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Heed cardiac risk of BTKis for CLL
The report discourages the use of the drugs in patients with heart failure, and it specifies that ibrutinib should be avoided in cases of ventricular fibrillation. The consensus statement appeared in the journal Blood Advances.
However, a physician who studies the intersection of cardiology and oncology questioned the report's methodology and said that it goes too far in its warnings about the use of BTKis. Also, the report is funded by AstraZeneca, which produces acalabrutinib, a rival BTKi product to ibrutinib.
“BTK inhibitors have revolutionized treatment outcomes and strategies in both the upfront and refractory CLL disease settings. Led by ibrutinib, the drugs are associated with dramatic improvements in long-term survival and disease outcomes for most CLL patients,” report co-author and cardiologist Daniel Addison, MD, co-director of the cardio-oncology program at the Ohio State University, said in an interview. “The main cardiac concerns are abnormal heart rhythms, high blood pressure, and heart weakness. It is not completely clear at this time why these things develop when patients are treated with these important drugs.”
For the new consensus statement, colleagues met virtually and examined peer-reviewed research. “Generally, this statement reflects available knowledge from cancer clinical trials,” Dr. Addison said. “Because of the design of these trials, cardiac analyses were secondary analyses. In terms of clinic use, this should be balanced against a large number of heart-focused retrospective examinations specifically describing the cardiac effects of these drugs. Most of the available heart-focused studies have not been prospective trials. Primary outcome heart-focused trials with BTK inhibitors are needed. This statement acknowledges this.”
The report recommends that all patients under consideration for BTKi therapy undergo electrocardiograms and blood pressure measurement, and it states that echocardiograms are appropriate for patients with heart disease or at high risk. Patients under 70 without risk factors may take ibrutinib, acalabrutinib, or zanubrutinib, while the latter two drugs are “generally preferred” in patients with established heart disease, well-controlled atrial fibrillation (AFib), hypertension, heart failure, or valvular heart disease.
The authors noted: “If the patient has difficult-to-manage AF[ib], recent acute coronary syndromes, or difficult to control heart failure, alternatives to BTKi treatment, including venetoclax, should be considered.”
As for patients with heart failure, the authors wrote that BTKis should be avoided, “but this is a relative contraindication, not an absolute one.” Ibrutinib should definitely be avoided because of the risk of AFib.
Finally, the authors stated that “the use of BTKis, especially ibrutinib, should be avoided in patients with a history of ventricular arrhythmias and cardiac arrest. Ibrutinib has been shown to increase the incidence of ventricular arrhythmias and sudden cardiac death. Although data are not yet available regarding whether second-generation BTKis [acalabrutinib or zanubrutinib] are also associated with these events, a Bcl-2 antagonist is preferred to any BTKi in these patients.”
Darryl P. Leong, MBBS, PhD, MPH, director of the cardio-oncology program at McMaster University, Hamilton, Ont., and Hamilton Health Sciences, said in an interview that the consensus statement has important limitations.
“The data extracted were not standardized. The authors of the original research were not contacted to provide data that might have been informative,” he said. “Finally and perhaps most importantly, I am uncertain that the quality of the data on which recommendations are made was well evaluated or described.”
Specifically, Dr. Leong said the report’s conclusions about heart failure and arrhythmias are not “necessarily well-supported by the evidence.”
He added: “While there is some evidence to suggest that BTKIs may increase heart failure risk, ibrutinib leads to substantial reductions in mortality. It is a large extrapolation to accept that a mostly theoretic risk of heart failure –with modest supporting empiric data – should outweigh proven reductions in death.”
As for the recommendation against the use of ibrutinib in patients with ventricular arrhythmias and cardiac arrest, he said the evidence cited by the report – an analysis of adverse event data prompted by a case report and a retrospective analysis – is limited. “The statement that ibrutinib increases the risk of ventricular arrhythmias and sudden death is more of a hypothesis at present, and the evidence to support this hypothesis is far from conclusive.”
As for the future, report co-author Dr. Addison said that “additional prospective and lab-based studies of these drugs are needed to guide how to best manage their cardiac effects in the future. This will be critical, as the use of these drugs continues to rapidly expand. Currently, we do not know a lot about why these heart issues really happen.”
The study was funded by AstraZeneca. Several authors reported multiple disclosures. Dr. Addison disclosed funding from AstraZeneca. Dr. Leong reported consulting and speaker fees from Janssen, maker of ibrutinib, as well as AstraZeneca.
The report discourages the use of the drugs in patients with heart failure, and it specifies that ibrutinib should be avoided in cases of ventricular fibrillation. The consensus statement appeared in the journal Blood Advances.
However, a physician who studies the intersection of cardiology and oncology questioned the report's methodology and said that it goes too far in its warnings about the use of BTKis. Also, the report is funded by AstraZeneca, which produces acalabrutinib, a rival BTKi product to ibrutinib.
