DLBCL

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

Firstly, abatacept – initially approved in 2005 as a treatment for rheumatoid arthritis – was being repurposed for a different indication. Secondly, the new use for abatacept held promise for patients who are receiving HSCT and have trouble finding available, matched unrelated donors, a problem that disproportionately affects people of color.

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.

Firstly, abatacept – initially approved in 2005 as a treatment for rheumatoid arthritis – was being repurposed for a different indication. Secondly, the new use for abatacept held promise for patients who are receiving HSCT and have trouble finding available, matched unrelated donors, a problem that disproportionately affects people of color.

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.

Firstly, abatacept – initially approved in 2005 as a treatment for rheumatoid arthritis – was being repurposed for a different indication. Secondly, the new use for abatacept held promise for patients who are receiving HSCT and have trouble finding available, matched unrelated donors, a problem that disproportionately affects people of color.

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.

A new cell therapy will be available in Europe soon for the treatment of certain blood cancers.

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.

A new cell therapy will be available in Europe soon for the treatment of certain blood cancers.

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.

A new cell therapy will be available in Europe soon for the treatment of certain blood cancers.

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.

The label for axicabtagene ciloleucel (Yescarta, Kite) has been updated to include prophylactic corticosteroids to manage cytokine release syndrome (CRS).

This is a chimeric antigen receptor T-cell product indicated for use in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy.

The product label carries a black box warning that CRS is a potentially fatal complication. With the update, the new labeling advises clinicians to “consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks ... to delay the onset and decrease the duration of CRS.”

However, labeling also notes that “prophylactic corticosteroids ... may result in [a] higher grade of neurologic toxicities or prolongation of neurologic toxicities,” another potentially fatal complication noted in the black box warning.

The addition of prophylactic corticosteroids to labeling was based on data from 39 patients with relapsed or refractory LBCL who received dexamethasone 10 mg orally once daily for 3 days starting prior to Yescarta infusion. In this cohort, 31 of the 39 patients (79%) developed CRS, at which point they were managed with tocilizumab and/or corticosteroids. No one developed grade 3 or higher CRS. The median time to CRS onset was 5 days and the median duration was 4 days, according to labeling.

In contrast, in another cohort of 41 patients who were started on tocilizumab and/or corticosteroids only after becoming symptomatic, the overall incidence of CRS was 93% (38/41), with a median onset at 2 days, median duration of 7 days, and two patients who developed grade 3 CRS.

Prophylactic steroids do not compromise the activity of the cell therapy, Kite said in a press release.

“These new data will enable doctors to more easily and confidently manage treatment for patients,” said Frank Neumann, MD, PhD, the company’s global head of clinical development.

Yescarta is currently under review in the United States and Europe for second-line use in relapsed or refractory LBCL, Kite noted.

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

The label for axicabtagene ciloleucel (Yescarta, Kite) has been updated to include prophylactic corticosteroids to manage cytokine release syndrome (CRS).

This is a chimeric antigen receptor T-cell product indicated for use in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy.

The product label carries a black box warning that CRS is a potentially fatal complication. With the update, the new labeling advises clinicians to “consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks ... to delay the onset and decrease the duration of CRS.”

However, labeling also notes that “prophylactic corticosteroids ... may result in [a] higher grade of neurologic toxicities or prolongation of neurologic toxicities,” another potentially fatal complication noted in the black box warning.

The addition of prophylactic corticosteroids to labeling was based on data from 39 patients with relapsed or refractory LBCL who received dexamethasone 10 mg orally once daily for 3 days starting prior to Yescarta infusion. In this cohort, 31 of the 39 patients (79%) developed CRS, at which point they were managed with tocilizumab and/or corticosteroids. No one developed grade 3 or higher CRS. The median time to CRS onset was 5 days and the median duration was 4 days, according to labeling.

In contrast, in another cohort of 41 patients who were started on tocilizumab and/or corticosteroids only after becoming symptomatic, the overall incidence of CRS was 93% (38/41), with a median onset at 2 days, median duration of 7 days, and two patients who developed grade 3 CRS.

Prophylactic steroids do not compromise the activity of the cell therapy, Kite said in a press release.

“These new data will enable doctors to more easily and confidently manage treatment for patients,” said Frank Neumann, MD, PhD, the company’s global head of clinical development.

Yescarta is currently under review in the United States and Europe for second-line use in relapsed or refractory LBCL, Kite noted.

