Aggressive Lymphomas

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

Shortages of carboplatin and cisplatin have become widespread among major cancer centers, according to a survey released this week from the National Comprehensive Cancer Network.

The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.

“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.

“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”

The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.

“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.

Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.

The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.

The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.

“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”

In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:

• “Current shipments from established manufacturers have been paused.”
• “The supply of carboplatin available is not meeting our demands.”
• “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”

Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”

Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.

The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.

The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”

Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”

A version of this article first appeared on Medscape.com.

The number of cancer survivors who report functional limitation has more than doubled in 20 years, according to a research letter published in JAMA Oncology.

Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.

Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.

The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.

For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
 

Patients surveyed on function

Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.

Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
 

Not just a result of living longer

Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.

“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.

Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.

Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.

“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
 

Quality of life beyond survivorship

Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.

“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.

The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.

There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”

Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.

“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.

A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.

The number of cancer survivors who report functional limitation has more than doubled in 20 years, according to a research letter published in JAMA Oncology.

Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.

Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.

The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.

For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
 

Patients surveyed on function

Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.

Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
 

Not just a result of living longer

Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.

“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.

Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.

Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.

“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
 

Quality of life beyond survivorship

Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.

“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.

The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.

There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”

Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.

“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.

A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.

The number of cancer survivors who report functional limitation has more than doubled in 20 years, according to a research letter published in JAMA Oncology.

Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.

Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.

The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.

For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
 

Patients surveyed on function

Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.

Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
 

Not just a result of living longer

Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.

“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.

Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.

Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.

“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
 

Quality of life beyond survivorship

Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.

“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.

The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.

There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”

Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.

“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.

A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.

Patients undergoing chimeric antigen receptor (CAR) T-cell therapy who develop potentially serious neurotoxicity from the therapy show elevated plasma levels of neurofilament light chain (NfL) prior to the treatment, suggesting a possibly important predictor of risk for the side effect.

“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.

“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.

CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.

Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.

NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.

To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.

The patients had a median age of 64 and were 40% female.

Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.

Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.

A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).

Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.

However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.

The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
 

Interest in NfL levels on the rise

NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.

Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.

“Future studies will explore validating NfL for ICANS and additional indications,” he said.

ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.

The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.

Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.

“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
 

Limitations: Validation, preventive measures needed

Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.

“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.

The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.

“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”

A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.

“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”

Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.

Patients undergoing chimeric antigen receptor (CAR) T-cell therapy who develop potentially serious neurotoxicity from the therapy show elevated plasma levels of neurofilament light chain (NfL) prior to the treatment, suggesting a possibly important predictor of risk for the side effect.

“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.

“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.

CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.

Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.

NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.

To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.

The patients had a median age of 64 and were 40% female.

Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.

Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.

A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).

Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.

However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.

The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
 

Interest in NfL levels on the rise

NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.

Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.

“Future studies will explore validating NfL for ICANS and additional indications,” he said.

ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.

The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.

Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.

“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
 

Limitations: Validation, preventive measures needed

Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.

“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.

The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.

“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”

A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.

“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”

Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.

Patients undergoing chimeric antigen receptor (CAR) T-cell therapy who develop potentially serious neurotoxicity from the therapy show elevated plasma levels of neurofilament light chain (NfL) prior to the treatment, suggesting a possibly important predictor of risk for the side effect.

“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.

“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.

CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.

Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.

NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.

To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.

The patients had a median age of 64 and were 40% female.

Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.

Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.

A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).

Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.

However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.

The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
 

Interest in NfL levels on the rise

NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.

Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.

“Future studies will explore validating NfL for ICANS and additional indications,” he said.

ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.

The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.

Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.

“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
 

Limitations: Validation, preventive measures needed

Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.

“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.

The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.

“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”

A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.

“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”

Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

A version of this article first appeared on Medscape.com.

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

A version of this article first appeared on Medscape.com.

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

A version of this article first appeared on Medscape.com.

The Food and Drug Administration announced on June 1 it has withdrawn approval of the lymphoma drug umbralisib (Ukoniq) following an investigation into a “possible increased risk of death.”

Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.

But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.

Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.

Five months later, the results are in.

“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.

In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.

The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”

In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.

The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration announced on June 1 it has withdrawn approval of the lymphoma drug umbralisib (Ukoniq) following an investigation into a “possible increased risk of death.”

Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.

But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.

Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.

Five months later, the results are in.

“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.

In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.

The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”

In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.

The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration announced on June 1 it has withdrawn approval of the lymphoma drug umbralisib (Ukoniq) following an investigation into a “possible increased risk of death.”

Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.

But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.

Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.

Five months later, the results are in.

“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.

In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.

The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”

In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.

The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.

A version of this article first appeared on Medscape.com.

Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.

Investigators found long-term clozapine use of more than 5 years was linked to a 2.7-fold increased risk of hematological malignancies in a dose-dependent manner, compared with other antipsychotics.

Karolinska Institute

An unresolved issue

Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.  

Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.

Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.

“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen. 

Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.

To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.

“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.

The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.

Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
 

Patient education, vigilant monitoring

The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.

Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.

Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.

Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).

Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.

Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.

The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.

These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
 

A ‘vital’ medication

Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.

UCLA

“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.

In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.

The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.

“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.

“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.

Investigators found long-term clozapine use of more than 5 years was linked to a 2.7-fold increased risk of hematological malignancies in a dose-dependent manner, compared with other antipsychotics.

Karolinska Institute

An unresolved issue

Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.  

Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.

Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.

“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen. 

Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.

To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.

“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.

The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.

Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
 

Patient education, vigilant monitoring

The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.

Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.

Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.

Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).

Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.

Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.

The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.

These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
 

A ‘vital’ medication

Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.

UCLA

“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.

In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.

The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.

“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.

“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.

Investigators found long-term clozapine use of more than 5 years was linked to a 2.7-fold increased risk of hematological malignancies in a dose-dependent manner, compared with other antipsychotics.

Karolinska Institute

An unresolved issue

Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.  

Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.

Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.

“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen. 

Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.

To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.

“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.

The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.

Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
 

Patient education, vigilant monitoring

The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.

Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.

Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.

Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).

Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.

Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.

The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.

These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
 

A ‘vital’ medication

Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.

UCLA

“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.

In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.

The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.

“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.

“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

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.

1995 Indian stamp; photo in public domain

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.

1995 Indian stamp; photo in public domain

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.

1995 Indian stamp; photo in public domain

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.

Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.

The results appeared March 21, 2022, in Nature Medicine.

“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”

Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”

Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.

For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).

The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).

At a median follow-up of 15.9 months, 73% were still in objective response.

“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”

Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”

As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).

“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”

Six patients (15%) died, 4 of progressive disease after going forward to other therapies.

As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).

The study was funded by Kite. The authors reported various disclosures.

Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.

The results appeared March 21, 2022, in Nature Medicine.

“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”

Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”

Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.

For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).

The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).

At a median follow-up of 15.9 months, 73% were still in objective response.

“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”

Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”

As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).

“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”

Six patients (15%) died, 4 of progressive disease after going forward to other therapies.

As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).

The study was funded by Kite. The authors reported various disclosures.

Results of the phase 2 ZUMA-12 trial suggest that axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor (CAR) T-cell therapy approved to treat certain types of lymphoma, also shows promise as a treatment for another group of lymphoma patients – those with high-risk large B-cell lymphoma (LBCL) who failed two rounds of standard chemoimmunotherapy. In fact, a study author said, first-line treatment with this therapy could help usher some patients toward a cure.

The results appeared March 21, 2022, in Nature Medicine.

“The high efficacy with manageable safety profile suggest that further evaluation of axi-cel in first-line setting in patients with high-risk LBCL is warranted in a randomized, phase 3 trial comparing it to standard chemoimmunotherapy,” study lead author Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

According to Dr. Neelapu, “patients with high-risk LBCL include those with high-intermediate or high International Prognostic Index score and those with certain molecular subtypes such as double- or triple-hit lymphoma. These patients have lower response rates and lower progression-free and overall survival with standard chemoimmunotherapy.”

Treatment of these patients can be especially challenging because they are underrepresented in clinical research, hematologist Michael Dickinson, MBBS, of the Peter MacCallum Cancer Center in Melbourne, said in an interview. “They often have disease that requires urgent treatment, so there is no time to recruit them into trials. A feature of ZUMA-12 is that it allowed patients to be recruited after short exposure to chemotherapy, which means that higher-risk patients could successfully be recruited into the trial.”

Axi-cel is already Food and Drug Administration approved for treatment of relapsed or refractory LBCL after 2 or more lines of systemic therapy plus relapsed or refractory follicular lymphoma, also after two or more lines of systemic therapy, Dr. Neelapu said.

For this study, researchers administered the treatment to 40 subjects with high-risk disease from 2019-2020 (median age, 61 years; 68% male; 95% at disease stage III or IV).

The researchers reported that 78% of 37 patients in the primary efficacy analysis reached complete response rate (95% confidence interval, 62-90); the median time to first complete response rate was 30 days (range, 27-207). About 89% of these subjects reached the secondary endpoint of objective response rate (95% CI, 75-97); the median time to first objective response was 29 days (range, 27-207).

At a median follow-up of 15.9 months, 73% were still in objective response.

“This is quite remarkable,” Dr. Neelapu said. “The durability of more than 70% is far higher than what would be expected with standard chemoimmunotherapy in these patients – under 40% durability with standard chemoimmunotherapy. Also, axi-cel induces durable responses in about 40% of patients in second- and third-line setting. However, when used as part of first-line therapy in this study, durable responses were observed in more than 70% of patients, suggesting that the efficacy of axi-cel may be much higher when used in first-line setting.”

Dr. Neelapu added: “Although the follow-up is short, it is highly likely that the majority of the patients with ongoing response beyond 1 year will likely be cured of their lymphoma.”

As for side effects, no treatment-related grade 5 events occurred, but 18 patients (45%) experienced serious adverse events. Grade 3 or higher cytokine release syndrome occurred in three patients (8%) and nine experienced neurologic events (23%).

“The majority of the higher-grade adverse events observed were due to cytopenias, which were expected due to the conditioning therapy,” Dr. Neelapu said. “Such cytopenias would also have been expected if these patients had received standard chemoimmunotherapy.”

Six patients (15%) died, 4 of progressive disease after going forward to other therapies.

As for cost, Dr. Neelapu said it should be similar to that of axi-cel as an FDA-approved third-line therapy. Axi-cel is highly expensive. Research has suggested that CAR T-cell therapy can boost costs beyond standard chemotherapy by $350,000-$490,000 with gains of 2-8 years of life (J Med Econ. Jan-Dec 2021;24[1]:458-68).

The study was funded by Kite. The authors reported various disclosures.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.