“BTK inhibitors have revolutionized treatment outcomes and strategies in both the upfront and refractory CLL disease settings. Led by ibrutinib, the drugs are associated with dramatic improvements in long-term survival and disease outcomes for most CLL patients,” report co-author and cardiologist Daniel Addison, MD, co-director of the cardio-oncology program at the Ohio State University, said in an interview. “The main cardiac concerns are abnormal heart rhythms, high blood pressure, and heart weakness. It is not completely clear at this time why these things develop when patients are treated with these important drugs.”
For the new consensus statement, colleagues met virtually and examined peer-reviewed research. “Generally, this statement reflects available knowledge from cancer clinical trials,” Dr. Addison said. “Because of the design of these trials, cardiac analyses were secondary analyses. In terms of clinic use, this should be balanced against a large number of heart-focused retrospective examinations specifically describing the cardiac effects of these drugs. Most of the available heart-focused studies have not been prospective trials. Primary outcome heart-focused trials with BTK inhibitors are needed. This statement acknowledges this.”
The report recommends that all patients under consideration for BTKi therapy undergo electrocardiograms and blood pressure measurement, and it states that echocardiograms are appropriate for patients with heart disease or at high risk. Patients under 70 without risk factors may take ibrutinib, acalabrutinib, or zanubrutinib, while the latter two drugs are “generally preferred” in patients with established heart disease, well-controlled atrial fibrillation (AFib), hypertension, heart failure, or valvular heart disease.
The authors noted: “If the patient has difficult-to-manage AF[ib], recent acute coronary syndromes, or difficult to control heart failure, alternatives to BTKi treatment, including venetoclax, should be considered.”
As for patients with heart failure, the authors wrote that BTKis should be avoided, “but this is a relative contraindication, not an absolute one.” Ibrutinib should definitely be avoided because of the risk of AFib.
Finally, the authors stated that “the use of BTKis, especially ibrutinib, should be avoided in patients with a history of ventricular arrhythmias and cardiac arrest. Ibrutinib has been shown to increase the incidence of ventricular arrhythmias and sudden cardiac death. Although data are not yet available regarding whether second-generation BTKis [acalabrutinib or zanubrutinib] are also associated with these events, a Bcl-2 antagonist is preferred to any BTKi in these patients.”
Darryl P. Leong, MBBS, PhD, MPH, director of the cardio-oncology program at McMaster University, Hamilton, Ont., and Hamilton Health Sciences, said in an interview that the consensus statement has important limitations.
“The data extracted were not standardized. The authors of the original research were not contacted to provide data that might have been informative,” he said. “Finally and perhaps most importantly, I am uncertain that the quality of the data on which recommendations are made was well evaluated or described.”
Specifically, Dr. Leong said the report’s conclusions about heart failure and arrhythmias are not “necessarily well-supported by the evidence.”
He added: “While there is some evidence to suggest that BTKIs may increase heart failure risk, ibrutinib leads to substantial reductions in mortality. It is a large extrapolation to accept that a mostly theoretic risk of heart failure –with modest supporting empiric data – should outweigh proven reductions in death.”
As for the recommendation against the use of ibrutinib in patients with ventricular arrhythmias and cardiac arrest, he said the evidence cited by the report – an analysis of adverse event data prompted by a case report and a retrospective analysis – is limited. “The statement that ibrutinib increases the risk of ventricular arrhythmias and sudden death is more of a hypothesis at present, and the evidence to support this hypothesis is far from conclusive.”
As for the future, report co-author Dr. Addison said that “additional prospective and lab-based studies of these drugs are needed to guide how to best manage their cardiac effects in the future. This will be critical, as the use of these drugs continues to rapidly expand. Currently, we do not know a lot about why these heart issues really happen.”
The study was funded by AstraZeneca. Several authors reported multiple disclosures. Dr. Addison disclosed funding from AstraZeneca. Dr. Leong reported consulting and speaker fees from Janssen, maker of ibrutinib, as well as AstraZeneca.
The report discourages the use of the drugs in patients with heart failure, and it specifies that ibrutinib should be avoided in cases of ventricular fibrillation. The consensus statement appeared in the journal Blood Advances.
However, a physician who studies the intersection of cardiology and oncology questioned the report's methodology and said that it goes too far in its warnings about the use of BTKis. Also, the report is funded by AstraZeneca, which produces acalabrutinib, a rival BTKi product to ibrutinib.
“BTK inhibitors have revolutionized treatment outcomes and strategies in both the upfront and refractory CLL disease settings. Led by ibrutinib, the drugs are associated with dramatic improvements in long-term survival and disease outcomes for most CLL patients,” report co-author and cardiologist Daniel Addison, MD, co-director of the cardio-oncology program at the Ohio State University, said in an interview. “The main cardiac concerns are abnormal heart rhythms, high blood pressure, and heart weakness. It is not completely clear at this time why these things develop when patients are treated with these important drugs.”
For the new consensus statement, colleagues met virtually and examined peer-reviewed research. “Generally, this statement reflects available knowledge from cancer clinical trials,” Dr. Addison said. “Because of the design of these trials, cardiac analyses were secondary analyses. In terms of clinic use, this should be balanced against a large number of heart-focused retrospective examinations specifically describing the cardiac effects of these drugs. Most of the available heart-focused studies have not been prospective trials. Primary outcome heart-focused trials with BTK inhibitors are needed. This statement acknowledges this.”