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

The label for axicabtagene ciloleucel (Yescarta, Kite) has been updated to include prophylactic corticosteroids to manage cytokine release syndrome (CRS).

This is a chimeric antigen receptor T-cell product indicated for use in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy.

The product label carries a black box warning that CRS is a potentially fatal complication. With the update, the new labeling advises clinicians to “consider the use of prophylactic corticosteroid in patients after weighing the potential benefits and risks ... to delay the onset and decrease the duration of CRS.”

However, labeling also notes that “prophylactic corticosteroids ... may result in [a] higher grade of neurologic toxicities or prolongation of neurologic toxicities,” another potentially fatal complication noted in the black box warning.

The addition of prophylactic corticosteroids to labeling was based on data from 39 patients with relapsed or refractory LBCL who received dexamethasone 10 mg orally once daily for 3 days starting prior to Yescarta infusion. In this cohort, 31 of the 39 patients (79%) developed CRS, at which point they were managed with tocilizumab and/or corticosteroids. No one developed grade 3 or higher CRS. The median time to CRS onset was 5 days and the median duration was 4 days, according to labeling.

In contrast, in another cohort of 41 patients who were started on tocilizumab and/or corticosteroids only after becoming symptomatic, the overall incidence of CRS was 93% (38/41), with a median onset at 2 days, median duration of 7 days, and two patients who developed grade 3 CRS.

Prophylactic steroids do not compromise the activity of the cell therapy, Kite said in a press release.

“These new data will enable doctors to more easily and confidently manage treatment for patients,” said Frank Neumann, MD, PhD, the company’s global head of clinical development.

Yescarta is currently under review in the United States and Europe for second-line use in relapsed or refractory LBCL, Kite noted.

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

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

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

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

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

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

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

Courtesy MSKCC

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

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

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

Global leaders in HSCT

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

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

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

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

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

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

Courtesy MSKCC

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

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

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

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

Impact of the pandemic

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

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

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

Something more in common

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

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

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

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

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

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

This article was updated 1/26/22.

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

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

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

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

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

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

Courtesy MSKCC

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

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

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

Global leaders in HSCT

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

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

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

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

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

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

Courtesy MSKCC

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

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

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

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

Impact of the pandemic

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

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

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

Something more in common

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

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

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

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

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

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

This article was updated 1/26/22.

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

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

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

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

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

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

Courtesy MSKCC

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

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

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

Global leaders in HSCT

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

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

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

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

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

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

Courtesy MSKCC

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

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

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

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

Impact of the pandemic

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

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

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

Something more in common

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

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

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

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

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

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

This article was updated 1/26/22.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

Rituximab has presented something of a conundrum for patients taking the monoclonal antibody during the COVID-19 pandemic.

Used to manage a variety of autoimmune diseases and cancers, rituximab acts against CD20 proteins expressed on the surface of B cells, causing B-cell depletion. However, it is this B-cell depletion that may put these patients at greater risk of COVID-19 development, progression to more severe disease, and in-hospital mortality. Evidence for this appears to be mixed, with studies showing both that patients using rituximab to manage various diseases are and are not at increased risk for SARS-CoV-2 infection, COVID-19 progression, and mortality.

peterschreiber_media/iStock/Getty Images

As COVID-19 vaccine rollouts take place across the world, more questions have been raised about the relationship between B-cell depletion from anti-CD20 therapies and COVID-19 vaccines. Do rituximab and other anti-CD20 therapies affect a patient’s response to COVID-19 vaccines? If this is the case, does the timing of anti-CD20 treatment matter to maximize B-cell levels and improve the vaccine’s effectiveness? And how do COVID-19 vaccine booster doses factor into the equation?

This article aims to summarize the latest research on how rituximab affects humoral and cell-mediated response following a COVID-19 vaccine primary series, and whether the addition of a COVID-19 vaccine booster dose changes patient response.
 

Humoral and cell-mediated responses following COVID-19 vaccination

First, the bad news: The vaccine is unquestionably safe to administer in patients taking rituximab, but one thing that has been well established is that antibody response to COVID-19 vaccination in these individuals does is reduced. This isn’t entirely unprecedented, as previous studies have shown a weakened immune response to pneumococcal polysaccharide and keyhole limpet hemocyanin vaccines among patients taking rituximab.

“Compromised immunogenicity to the SARS-CoV-2 vaccines has been demonstrated in rituximab-treated patients, which is of particular concern given the observation that B-cell–depleting therapies may be associated with worse COVID outcomes,” Robert F. Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, said in an interview.

