Dr. B.C. Mehta, a true legend and pioneer in India, had started hematology-oncology training. I was a post-doc research fellow with him for a little over a year but when I started seeing patients, I had to answer to myself, Am I doing everything I can to help these people? I saw that the U.K. had one of the best training programs in hem malignancy, so I started applying. Then something happened that was almost like a miracle.
In April 1992, Dr. Patel was working at the Institute of Kidney Diseases in Ahmedabad. One afternoon, just as the clinic was closing for siesta, a family brought in a young girl. She had drug-induced thrombocytopenia and needed an immediate transfusion. The father offered to sell his wedding ring to pay Dr. Patel if he would supervise the treatment and stay by the girl’s side. Dr. Patel told the man to keep his ring, then he remained in the office with the child. At 4 p.m., the office phone rang. It was Dr. H.K. Parikh, an eminent British physician who was wintering in India and needed to make a medical appointment for his wife. On a normal day, Dr. Patel would have missed the call.
“This is how I got to meet Dr. Parikh, out of the blue,” said Dr. Patel. “His wife came to the office for 6 weeks and after 6 weeks, he said, You’re a smart guy; you should come to England. That was in April. I sent a resume and all the usual paperwork. On July 16, 1992, at 2 in the morning, I got a call from the U.K. saying, Your job is confirmed. I’m going to fax your appointment through the Royal College of Physicians, and you’re coming to Manchester to work with us. I’d been sponsored by the Overseas Doctors Training Program.
“So, it turns out that if I’d declined to see that patient and declined to stay in my clinic that afternoon, if I’d declined to see this doctor’s wife, I would never have been in the U.K. And that opened up the doors for me. I like that story because I’ve found that standing up for people who do not have a voice, who do not have hope, always leads to what is destined for me.”
Q: After working as a registrar in the United Kingdom 4 years, you found yourself in the United States and, once again, had to train as an internist. What was new about U.S. oncology?
A: I took 3 years to get recertified in Jamaica Hospital in Queens, then became a fellow in hematology-oncology at the Thomas Jefferson in Philadelphia. My U.K. training was all based on hematological malignancy. In the United States, I shifted into solid tumors.
Q: You have a long history of advocating for affordable oncology at the community, state, and federal level, and you recently launched a disparities initiative in your center called NOLA (No One Left Alone). What was the trigger for NOLA?
A: In the spring of 2020, when we started seeing the COVID surge and the difference in mortality rate between the multiple races, at the same time I saw the AACR [American Association for Cancer Research] 2020 disparity report showing that 34% of cancer deaths are preventable – one in three – if we took care of disparities. The same year, the Community Oncology Alliance asked me to become the president. So, I felt that there is something herding me, leading me, to this position. Eighty percent of cancer patients are treated in community clinics like ours. It put the onus on me to do something.
I learned from Gandhi that I cannot depend on government, I cannot depend on the policy, I have to act myself.
I said, I would not worry about making money, I would rather lose funding on this. So, we started. I read 400+ papers; I spent over 1,000 hours reading about disparities. And I realized that it’s not complicated. There are five pillars to eliminate disparity: access to care for financial reasons, access to biomarker testing or precision medicine, access to social determinants of health, access to cancer screening, and trials. If we focus on these five, we can at least bring that number from 34% to 20%, if not lower.
So, we put that plan in place. I dedicated three employees whose only role is to ensure that not a single patient has to take financial burden from my practice. And we showed it’s doable.
This has now become my mission for the last quarter of my life.
In 2020, Dr. Patel published a book on dying well titled “Between Life and Death.” It’s framed as a series of his conversations with a former patient, Harry Falls. Harry wanted to understand death better, so Dr. Patel narrated five patient stories, drawing the threads together to help Harry face the inevitable. Dr. Patel now uses a similar approach to train clinicians on having meaningful end-of-life conversations with patients.
Q: Why did you feel the need to write a book about dying?
A: The more I’ve witnessed, the more I’m convinced that there are things that we don’t know about this process, which needs to be explored much more. However, I do feel that there’s a power within all of us to steer the process of leaving this world.
Before I sat down with Harry, I loved to counsel patients, but I didn’t have any structural ideas. It was Harry himself who told me that I now had a simple way to explain dying to a much larger audience.
Q: What is your secret for fitting everything into your life?