The report recommends that all patients under consideration for BTKi therapy undergo electrocardiograms and blood pressure measurement, and it states that echocardiograms are appropriate for patients with heart disease or at high risk. Patients under 70 without risk factors may take ibrutinib, acalabrutinib, or zanubrutinib, while the latter two drugs are “generally preferred” in patients with established heart disease, well-controlled atrial fibrillation (AFib), hypertension, heart failure, or valvular heart disease.
The authors noted: “If the patient has difficult-to-manage AF[ib], recent acute coronary syndromes, or difficult to control heart failure, alternatives to BTKi treatment, including venetoclax, should be considered.”
As for patients with heart failure, the authors wrote that BTKis should be avoided, “but this is a relative contraindication, not an absolute one.” Ibrutinib should definitely be avoided because of the risk of AFib.
Finally, the authors stated that “the use of BTKis, especially ibrutinib, should be avoided in patients with a history of ventricular arrhythmias and cardiac arrest. Ibrutinib has been shown to increase the incidence of ventricular arrhythmias and sudden cardiac death. Although data are not yet available regarding whether second-generation BTKis [acalabrutinib or zanubrutinib] are also associated with these events, a Bcl-2 antagonist is preferred to any BTKi in these patients.”
Darryl P. Leong, MBBS, PhD, MPH, director of the cardio-oncology program at McMaster University, Hamilton, Ont., and Hamilton Health Sciences, said in an interview that the consensus statement has important limitations.
“The data extracted were not standardized. The authors of the original research were not contacted to provide data that might have been informative,” he said. “Finally and perhaps most importantly, I am uncertain that the quality of the data on which recommendations are made was well evaluated or described.”
Specifically, Dr. Leong said the report’s conclusions about heart failure and arrhythmias are not “necessarily well-supported by the evidence.”
He added: “While there is some evidence to suggest that BTKIs may increase heart failure risk, ibrutinib leads to substantial reductions in mortality. It is a large extrapolation to accept that a mostly theoretic risk of heart failure –with modest supporting empiric data – should outweigh proven reductions in death.”
As for the recommendation against the use of ibrutinib in patients with ventricular arrhythmias and cardiac arrest, he said the evidence cited by the report – an analysis of adverse event data prompted by a case report and a retrospective analysis – is limited. “The statement that ibrutinib increases the risk of ventricular arrhythmias and sudden death is more of a hypothesis at present, and the evidence to support this hypothesis is far from conclusive.”
As for the future, report co-author Dr. Addison said that “additional prospective and lab-based studies of these drugs are needed to guide how to best manage their cardiac effects in the future. This will be critical, as the use of these drugs continues to rapidly expand. Currently, we do not know a lot about why these heart issues really happen.”
The study was funded by AstraZeneca. Several authors reported multiple disclosures. Dr. Addison disclosed funding from AstraZeneca. Dr. Leong reported consulting and speaker fees from Janssen, maker of ibrutinib, as well as AstraZeneca.
FROM BLOOD ADVANCES
Drug shortages plague hematology, but preparedness helps
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
FDA approves liso-cel as second-line therapy for LBCL
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
This expanded indication is based on findings from the pivotal phase 3 TRANSFORM study, which showed significant and clinically meaningful improvements with CD19-directed chimeric antigen receptor T-cell immunotherapy over salvage chemotherapy followed by high-dose chemotherapy plus autologous stem cell transplant. The latter course of treatment had been the standard of care for more than 2 decades.
Data from the global, randomized, multicenter TRANSFORM study, as reported in December 2021 at the annual meeting of the American Society of Hematology, showed that second-line treatment with liso-cel in 92 patients with r/r LBCL within 12 months after first-line therapy, compared with 92 patient who received standard of care therapy, was associated with highly statistically significant and clinically meaningful improvement in event-free survival (10.1 vs. 2.3 months; hazard ratio, 0.349), complete response rate (66% vs. 39%), and progression-free survival (14.8 vs. 5.7 months; HR, 0.406).
A positive trend in overall survival was also observed (HR, 0.509 at median follow-up of 6.2 months). No new liso-cel safety signals were detected in the second-line setting.
Liso-cel was initially approved in February 2021 for the treatment of adults with LBCL, including diffuse LBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
- Refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy.
- Refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant because of comorbidities or age.
Liso-cel is not indicated for the treatment of patients with primary central nervous system lymphoma.
In February 2022, the FDA granted Priority Review status for a Bristol-Myers Squibb supplemental Biologics License Application (sBLA), based on the TRANSFORM study data, to expand the indication to include use after the failure of first-line therapy.
The agent “now has the potential to be a new standard of care for patients after failure of first-line therapy, offering significantly improved outcomes beyond the current mainstay of care,” Anne Kerber, the BMS senior vice president of cell therapy development, said in a press release at that time.