For example, in a recent study from the Medical University of Vienna, 29 (39%) of 74 patients receiving rituximab (43% as monotherapy, 57% with conventional-synthetic disease-modifying antirheumatic drugs) who were vaccinated with either the Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) COVID-19 vaccine achieved seroconversion, compared with 100% of patients in a healthy control group, and all but 1 patient without detectable CD19+ peripheral B cells did not develop anti–SARS-CoV-2 receptor-binding domain antibodies.

“There is an increasing number of studies in this field, and they confirm that patients treated with rituximab and other anti-CD20 agents have severely reduced serological responses to COVID-19 vaccines,” Ingrid Jyssum, MD, of the division of rheumatology and research at Diakonhjemmet Hospital in Oslo, said in an interview.

One silver lining is that patients treated with anti-CD20 therapies appear to have a cell-mediated response following vaccination even if they don’t develop SARS-CoV-2 antibodies. “Studies that also investigate T-cell responses are starting to emerge, and so far, they show that, even if the patients do not have antibodies, they may have T-cell responses,” Dr. Jyssum said.

One study of 24 patients with autoimmune diseases taking rituximab that evaluated humoral and T-cell responses following vaccination with the Comirnaty vaccine found that none had a humoral response to the vaccine, but the T-cell response from that group did not significantly differ from 35 patients receiving other immunosuppressants and 26 patients in a healthy control group. In another study of rituximab- or ocrelizumab-treated patients who received mRNA-based COVID-19 vaccines, 69.4% developed SARS-CoV-2–specific antibodies, compared with a control group, but 96.2% of patients taking ocrelizumab and 81.8% of patients taking rituximab mounted a spike-specific CD8+ T-cell response, compared with 66.7% in the control group, and there were comparable rates (85%-90%) of spike-specific CD4+ T cells in all groups. In the study from the Medical University of Vienna, T-cell response was detected in rituximab-treated patients who both did and did not mount an antibody response.

The clinical relevance of how a blunted humoral immune response but a respectable T-cell response to COVID-19 vaccines affects patients treated with anti-CD20 therapies isn’t currently known, Dr. Jyssum said.

While these data are reassuring, they’re also incomplete, Dr. Spiera noted. “The ultimate outcome of relevance to assess vaccine efficacy is protection from COVID and from severe outcomes of COVID infection (i.e., hospitalization, mechanical ventilation, death). That data will require assessment of very large numbers of rituximab-treated vaccinated patients to be compared with rituximab-treated unvaccinated patients, and is unlikely to be forthcoming in the very near future.

“In the meantime, however, achieving serologic positivity, meaning having evidence of serologic as well as cellular immunity following vaccination, is a desired outcome, and likely implies more robust immunity.”
 

Does treatment timing impact COVID-19 vaccine response?

Given enough time, B-cell reconstitution will occur in patients taking rituximab. With that in mind, is it beneficial to wait a certain amount of time after a patient has stopped rituximab therapy or time since their last dose before giving them a COVID-19 vaccine? In their guidance on COVID-19 vaccines for patients with rheumatic and musculoskeletal diseases, the American College of Rheumatology said there is moderate evidence to consider “optimal timing of dosing and vaccination with the rheumatology provider before proceeding.”

“Guidelines and preliminary studies of serologic response to COVID vaccine in rituximab-treated patients have suggested that longer time from last rituximab exposure is associated with a greater likelihood of a serologic response,” Dr. Spiera said.

In a brief report published in Arthritis & Rheumatology, Dr. Spiera and colleagues performed a retrospective chart review of 56 patients with varying levels of last exposure to rituximab who received a COVID-19 vaccine. Their results showed that, when patients were vaccinated 6-12 months after the last rituximab dose, 55% were seronegative, and when this was more than 12 months, only 13% were seronegative, compared with seronegativity in 86% who were vaccinated less than 6 months after their last rituximab dose.

The RituxiVac trial, conducted by researchers in Switzerland, also examined vaccine responses of 96 rituximab-treated patients who received Comirnaty or Spikevax; results recently published in The Lancet Rheumatology showed findings similar to other studies, with reduced humoral and cell-mediated responses. In the RituxiVac trial, the median time to last anti-CD20 treatment was 1.07 years.