A: I’ll tell you, it’s very simple. If I put my soul, heart, mind, actions, and language on the one plane and don’t let my brain and conditioning influence my choices, then I live in the moment. Whenever I let my conditioned mind take all the decisions, those are crooked, because you know, we’re selfish creatures – we can use what we call the convenient lie to hide inconvenient truth. And I try not to do that. I mean, it’s been a journey. It didn’t come overnight. I learned. And I feel that over all these years, the only thing that rewarded me, that opened the door of where I am today, was pure, selfless process, whether it’s the act of talking, speaking, or doing.
First drug therapy approved for childhood GVHD
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
Phase 3 data: Zanubrutinib bests standard CLL treatment
At a median follow-up of 26.2 months, progression to worsening disease or death was much lower in patients with these conditions who took zanubrutinib (Brukinsa), compared with those who took bendamustine-rituximab (hazard ratio. 0.42; 95% confidence interval, 0.28-0.63; P < .00011). The study was published in The Lancet Oncology.
Researchers already knew that ibrutinib, another BTKi, improves progression-free survival, study coauthor Paolo Ghia, MD, PhD, professor of medical oncology at Vita-Salute San Raffaele University, Milan, said in an interview. “Now we confirmed that the same advantage can be seen” in zanubrutinib.
According to Dr. Ghia, bendamustine-rituximab has long been a standard treatment in blood cancers and is considered well tolerated and inexpensive. But BTKis such as first-in-line ibrutinib have shown better results, he said, “and progressively, we are going to abandon bendamustine-rituximab.”
However, ibrutinib causes significant adverse effects such as bleeding, worsening hypertension and arrhythmia, he noted. As a result, second-generation BTKi such as zanubrutinib have entered the picture. The Food and Drug Administration approved it in 2019 for mantle cell lymphoma, and it has since been approved for Waldenström’s macroglobulinemia and marginal zone lymphoma.
In 2021, an interim analysis in a trial of the drug in patients with previously treated CLL, compared with ibrutinib, found that “zanubrutinib was shown to have a superior response rate, an improved PFS, and a lower rate of atrial fibrillation/flutter.”
The drug’s manufacturer, BeiGene, launched the new open-label, multicenter study, in a bid for FDA approval of the drug as a frontline treatment for CLL and SLL. More than 150 hospitals in 14 countries participated in the trial from 2017 to 2019.
The subjects were all adults and at least 65 years old or with comorbidities; None had the genetic trait del(17)(p13.1); 241 were assigned to take zanubrutinib and 238 to bendamustine-rituximab. Another group consisted of 111 patients with CLL and del(17)(p13·1). According to the study authors, these patients are especially difficult to treat.
The vast majority of patients were White (92%-95% depending on group) and male (61%-71%); 90%-92% had CLL.
At follow-up, there was no difference in overall survival between the main zanubrutinib and bendamustine-rituximab groups; 29 (12%) of the 241 patients in the zanubrutinib group and 57 (24%) of 238 patients in the bendamustine-rituximab group had progressed or died (HR, 0.42; 95% CI, 0.27-0.66; P < .00011). Adverse events leading to discontinuation were more common in the bendamustine-rituximab group (14%) versus zanubrutinib (8%).
In the third group, which only received zanubrutinib, 14% of patients died at median follow-up of 30.5 months; 98% of patients had adverse effects, and 5% discontinued treatment.
The researchers wrote that “zanubrutinib showed superior progression-free survival versus bendamustine-rituximab in older patients or those with comorbidities with untreated CLL, with a low incidence of cardiac arrhythmia. Similar efficacy was observed in patients with del(17p)–positive disease.”
The study didn’t examine cost; zanubrutinib is quite expensive.
In an interview, hematologist-oncologist Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York said the new study is important although not surprising, since other medications in the same class have shown similar results. Zanubrutinib is an alternative to ibrutinib, although the latter remains “an excellent drug,” he said.
“The era of chemotherapy being a first choice is over,” he said. “We’ve had several randomized studies that show targeted therapies are better tolerated and have better outcomes. We now need to look through the choices to decide which one of these good options are the best for our patients.”
In an interview, hematologist-oncologist Joanna Rhodes, MD, of Northwell Health in Hempstead, N.Y., highlighted the side effect profile of zanubrutinib, noting that it is low and resembles that of other BTKis, making it “another excellent treatment option.”
“We are seeing that bruising, upper respiratory tract infections, diarrhea, and arthralgias are the most common side effects,” she said. “Bleeding also is a common side effect, which is consistent across the class of BTKis, with 5% of patients developing a major bleed. Also, 3% of patients treated with zanubrutinib developed atrial fibrillation, which is consistent with data from other trials. Treatment discontinuation rates were low (8%).”