The European Medicines Agency has also validated a type II variation application for extension of the indication for liso-cel in this setting. Validation of the application “confirms the submission is complete and begins the EMA’s centralized review procedure,” BMS announced in a June 20, 2022, press release.
Liso-cel, which has been available only through a restricted program under a Risk Evaluation and Mitigation Strategy, includes a boxed warning regarding the risk for cytokine release syndrome (CRS) and neurologic toxicities.
The warning states that liso-cel should not be administered to patients with active infection or inflammatory disorders, and that severe or life-threatening CRS should be treated with tocilizumab with or without corticosteroids.
Patients should also be monitored for neurologic events after treatment with liso-cel, and supportive care and/or corticosteroids should be administered as needed.
Novel gene therapy offers hope for some lymphomas
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
Not all patients with relapsed or refractory large B cell lymphoma (r/r LBCL) are candidates for high-dose chemotherapy or hematopoietic stem cell transplantation (HSCT), and options for second-line therapies for this population are limited, said Dr. Alison Sehgal of the University of Pittsburgh Medical Center in her presentation of the findings.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed CAR T-cell product. In a previous phase 3 randomized trial (the TRANSFORM study), lisocabtagene showed superiority over salvage chemotherapy for LBCL patients who were fit candidates for stem cell transplant, but its use in older, frail patients who are not transplant candidates remains uncertain, wrote Dr. Sehgal and colleagues in their poster at the meeting.
In the study, the researchers identified 74 patients with r/r LBCL. Of these, 61 were treated with liso-cel. The patients ranged in age from 53 to 84 years, with a median age of 74 years, 61% were male, and 89% were white. Approximately half were refractory and half were relapsed.
For the therapy, patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by an infusion of liso-cel at a target dose of 100 x 106 CAR+ T cells; all patients had at least 6 months of follow-up from their first response.
The primary endpoint of overall response rate occurred in 80% of the patients, and clinically meaningful complete response occurred in 54% over a median follow-up of 12.3 months.
“Clinically meaningful CRs were observed across all subgroups,” Dr. Sehgal said in her presentation.
The response lasted a median of 21.7 months, and the median follow-up for duration of response was 15.5 months. The median overall survival was not reached, but the median progression-free survival was 9.0 months, with a median follow-up period of 13.0 months.
Responses occurred across all prespecified subgroups, with no significant differences in either safety or efficacy based on hematopoietic cell transplantation–specific comorbidity index (HCT-CI) scores.
“Despite the advanced age and comorbidities of the population, the safety profile was consistent with previous reports,” and no new or increased safety signals appeared, Dr. Sehgal said.
The most common treatment-emergent adverse events of grade 3 or higher were neutropenia (48%), leukopenia (21%), thrombocytopenia (20%), and anemia (11%). Cytokine-release syndrome (CRS) occurred in 23 patients (38%); of these, 1 patient was grade 3 and none were grades 4 or 5.
Approximately one-third of the patients (31%) experienced neurological events during the study; three cases were grade 3, none were grades 4 or 5. Patients with CRS or NE were treated with tocilizumab (10%), corticosteroids (3%), or both (20%). Treatment-emergent adverse events of grade 3 or higher occurred in 79% of patients overall, including grade 5 events in two patients because of COVID-19.
The study findings were limited by the small sample size and lack of controls. However, the results support the potential use of liso-cel as a second-line therapy for r/r LBCL patients who are not candidates for HSCT, Dr. Sehgal concluded.
Addressing an ongoing unmet need
In an interview, study coauthor Dr. Leo I. Gordon of Northwestern University, Chicago, observed, “Patients with relapsed or refractory large B-cell lymphoma who are not considered candidates for stem cell transplant following first-line treatment, based on age, comorbidities, health status, or other prognostic factors, have more difficult-to-treat disease, poor prognosis, and more limited treatment options.”
Dr. Gordon noted that the PILOT study is the only trial to evaluate a CAR T-cell therapy as a second-line treatment for r/r LBCL patients who are not considered candidates for stem cell transplant.
“Data from the primary analysis of the PILOT study further demonstrate the potential value of using CAR T-cell therapies earlier in the treatment paradigm for relapsed or refractory LBCL to help improve clinical outcomes and address ongoing unmet need,” he said.
CAR T-cell therapies have shown benefits in later lines for r/r LBCL and as a second-line treatment for r/r LBCL patients who are deemed candidates for stem cell transplant, “so we were encouraged and not surprised by these data.”
However, Dr. Gordon noted, “There may be some patients with similar presentations that might have a transplant, so one limitation of the trial is how one defines patients where transplant is the intended therapy, and that assessment varies among institutions and clinicians.”
An application for liso-cel as a treatment for patients with r/r LBCL who have failed front-line therapy is currently under Priority Review with the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of June 24, 2022, he added.
Liso-cel may fill treatment gap as second-line therapy
The current study is important because “the long-term outcomes of patients with relapsed or refractory large B-cell lymphoma who are not candidates for stem cell transplantation is very poor,” said Dr. Brian Till of Fred Hutchinson Cancer Research Center, Seattle, in an interview.