“The typical interval between rituximab doses [for treatment of rheumatoid arthritis, as well as for remission maintenance in antineutrophil cytoplasmic antibody–associated vasculitis] is typically 6 months, and this has become widely used as the interval from last rituximab to time of COVID vaccination, with a recommendation to wait 4 weeks (if possible) from time of vaccination until the next rituximab administration,” Dr. Spiera explained. However, this window seems to vary depending on the study.

Recent research published in Arthritis & Rheumatology indicates B-cell levels could be a relevant indicator for humoral and cell-mediated response in patients with rheumatic diseases treated with rituximab, with a level of 10 B cells/mcL (0.4% of lymphocytes) identified as one potential marker for likely seroconversion following COVID-19 vaccination.

“In some smaller case series, it has been further recognized that rituximab-treated patients who were beginning to reconstitute peripheral B cells were most likely to respond serologically. Our present study confirmed those findings, demonstrating that the presence of detectable B cells was strongly associated with vaccine responsiveness, and affords complementary information to time from last [rituximab dose] in informing the likelihood of a vaccine response,” Dr. Spiera said.

However, the literature is limited in this area, and an exact cutoff for B-cell counts in these patients isn’t currently known, Dr. Jyssum said. A better metric is time away from anti-CD20 therapies, with CD19 cell count being highly correlated with last infusion.

Dr. Spiera agreed that there is no consistent B-cell percentage that works as a cutoff. “In our study, we looked at it as a binary variable, although we did find that a higher percentage of B cells in the peripheral lymphocyte population was associated with a higher likelihood of seroconversion. We did not, however, identify a ‘threshold’ for vaccine serologic responsiveness.”

Should clinicians measure antibodies?

The Food and Drug Administration and the Centers for Disease Control and Prevention have recommended that health care providers and the public not use COVID-19 antibody tests as a way to gauge immunity after exposure to SARS-CoV-2 and after receiving a COVID-19 vaccination. The ACR’s guidance on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases strongly recommends against ordering antibody tests for patients with autoimmune inflammatory rheumatic diseases as a way to measure immunity.

“Generally, such measurements are not recommended as the clinical correlate of various antibody levels are not known,” Dr. Jyssum said. “With regular infusions of rituximab or other anti-CD20 agents, one cannot expect that these patients will develop significant levels of antibodies.”

However, she said there might be situations where it’s useful to know whether a patient has developed antibodies at all. “Assessing the significance of specific antibody levels is difficult, and the subject of scientific studies. Patients lacking a humoral vaccine response are left to rely on their T-cell responses and on infectious control measures to prevent disease.”

Dr. Spiera said he disagreed with guidelines recommending against checking antibody levels after vaccination, “particularly in patients treated with immunosuppressive medications that might be expected to blunt their serologic response to the vaccines.

“Although we cannot be sure what level of measurable antibodies offer what level of protection, most clinicians would agree that patients who demonstrate no detectable antibodies (which is a common finding in rituximab-treated patients) should be considered at higher risk,” he said. “Indeed, recommendations regarding booster vaccine administration in general was initially based on the observation of declining antibody levels with longer time from vaccination.”

Do COVID-19 vaccine boosters help patients on anti-CD20 therapy?

As of January 2022, the FDA and CDC have recommended a third primary series shot of COVID-19 vaccines for some moderately to severely immunocompromised patients as young as 5 years old (for Comirnaty vaccine) or a booster shot of either Comirnaty or Spikevax for everyone aged 12 years and older, including immunocompromised people, while the ACR goes into more detail and recommends clinicians time a patient’s booster shot with temporary treatment interruption.

In The Lancet Rheumatology, Dr. Jyssum and colleagues recently published results from the prospective Nor-vaC study examining the humoral and cell-mediated immune responses of 87 patients with RA being treated with rituximab who received the Comirnaty, Spikevax, or Vaxzevria (AstraZeneca) COVID-19 vaccines; of these, 49 patients received a booster dose at a median of 70 days after completing their primary series. The results showed 19 patients (28.1%) had a serologic response after their primary series, while 8 of 49 patients (16.3%) who received their booster dose had a serologic response.

All patients who received a third dose in the study had a T-cell response, Dr. Jyssum said. “This is reassuring for patients and clinicians. T cells have been found to be important in countering COVID-19 disease, but whether we can rely on the T-cell response alone in the absence of antibodies to protect patients from infection or from serious COVID disease is still not determined,” she said.

When asked if she would recommend COVID-19 vaccine booster doses for patients on rituximab, Dr. Jyssum replied: “Absolutely.”