The study was funded by BeiGene. The authors reported multiple disclosures. Dr. Mato reported research or consulting relationships with BeiGene, AstraZeneca, and AbbVie. Dr. Rhodes reported multiple research or consulting relationships with Abbvie, BeiGene, Genentech, and others.
At a median follow-up of 26.2 months, progression to worsening disease or death was much lower in patients with these conditions who took zanubrutinib (Brukinsa), compared with those who took bendamustine-rituximab (hazard ratio. 0.42; 95% confidence interval, 0.28-0.63; P < .00011). The study was published in The Lancet Oncology.
Researchers already knew that ibrutinib, another BTKi, improves progression-free survival, study coauthor Paolo Ghia, MD, PhD, professor of medical oncology at Vita-Salute San Raffaele University, Milan, said in an interview. “Now we confirmed that the same advantage can be seen” in zanubrutinib.
According to Dr. Ghia, bendamustine-rituximab has long been a standard treatment in blood cancers and is considered well tolerated and inexpensive. But BTKis such as first-in-line ibrutinib have shown better results, he said, “and progressively, we are going to abandon bendamustine-rituximab.”
However, ibrutinib causes significant adverse effects such as bleeding, worsening hypertension and arrhythmia, he noted. As a result, second-generation BTKi such as zanubrutinib have entered the picture. The Food and Drug Administration approved it in 2019 for mantle cell lymphoma, and it has since been approved for Waldenström’s macroglobulinemia and marginal zone lymphoma.
In 2021, an interim analysis in a trial of the drug in patients with previously treated CLL, compared with ibrutinib, found that “zanubrutinib was shown to have a superior response rate, an improved PFS, and a lower rate of atrial fibrillation/flutter.”
The drug’s manufacturer, BeiGene, launched the new open-label, multicenter study, in a bid for FDA approval of the drug as a frontline treatment for CLL and SLL. More than 150 hospitals in 14 countries participated in the trial from 2017 to 2019.
The subjects were all adults and at least 65 years old or with comorbidities; None had the genetic trait del(17)(p13.1); 241 were assigned to take zanubrutinib and 238 to bendamustine-rituximab. Another group consisted of 111 patients with CLL and del(17)(p13·1). According to the study authors, these patients are especially difficult to treat.
The vast majority of patients were White (92%-95% depending on group) and male (61%-71%); 90%-92% had CLL.
At follow-up, there was no difference in overall survival between the main zanubrutinib and bendamustine-rituximab groups; 29 (12%) of the 241 patients in the zanubrutinib group and 57 (24%) of 238 patients in the bendamustine-rituximab group had progressed or died (HR, 0.42; 95% CI, 0.27-0.66; P < .00011). Adverse events leading to discontinuation were more common in the bendamustine-rituximab group (14%) versus zanubrutinib (8%).
In the third group, which only received zanubrutinib, 14% of patients died at median follow-up of 30.5 months; 98% of patients had adverse effects, and 5% discontinued treatment.
The researchers wrote that “zanubrutinib showed superior progression-free survival versus bendamustine-rituximab in older patients or those with comorbidities with untreated CLL, with a low incidence of cardiac arrhythmia. Similar efficacy was observed in patients with del(17p)–positive disease.”
The study didn’t examine cost; zanubrutinib is quite expensive.
In an interview, hematologist-oncologist Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York said the new study is important although not surprising, since other medications in the same class have shown similar results. Zanubrutinib is an alternative to ibrutinib, although the latter remains “an excellent drug,” he said.
“The era of chemotherapy being a first choice is over,” he said. “We’ve had several randomized studies that show targeted therapies are better tolerated and have better outcomes. We now need to look through the choices to decide which one of these good options are the best for our patients.”
In an interview, hematologist-oncologist Joanna Rhodes, MD, of Northwell Health in Hempstead, N.Y., highlighted the side effect profile of zanubrutinib, noting that it is low and resembles that of other BTKis, making it “another excellent treatment option.”
“We are seeing that bruising, upper respiratory tract infections, diarrhea, and arthralgias are the most common side effects,” she said. “Bleeding also is a common side effect, which is consistent across the class of BTKis, with 5% of patients developing a major bleed. Also, 3% of patients treated with zanubrutinib developed atrial fibrillation, which is consistent with data from other trials. Treatment discontinuation rates were low (8%).”
The study was funded by BeiGene. The authors reported multiple disclosures. Dr. Mato reported research or consulting relationships with BeiGene, AstraZeneca, and AbbVie. Dr. Rhodes reported multiple research or consulting relationships with Abbvie, BeiGene, Genentech, and others.