“CAR T therapy leads to about a 40% cure rate, but is currently only available in this population after the failure of second-line therapy,” said Dr. Till, who was not involved in the study.
“Given that liso-cel was shown to improve outcomes in the second-line setting among transplant candidates, it is logical to consider it as second-line therapy in nontransplant candidates as well, who are otherwise fit enough to receive CAR T therapy,” Dr. Till explained.
“This study showed a rate of long-term progression-free survival similar to what has been observed in the third-line setting and was reasonably well tolerated in these older patients,” said Dr. Till. The results suggest “that second-line liso-cel may be an attractive treatment strategy for patients who are not candidates for stem cell transplantation due to advanced age or comorbidities,” he noted.
Dr. Till had no relevant financial conflicts to disclose.
The study was funded by Bristol Myers Squibb.
FROM ASCO 2022
Glofitamab prevails against r/r DLBCL
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
“We know that relapsed diffuse large B-cell lymphoma has a particularly poor prognosis,” especially for patients who have undergone at least two therapies, Dr. Michael Dickinson, MBBS, of the University of Melbourne said in a presentation at the annual meeting of the American Society of Clinical Oncology.
Bispecific T cell–recruiting antibodies are emerging as a novel treatment option for B-cell cancers, said Dr. Dickinson.
Glofitamab is distinct among these therapies for its configuration that is bivalent for CD20 and monovalent for CD3, providing more potency than a 1:1 format, Dr. Dickinson explained in his presentation.
The study population included 154 adults aged 21-90 years with DLBCL who had received at least two prior treatments; all had received prior anti-CD20 Ab, and 149 had received anthracycline. The median age of the patients was 66 years, 65% were male, 75% had Ann Arbor stage III or IV disease, and 90% were refractory to any prior therapy.
The patients received intravenous glutamate-pyruvate transaminase, followed by an initial intravenous dose of glofitamab 7 days later. Glofitamab was given as step-up doses starting with 2.5 mg to a target of 30 mg.
The primary endpoint was complete response (CR) during initial treatment using Independent Review Committee (IRC) criteria, with overall response rate, duration of response, duration of complete response, progression-free survival, and overall survival as key secondary outcomes.
At a median of 12.6 months’ follow-up, the CR and overall response rates were 39.4% and 51.6%, respectively.
“Responses were achieved early; the median time to first complete response was 42 days,” Dr. Dickinson reported. Of the 38 patients with CR at the data cutoff point, 33 remained in complete remission (87%) based on IRC criteria. Complete response rates were consistent across prespecified subgroups, notably 42% of patients with no prior chimeric antigen receptor T-cell therapy and 70% and 34%, of those who were relapsed or refractory, respectively, to their last prior treatments.
The median duration of overall response was 18.4 months, and the median duration of complete response had not yet been estimated, Dr. Dickinson said. The median progression-free survival and overall survival rates were 4.9 months and 11.5 months, respectively, and the estimated 12-month overall survival was 49.8%.
“These are highly clinically significant results for this difficult to treat population,” Dr. Dickinson said in his presentation.
The most common adverse event was cytokine release syndrome (CRS), which occurred in 63% of patients. Of these, 3.9% were grade 3 or 4. Patients received corticosteroids (27.8%) or tocilizumab for management of CRS.
“As we have shown before, this is a first-course phenomenon, becoming far less frequent once step up dosing is complete,” Dr. Dickinson said in the presentation. “The median time to CRS is predictable, occurring around 10 hours after the IV infusion,” he said. Overall, 3.2% of the patients discontinued because of an adverse event.
A total of eight deaths occurred during the study; five of these were related to COVID-19 and the remaining three were in patients with manifest progression of disease.
Infections are to be expected in such a heavily treated population, and 14.9% of patients developed infections of grade 3 or higher, said Dr. Dickinson. Neutropenia of any grade occurred in 37.7%, febrile neutropenia in 2.6%. Neurological events occurred in 38.3% of patients; 3.2% were grade 3 or higher.
The study did not prospectively record immune effector cell–associated neurotoxicity syndrome, Dr. Dickinson said, but an estimate suggests a rate of 2.6%, and none of the events were considered to be related to glofitamab, he noted.
The researchers also looked at a supporting cohort of 35 patients with a median follow up of more than 2 years. In this group, the complete remission rate was 35% and the median duration of remission was 34.2 months. “Our six longest patients have been in remission for longer than 3 years,” Dr. Dickinson said.
The latest glofitamab data “reflect routine practice and an area of need for this disease,” said Dr. Dickinson.
“I think these results will prove to be very meaningful for our patients with large cell lymphoma, and this drug will prove to be an important treatment option,” he said.
More follow-up needed, but findings show promise
A number of CD20/CD3-bispecific antibodies are in development for patients with relapsed/refractory B-cell lymphomas, said study discussant Kerry J. Savage, MD, of the University of British Columbia, Vancouver, who served as the discussant for the session.