Another study, recently published in Annals of the Rheumatic Diseases, examined heterologous and homologous booster doses for 60 patients receiving rituximab without seroconversion after their COVID-19 vaccine primary series. The results showed no significant difference in new seroconversion at 4 weeks based on whether the patient received a vector or mRNA vaccine (22% vs. 32%), but all patients who received a booster dose with a vector vaccine had specific T-cell responses, compared with 81% of patients who received an mRNA vaccine booster. There was a new humoral and/or cellular response in 9 of 11 patients (82%), and most patients with peripheral B cells (12 of 18 patients; 67%) achieved seroconversion.

“Our data show that a cellular and/or humoral immune response can be achieved on a third COVID-19 vaccination in most of the patients who initially developed neither a humoral nor a cellular immune response,” the researchers concluded. “The efficacy data together with the safety data seen in our trial provide a favorable risk/benefit ratio and support the implementation of a third vaccination for nonseroconverted high-risk autoimmune disease patients treated with B-cell–depleting agents.”

Dr. Spiera said booster doses are an important part of the equation, and “it is important to consider factors that would be associated with a greater likelihood of achieving a serologic response, particularly in those patients who did not demonstrate a serologic response to the initial vaccines series.

“Preliminary data shows that the beginnings of B-cell reconstitution is also associated with a positive serologic response following a booster of the COVID-19 vaccine,” he said.

The authors of the cited studies reported numerous relevant financial disclosures. Dr. Spiera and Dr. Jyssum reported no relevant financial disclosures.

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

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

Courtesy DKMS.org

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

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

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

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

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

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

World’s largest registry

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

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

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

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

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

Global partners

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

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

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

Pandemic affects donations

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

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

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

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

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

Workforce and clinical problems

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

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

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

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

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

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

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

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

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

‘Every patient saved’

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

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

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

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

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

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

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

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

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

Courtesy DKMS.org

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

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

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

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

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

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

World’s largest registry

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

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

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

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

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

Global partners

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

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

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

Pandemic affects donations

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

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

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

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

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

Workforce and clinical problems

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

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

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

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

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

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

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

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

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

‘Every patient saved’

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

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

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

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

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

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

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

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

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

Courtesy DKMS.org

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

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

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

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

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

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

World’s largest registry

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

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

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

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

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

Global partners

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

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

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

Pandemic affects donations

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

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

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

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

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

Workforce and clinical problems

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

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

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

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

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

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

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

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

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

‘Every patient saved’

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

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

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

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

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

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

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

Younger patients with two genetic subtypes of diffuse large B cell lymphoma (DLBCL) – specifically MCD and N1 – show substantial improvements in survival with the addition of ibrutinib to standard R-CHOP chemotherapy, compared with R-CHOP alone, new research shows.

The findings, published Nov. 4, 2021, in Cancer Cell, come from a subanalysis of the phase 3 Phoenix trial. They show that patients with DLBCL aged 60 and younger with either the MCD or N1 genetic subtype had 3-year event-free survival rates as high as 100% when treated with ibrutinib plus R-CHOP, whereas with R-CHOP chemotherapy alone, the survival rates were approximately half of that rate.

“A 100% 3-year event-free survival is almost unheard-of in DLBCL and speaks to the intense dependency of these subtypes to constitutive B cell receptor signaling and their vulnerability to ibrutinib,” first author Louis M. Staudt, MD, of the Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md., said in an interview.

“By contrast, in ABC DLBCL, the addition of ibrutinib to R-CHOP increased event-free survival by 12.4% to 76.9% in younger patients,” Dr. Staudt said.

ABC, along with GCB and unclassified, are among three key genetic classifications of DLBCL, which is the most common type of lymphoma. While previous studies have shown the Bruton kinase (BTK) inhibitor ibrutinib to induce very low responses among those with the GCB type, favorable responses are seen with the ABC type, of which MCD and N1 are genetic subtypes.

For the Phoenix trial, 838 previously untreated DLBCL patients of the ABC subtype were randomized to ibrutinib (560 mg per day, orally) or placebo plus R-CHOP, in a 21-day cycle for 6 or 8 cycles.

In the overall population, the study failed to achieve its primary survival endpoint of improved survival with ibrutinib. However, a subset analysis stratifying patients by age revealed significant event-free, progression-free, and overall survival benefits with ibrutinib among patients aged 60 and under, with manageable safety. Unexpectedly, this treatment was associated with a worsening of survival outcomes among patients over 60, due to toxicities.