At a median follow-up of 26.2 months, progression to worsening disease or death was much lower in patients with these conditions who took zanubrutinib (Brukinsa), compared with those who took bendamustine-rituximab (hazard ratio. 0.42; 95% confidence interval, 0.28-0.63; P < .00011). The study was published in The Lancet Oncology.
Researchers already knew that ibrutinib, another BTKi, improves progression-free survival, study coauthor Paolo Ghia, MD, PhD, professor of medical oncology at Vita-Salute San Raffaele University, Milan, said in an interview. “Now we confirmed that the same advantage can be seen” in zanubrutinib.
According to Dr. Ghia, bendamustine-rituximab has long been a standard treatment in blood cancers and is considered well tolerated and inexpensive. But BTKis such as first-in-line ibrutinib have shown better results, he said, “and progressively, we are going to abandon bendamustine-rituximab.”
However, ibrutinib causes significant adverse effects such as bleeding, worsening hypertension and arrhythmia, he noted. As a result, second-generation BTKi such as zanubrutinib have entered the picture. The Food and Drug Administration approved it in 2019 for mantle cell lymphoma, and it has since been approved for Waldenström’s macroglobulinemia and marginal zone lymphoma.
In 2021, an interim analysis in a trial of the drug in patients with previously treated CLL, compared with ibrutinib, found that “zanubrutinib was shown to have a superior response rate, an improved PFS, and a lower rate of atrial fibrillation/flutter.”
The drug’s manufacturer, BeiGene, launched the new open-label, multicenter study, in a bid for FDA approval of the drug as a frontline treatment for CLL and SLL. More than 150 hospitals in 14 countries participated in the trial from 2017 to 2019.
The subjects were all adults and at least 65 years old or with comorbidities; None had the genetic trait del(17)(p13.1); 241 were assigned to take zanubrutinib and 238 to bendamustine-rituximab. Another group consisted of 111 patients with CLL and del(17)(p13·1). According to the study authors, these patients are especially difficult to treat.
The vast majority of patients were White (92%-95% depending on group) and male (61%-71%); 90%-92% had CLL.
At follow-up, there was no difference in overall survival between the main zanubrutinib and bendamustine-rituximab groups; 29 (12%) of the 241 patients in the zanubrutinib group and 57 (24%) of 238 patients in the bendamustine-rituximab group had progressed or died (HR, 0.42; 95% CI, 0.27-0.66; P < .00011). Adverse events leading to discontinuation were more common in the bendamustine-rituximab group (14%) versus zanubrutinib (8%).
In the third group, which only received zanubrutinib, 14% of patients died at median follow-up of 30.5 months; 98% of patients had adverse effects, and 5% discontinued treatment.
The researchers wrote that “zanubrutinib showed superior progression-free survival versus bendamustine-rituximab in older patients or those with comorbidities with untreated CLL, with a low incidence of cardiac arrhythmia. Similar efficacy was observed in patients with del(17p)–positive disease.”
The study didn’t examine cost; zanubrutinib is quite expensive.
In an interview, hematologist-oncologist Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York said the new study is important although not surprising, since other medications in the same class have shown similar results. Zanubrutinib is an alternative to ibrutinib, although the latter remains “an excellent drug,” he said.
“The era of chemotherapy being a first choice is over,” he said. “We’ve had several randomized studies that show targeted therapies are better tolerated and have better outcomes. We now need to look through the choices to decide which one of these good options are the best for our patients.”
In an interview, hematologist-oncologist Joanna Rhodes, MD, of Northwell Health in Hempstead, N.Y., highlighted the side effect profile of zanubrutinib, noting that it is low and resembles that of other BTKis, making it “another excellent treatment option.”
“We are seeing that bruising, upper respiratory tract infections, diarrhea, and arthralgias are the most common side effects,” she said. “Bleeding also is a common side effect, which is consistent across the class of BTKis, with 5% of patients developing a major bleed. Also, 3% of patients treated with zanubrutinib developed atrial fibrillation, which is consistent with data from other trials. Treatment discontinuation rates were low (8%).”
The study was funded by BeiGene. The authors reported multiple disclosures. Dr. Mato reported research or consulting relationships with BeiGene, AstraZeneca, and AbbVie. Dr. Rhodes reported multiple research or consulting relationships with Abbvie, BeiGene, Genentech, and others.
FROM THE LANCET ONCOLOGY
Drug shortages plague hematology, but preparedness helps
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
'New benchmark' set in phase-3 blood cancer study
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
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.