Glofitamab differs from other treatments in that it is bivalent for CD20 and monovalent for CD3, “which imparts greater potency,” she noted. Glofitamab also has a silent Fc region that is designed to extend half-life and reduce toxicity.
Patients in the current study had at least two prior regimens, and importantly, “CR rates were similar, regardless of prior therapy,” said Dr. Savage. The longer follow-up cohort provides “a hint that the response may be durable.”
Looking ahead, “the important thing will be response durability” with longer follow-up, she added. “We don’t know the curative potential yet, but the results are encouraging so far.”
In the meantime, “the best use of bispecific antibodies is through clinical trials,” Dr. Savage said. “Keep an eye out for bispecific antibody combination trials as well.”
The study was funded by F. Hoffmann–La Roche. Dr. Dickinson disclosed honoraria from or serving as a consultant to companies including Amgen, Bristol Myers-Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Dr. Savage disclosed relationships, funding, and support from multiple companies including Bristol Myers-Squibb, Janssen Oncology, Kyowa, Merck, Novartis Canada Pharmaceuticals, Seattle Genetics and Roche.
FROM ASCO 2022
‘Exciting’ new gene therapy yields promising results
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
Third-generation Black woman physician makes cancer research history
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
Ex–hospital porter a neglected giant of cancer research
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
Repurposed drug could revolutionize stem cell transplantation
When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.
Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.
Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.
Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).
Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)
A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).
The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
Could abatacept fuel greater use of mismatched, unrelated donors?
One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.
Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.
Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.
Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.
“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.
That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
Further study of abatacept
With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.
Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”
Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”
Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”
Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.
When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.
Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.
Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.
Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).
Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)
A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).
The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
Could abatacept fuel greater use of mismatched, unrelated donors?
One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.
Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.
Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.
Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.
“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.
That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
Further study of abatacept
With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.
Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”
Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”
Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”
Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.
When the Food and Drug Administration approved abatacept in December 2021 as prophylaxis for acute graft-versus-host disease (aGVHD) in adults and children 2 years and older who are undergoing hematopoietic stem cell transplantation (HSCT), the announcement was notable for couple of key reasons.
Abatacept was approved based on results from the ABA2 trial, which evaluated 142 adults and children with hematologic malignancies who received a four-dose regimen of abatacept in addition to standard of care – a calcineurin inhibitor (CNI) plus methotrexate (MTX) – prior to undergoing an 8/8 HLA-matched, unrelated donor (URD) HSCT, or standard of care alone.
Another arm of the trial examined 43 recipients of a 7/8 HLA-mismatched URD HSCT who received abatacept plus standard of care, compared with a prespecified registry cohort group provided by the Center for International Blood and Marrow Transplant Research, who received CNI and MTX.
Results published in the Journal of Clinical Oncology showed the proportion of patients in the 8/8 group with severe aGVHD in the abatacept group 100 days after HSCT was not significantly lower, compared with the standard of care group (6.8% vs. 14.8%; P = .13), but there was a significant improvement in severe aGVHD–free survival (SGFS) 180 days after HSCT in the abatacept group, compared with the group that received standard of care (93.2% vs. 80%; P = .05).
Among patients in the 7/8 group, there was a significant difference in the proportion of patients with severe aGVHD favoring the abatacept group (2.3% vs. 30.2%; P < .001), and significantly improved SGFS, compared with the CIBMTR registry cohort (97.7% vs. 58.7%; P < .001)
A post hoc analysis of ABA2 published as a research letter in Blood Advances assessed abatacept using real-world data from CIBMTR. Researchers compared the 8/8 group that received standard of care with the 7/8 group that received abatacept plus standard of care and found no significant differences between relapse-free survival and overall survival for patients in the 8/8 group (adjusted hazard ratio, 0.60; 95% confidence interval, 0.28-1.28; P = .19) and 7/8 group (aHR, 0.77; 95% CI, 0.34-1.71; P = .51).
The results suggest “abatacept may eliminate that risk of a mismatched transplant in the setting of that analysis and that small cohort that was assessed there, which is good news for patients that may not have a fully matched donor on the registry,” said Stephen Spellman, vice president at Be The Match Research (operated by the National Marrow Donor Program), and senior scientific director of CIBMTR. The findings from ABA2 “were even more impressive than necessarily expected, especially in the 7/8 arm. This is a truly substantial reduction in acute GVHD risk in that patient population,” he said in an interview.
Could abatacept fuel greater use of mismatched, unrelated donors?
One downside of using an HLA-mismatched donor is the potential risk of developing aGVHD, Doris M. Ponce, MD, a hematologic oncologist with Memorial Sloan Kettering Cancer Center in New York, who was not involved with the research, said in an interview.
Potential risk factors for aGVHD include “having a female multiparous donor, HLA-mismatched donor, unrelated donor, donor and recipient age (>40 years), [peripheral blood stem cell] stem cell graft, recipient [cytomegalovirus] serostatus (recipient/donor), myeloablative conditioning, [total body irradiation]–based conditioning, [and] gut microbiome dysbiosis,” Dr. Ponce explained.