In the new subanalysis, focusing on patients aged 60 and under, Dr. Staudt and his colleagues found that those with the MCD subtype of ABC DLBCL (n = 31) who were treated with ibrutinib had 3-year event-free survival and overall survival rates as high as 100% each, while these rates were significantly lower with R-CHOP alone (48%; P = .01, and 69.6%; P = .032, respectively).

Likewise, among younger patients with the N1 subtype (n = 13), the addition of ibrutinib was associated 3-year event-free and overall survival of 100%, while the R-CHOP alone patients had a significantly lower event-free- (50%; P = .0161) and overall survival (50%; P = .0134).

In the study in general, younger patients who were neither MCD nor N1 also showed better responses with ibrutinib versus placebo; however, the effects were not as strong as those with the MCD and N1 genetic subtypes.

Older patients over 60 showed no benefit from ibrutinib, regardless of their genetic subtype. And benefits were not observed in younger patients with BN2 DLBCL (n = 21), another ABC subtype.

The results are important – despite being secondary endpoints, Dr. Staudt emphasized.

“The automatic assumption regarding secondary endpoints is that any positive findings might have occurred by chance. In the present study, we show that this is not the case.”

“Rather, two previously defined genetic subtypes of DLBCL had an exceptional benefit from ibrutinib,” he said.

“Our study provides strong biological support for the view that the original Phoenix trial should be viewed as a positive trial for younger patients (under 60) with non-GCB DLBCL,” Dr. Staudt said.

While the responses to ibrutinib among younger ABC patients in general were not as robust as with the MCD and N1 subtypes, those improvements nevertheless suggest important benefit with the added treatment, he noted.

“Overall, MCD and N1 constitute roughly 10% of DLBCLs; however, our conclusion is that ibrutinib should be considered in younger patients with non-GCB DLBCL, which constitutes roughly 43% of all DLBCLs,” he said.

Dr. Staudt and other authors are inventors on NIH patent applications covering the LymphGen algorithm (a genetic predictor tool) and covering the use of BTK inhibitors in genetic subtypes of DLBCL. The Phoenix trial received support from Janssen Global Services.

Younger patients with two genetic subtypes of diffuse large B cell lymphoma (DLBCL) – specifically MCD and N1 – show substantial improvements in survival with the addition of ibrutinib to standard R-CHOP chemotherapy, compared with R-CHOP alone, new research shows.

The findings, published Nov. 4, 2021, in Cancer Cell, come from a subanalysis of the phase 3 Phoenix trial. They show that patients with DLBCL aged 60 and younger with either the MCD or N1 genetic subtype had 3-year event-free survival rates as high as 100% when treated with ibrutinib plus R-CHOP, whereas with R-CHOP chemotherapy alone, the survival rates were approximately half of that rate.

“A 100% 3-year event-free survival is almost unheard-of in DLBCL and speaks to the intense dependency of these subtypes to constitutive B cell receptor signaling and their vulnerability to ibrutinib,” first author Louis M. Staudt, MD, of the Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md., said in an interview.

“By contrast, in ABC DLBCL, the addition of ibrutinib to R-CHOP increased event-free survival by 12.4% to 76.9% in younger patients,” Dr. Staudt said.

ABC, along with GCB and unclassified, are among three key genetic classifications of DLBCL, which is the most common type of lymphoma. While previous studies have shown the Bruton kinase (BTK) inhibitor ibrutinib to induce very low responses among those with the GCB type, favorable responses are seen with the ABC type, of which MCD and N1 are genetic subtypes.

For the Phoenix trial, 838 previously untreated DLBCL patients of the ABC subtype were randomized to ibrutinib (560 mg per day, orally) or placebo plus R-CHOP, in a 21-day cycle for 6 or 8 cycles.

In the overall population, the study failed to achieve its primary survival endpoint of improved survival with ibrutinib. However, a subset analysis stratifying patients by age revealed significant event-free, progression-free, and overall survival benefits with ibrutinib among patients aged 60 and under, with manageable safety. Unexpectedly, this treatment was associated with a worsening of survival outcomes among patients over 60, due to toxicities.

In the new subanalysis, focusing on patients aged 60 and under, Dr. Staudt and his colleagues found that those with the MCD subtype of ABC DLBCL (n = 31) who were treated with ibrutinib had 3-year event-free survival and overall survival rates as high as 100% each, while these rates were significantly lower with R-CHOP alone (48%; P = .01, and 69.6%; P = .032, respectively).

Likewise, among younger patients with the N1 subtype (n = 13), the addition of ibrutinib was associated 3-year event-free and overall survival of 100%, while the R-CHOP alone patients had a significantly lower event-free- (50%; P = .0161) and overall survival (50%; P = .0134).

In the study in general, younger patients who were neither MCD nor N1 also showed better responses with ibrutinib versus placebo; however, the effects were not as strong as those with the MCD and N1 genetic subtypes.

Older patients over 60 showed no benefit from ibrutinib, regardless of their genetic subtype. And benefits were not observed in younger patients with BN2 DLBCL (n = 21), another ABC subtype.

The results are important – despite being secondary endpoints, Dr. Staudt emphasized.

“The automatic assumption regarding secondary endpoints is that any positive findings might have occurred by chance. In the present study, we show that this is not the case.”

“Rather, two previously defined genetic subtypes of DLBCL had an exceptional benefit from ibrutinib,” he said.

“Our study provides strong biological support for the view that the original Phoenix trial should be viewed as a positive trial for younger patients (under 60) with non-GCB DLBCL,” Dr. Staudt said.

While the responses to ibrutinib among younger ABC patients in general were not as robust as with the MCD and N1 subtypes, those improvements nevertheless suggest important benefit with the added treatment, he noted.

“Overall, MCD and N1 constitute roughly 10% of DLBCLs; however, our conclusion is that ibrutinib should be considered in younger patients with non-GCB DLBCL, which constitutes roughly 43% of all DLBCLs,” he said.

Dr. Staudt and other authors are inventors on NIH patent applications covering the LymphGen algorithm (a genetic predictor tool) and covering the use of BTK inhibitors in genetic subtypes of DLBCL. The Phoenix trial received support from Janssen Global Services.

Younger patients with two genetic subtypes of diffuse large B cell lymphoma (DLBCL) – specifically MCD and N1 – show substantial improvements in survival with the addition of ibrutinib to standard R-CHOP chemotherapy, compared with R-CHOP alone, new research shows.

The findings, published Nov. 4, 2021, in Cancer Cell, come from a subanalysis of the phase 3 Phoenix trial. They show that patients with DLBCL aged 60 and younger with either the MCD or N1 genetic subtype had 3-year event-free survival rates as high as 100% when treated with ibrutinib plus R-CHOP, whereas with R-CHOP chemotherapy alone, the survival rates were approximately half of that rate.

“A 100% 3-year event-free survival is almost unheard-of in DLBCL and speaks to the intense dependency of these subtypes to constitutive B cell receptor signaling and their vulnerability to ibrutinib,” first author Louis M. Staudt, MD, of the Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md., said in an interview.

“By contrast, in ABC DLBCL, the addition of ibrutinib to R-CHOP increased event-free survival by 12.4% to 76.9% in younger patients,” Dr. Staudt said.

ABC, along with GCB and unclassified, are among three key genetic classifications of DLBCL, which is the most common type of lymphoma. While previous studies have shown the Bruton kinase (BTK) inhibitor ibrutinib to induce very low responses among those with the GCB type, favorable responses are seen with the ABC type, of which MCD and N1 are genetic subtypes.

For the Phoenix trial, 838 previously untreated DLBCL patients of the ABC subtype were randomized to ibrutinib (560 mg per day, orally) or placebo plus R-CHOP, in a 21-day cycle for 6 or 8 cycles.

In the overall population, the study failed to achieve its primary survival endpoint of improved survival with ibrutinib. However, a subset analysis stratifying patients by age revealed significant event-free, progression-free, and overall survival benefits with ibrutinib among patients aged 60 and under, with manageable safety. Unexpectedly, this treatment was associated with a worsening of survival outcomes among patients over 60, due to toxicities.

In the new subanalysis, focusing on patients aged 60 and under, Dr. Staudt and his colleagues found that those with the MCD subtype of ABC DLBCL (n = 31) who were treated with ibrutinib had 3-year event-free survival and overall survival rates as high as 100% each, while these rates were significantly lower with R-CHOP alone (48%; P = .01, and 69.6%; P = .032, respectively).

Likewise, among younger patients with the N1 subtype (n = 13), the addition of ibrutinib was associated 3-year event-free and overall survival of 100%, while the R-CHOP alone patients had a significantly lower event-free- (50%; P = .0161) and overall survival (50%; P = .0134).