Abatacept’s approval may have particular relevance for people of color. “It’s been understood for a long time that the likelihood of finding an 8/8 well-matched, volunteer unrelated donor varies by race or ethnicity,” Steven Devine, MD, a board-certified oncologist who is chief medical officer of Be The Match and associate scientific director at CIBMTR, said in an interview.
Mr. Spellman noted that, of the more than 35 million donors on worldwide registries accessible through the National Marrow Donor Program’s Be The Match Registry, “the match rates differ quite substantially by race and ethnicity.” Approximately 29% of African Americans find a full match on the registry, compared with 81% of Whites, 49% of Hispanics, and 47% Asian/Pacific Islanders.
“Being able to utilize a 7/8 match in a safe, effective manner using abatacept, which abatacept has been approved for, does increase those match rates quite substantially,” he explained. Among African Americans, this means the match rate increases to 84%, among Hispanics and Asian/Pacific Islanders to approximately 90%, and among Whites to about 98%.
That kind of improvement in the match rate is “the equivalent of adding more than more than 10 million ethnically diverse donors to the registry in 1 day,” Dr. Devine said. “The availability of abatacept could really level the playing field for patients in need of a lifesaving transplant.”
Further study of abatacept
With abatacept, “I think the results are really encouraging, and I think that further studies [are needed] to better define how the drug would work and whether it can later prevent chronic graft versus host disease,” Dr. Devine said. He said the ABA3 trial has been designed around this question, with the hypothesis that extending abatacept to an eight-dose regimen may help with chronic GVHD.
Although the FDA’s approval of abatacept was recent, Mr. Spellman said, Be The Match has seen early indications that mismatched donors in the registry are being used, which may point to an increased utilization of abatacept. “Through October to December of 2021, there was a pretty substantial increase in the use of mismatched, unrelated donors in that time frame.”
Dr. Devine noted that he is seeing a lot of interest in using abatacept. “I think people are still learning how best to incorporate it into their standard of care right now.”
Meanwhile, Memorial Sloan Kettering Cancer Center is already planning to use abatacept, Dr. Ponce noted. “We have abatacept in our formulary for adult and children, and are planning on using it for patients receiving an unmodified graft from a [matched unrelated donor] or 1-allele [mismatched unrelated donor] using CNI and MTX-based GVHD prophylaxis.”
Dr. Devine and Mr. Spellman are employees of Be The Match and CIBMTR, which provided the registry control group for the ABA2 trial. Dr. Devine also reported that he has been a scientific advisory board member for Bristol-Myers Squibb. Dr. Ponce reports no relevant conflicts of interest.
EMA gives green light to new CAR T-cell therapy
At its late January meeting, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended for approval lisocabtagene maraleucel (Breyanzi, Bristol-Myers Squibb). This chimeric antigen receptor T-cell therapy is indicated for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B). The indication is for use in patients who have received at least two lines of treatment.
The benefits of lisocabtagene maraleucel, noted the CHMP, are its ability to provide high and durable responses in patients with relapsed or refractory DLBCL, PMBCL, and FL3B. The most common side effects reported are neutropenia, anemia, cytokine release syndrome, fatigue, and thrombocytopenia.
The product is already approved in the United States for the same indication. The Food and Drug Administration’s approval came with a Risk Evaluation and Mitigation Strategy because of the risk for serious adverse events, including cytokine release syndrome.
During development, it was designated as an orphan medicine. The EMA will now review the information available to date to determine if the orphan designation can be maintained.
Biosimilar pegfilgrastim
At the same meeting, the committee recommended approval of a biosimilar product for pegfilgrastim (Stimufend, Fresenius Kabi Deutschland), which is used to reduce the duration of neutropenia and the incidence of febrile neutropenia after cytotoxic chemotherapy.
The committee noted that this product has been shown to be highly similar to the reference product Neulasta (pegfilgrastim), which has been available in the EU for 2 decades (authorized in 2002). Data have demonstrated that Stimufend has comparable quality, safety, and efficacy to Neulasta.
Its full indication is to reduce the duration of neutropenia and incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancies, with the exception of chronic myeloid leukemia (CML) and myelodysplastic syndromes.
Generic versions of dasatinib
Also recommended for approval were for two generic formulations of dasatinib (Dasatinib Accord and Dasatinib Accordpharma, both from Accord Healthcare) for the treatment of various leukemias.
These are generic versions of dasatinib (Sprycel), which has been available in the European Union since 2006.
The CHMP noted that studies have demonstrated the satisfactory quality of Dasatinib Accord, as well as its bioequivalence to the reference product. This generic is indicated for the treatment of adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy and pediatric patients with newly diagnosed Ph+ ALL in combination with chemotherapy.
Dasatinib Accordpharma has a wider set of indications, which include the treatment of adult patients with newly diagnosed Ph+ CML in the chronic phase; chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib; and Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy. In addition, this generic is indicated for the treatment of pediatric patients with newly diagnosed Ph+ CML in the chronic phase or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib and newly diagnosed Ph+ ALL in combination with chemotherapy.
A version of this article first appeared on Medscape.com.
At its late January meeting, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended for approval lisocabtagene maraleucel (Breyanzi, Bristol-Myers Squibb). This chimeric antigen receptor T-cell therapy is indicated for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B). The indication is for use in patients who have received at least two lines of treatment.
The benefits of lisocabtagene maraleucel, noted the CHMP, are its ability to provide high and durable responses in patients with relapsed or refractory DLBCL, PMBCL, and FL3B. The most common side effects reported are neutropenia, anemia, cytokine release syndrome, fatigue, and thrombocytopenia.
The product is already approved in the United States for the same indication. The Food and Drug Administration’s approval came with a Risk Evaluation and Mitigation Strategy because of the risk for serious adverse events, including cytokine release syndrome.
During development, it was designated as an orphan medicine. The EMA will now review the information available to date to determine if the orphan designation can be maintained.
Biosimilar pegfilgrastim
At the same meeting, the committee recommended approval of a biosimilar product for pegfilgrastim (Stimufend, Fresenius Kabi Deutschland), which is used to reduce the duration of neutropenia and the incidence of febrile neutropenia after cytotoxic chemotherapy.
The committee noted that this product has been shown to be highly similar to the reference product Neulasta (pegfilgrastim), which has been available in the EU for 2 decades (authorized in 2002). Data have demonstrated that Stimufend has comparable quality, safety, and efficacy to Neulasta.
Its full indication is to reduce the duration of neutropenia and incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancies, with the exception of chronic myeloid leukemia (CML) and myelodysplastic syndromes.
Generic versions of dasatinib
Also recommended for approval were for two generic formulations of dasatinib (Dasatinib Accord and Dasatinib Accordpharma, both from Accord Healthcare) for the treatment of various leukemias.
These are generic versions of dasatinib (Sprycel), which has been available in the European Union since 2006.
The CHMP noted that studies have demonstrated the satisfactory quality of Dasatinib Accord, as well as its bioequivalence to the reference product. This generic is indicated for the treatment of adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy and pediatric patients with newly diagnosed Ph+ ALL in combination with chemotherapy.
Dasatinib Accordpharma has a wider set of indications, which include the treatment of adult patients with newly diagnosed Ph+ CML in the chronic phase; chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib; and Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy. In addition, this generic is indicated for the treatment of pediatric patients with newly diagnosed Ph+ CML in the chronic phase or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib and newly diagnosed Ph+ ALL in combination with chemotherapy.
A version of this article first appeared on Medscape.com.
At its late January meeting, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended for approval lisocabtagene maraleucel (Breyanzi, Bristol-Myers Squibb). This chimeric antigen receptor T-cell therapy is indicated for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B). The indication is for use in patients who have received at least two lines of treatment.
The benefits of lisocabtagene maraleucel, noted the CHMP, are its ability to provide high and durable responses in patients with relapsed or refractory DLBCL, PMBCL, and FL3B. The most common side effects reported are neutropenia, anemia, cytokine release syndrome, fatigue, and thrombocytopenia.
The product is already approved in the United States for the same indication. The Food and Drug Administration’s approval came with a Risk Evaluation and Mitigation Strategy because of the risk for serious adverse events, including cytokine release syndrome.
During development, it was designated as an orphan medicine. The EMA will now review the information available to date to determine if the orphan designation can be maintained.
Biosimilar pegfilgrastim
At the same meeting, the committee recommended approval of a biosimilar product for pegfilgrastim (Stimufend, Fresenius Kabi Deutschland), which is used to reduce the duration of neutropenia and the incidence of febrile neutropenia after cytotoxic chemotherapy.
The committee noted that this product has been shown to be highly similar to the reference product Neulasta (pegfilgrastim), which has been available in the EU for 2 decades (authorized in 2002). Data have demonstrated that Stimufend has comparable quality, safety, and efficacy to Neulasta.
Its full indication is to reduce the duration of neutropenia and incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancies, with the exception of chronic myeloid leukemia (CML) and myelodysplastic syndromes.
Generic versions of dasatinib
Also recommended for approval were for two generic formulations of dasatinib (Dasatinib Accord and Dasatinib Accordpharma, both from Accord Healthcare) for the treatment of various leukemias.
These are generic versions of dasatinib (Sprycel), which has been available in the European Union since 2006.
The CHMP noted that studies have demonstrated the satisfactory quality of Dasatinib Accord, as well as its bioequivalence to the reference product. This generic is indicated for the treatment of adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy and pediatric patients with newly diagnosed Ph+ ALL in combination with chemotherapy.
Dasatinib Accordpharma has a wider set of indications, which include the treatment of adult patients with newly diagnosed Ph+ CML in the chronic phase; chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy including imatinib; and Ph+ ALL and lymphoid blast CML with resistance or intolerance to prior therapy. In addition, this generic is indicated for the treatment of pediatric patients with newly diagnosed Ph+ CML in the chronic phase or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib and newly diagnosed Ph+ ALL in combination with chemotherapy.
A version of this article first appeared on Medscape.com.