In the study in general, younger patients who were neither MCD nor N1 also showed better responses with ibrutinib versus placebo; however, the effects were not as strong as those with the MCD and N1 genetic subtypes.

Older patients over 60 showed no benefit from ibrutinib, regardless of their genetic subtype. And benefits were not observed in younger patients with BN2 DLBCL (n = 21), another ABC subtype.

The results are important – despite being secondary endpoints, Dr. Staudt emphasized.

“The automatic assumption regarding secondary endpoints is that any positive findings might have occurred by chance. In the present study, we show that this is not the case.”

“Rather, two previously defined genetic subtypes of DLBCL had an exceptional benefit from ibrutinib,” he said.

“Our study provides strong biological support for the view that the original Phoenix trial should be viewed as a positive trial for younger patients (under 60) with non-GCB DLBCL,” Dr. Staudt said.

While the responses to ibrutinib among younger ABC patients in general were not as robust as with the MCD and N1 subtypes, those improvements nevertheless suggest important benefit with the added treatment, he noted.

“Overall, MCD and N1 constitute roughly 10% of DLBCLs; however, our conclusion is that ibrutinib should be considered in younger patients with non-GCB DLBCL, which constitutes roughly 43% of all DLBCLs,” he said.

Dr. Staudt and other authors are inventors on NIH patent applications covering the LymphGen algorithm (a genetic predictor tool) and covering the use of BTK inhibitors in genetic subtypes of DLBCL. The Phoenix trial received support from Janssen Global Services.

Collaboration between specialized centers and local oncologists could improve equitable access to cellular therapies for patients with diffuse, large B-cell lymphoma (DLBCL), but other “multifaceted and personalized” strategies are also needed, a new study shows.

Fox Chase Cancer Center, Philadelphia

The findings, from a survey focused on patients’ willingness to travel for treatment, offer valuable insights on DLBCL patients’ perspectives and care needs, and on racial and sociodemographic variations among their perspectives and needs, the investigators said.
 

Treatment decision factors

They used a choice-based conjoint analysis to assess the relative value that 302 patients with DLBCL place on clinical factors, continuity of care, and travel time. Patients were asked to select treatment plans, choosing between pairs of hypothetical options that varied in travel time, follow-up arrangement, oncologist continuity, 2-year overall survival, and intensive care unit admission rate, the authors explained.

When all follow-up care in the hypothetical scenario was provided at the treatment center, plans requiring travel time of longer than 30 minutes were less attractive, Zachary A. K. Frosch, MD, and colleagues reported in the Journal of Clinical Oncology.

Importance weights, when compared with 30-minute travel time, were –0.54, –0.57, and –0.17 for 60, 90, and 120 minute travel time, they found.

However, scenarios involving shared follow-up by the treatment center and patients’ local providers mitigated the negative impact of travel on treatment plan choice, they noted (importance weights, 0.63, 0.32, and 0.26 at 60, 90, and 120-minute travel times).

Importantly, an analysis of responses based on sociodemographic factors showed that Black participants were less likely to choose plans requiring longer travel, regardless of follow-up arrangement, the authors said.

“Black patients were also less likely than White patients to choose treatment plans that offered lower continuity with their current oncologist (importance weights, 2.50 to vs. 1.09, respectively),” they wrote.

Further, when making choices that required trade-offs, treatment efficacy was a weaker driver of treatment plan preferences for Black patient than for White patients (importance weights, 0.34 vs. 0.75 per 5% point increase in overall survival, respectively).
 

Why the findings matter

“Certain cancer treatments aren’t offered everywhere. Examples of this are the bone marrow transplants and [chimeric antigen receptor T-cell] therapies used to treat patients with blood cancers such as lymphoma,” Dr. Frosch said in an interview, adding that the limited geographic availability of these treatments means that patients who need them may have to travel farther and also to establish care with a new oncologist.

“These are both things that some patients may be reluctant to do,” added Dr. Frosch, who was with the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, at the time of the study, but is now assistant professor at Fox Chase Cancer Center in Philadelphia.

“We wanted to better understand how patients think about these trade-offs,” he said. “We found that they were less likely to choose treatments requiring more travel, or treatments that required them to transfer care to a new oncologist. This was the case, even if it meant choosing a treatment that might be less effective against their cancer. But when patients were offered a chance to have half of their follow-up appointments locally, travel was less of a barrier.”

Importantly, not all participants valued each aspect of treatments equally, Dr. Frosch noted, referencing the responses of Black versus White patients.

He and his colleagues stressed that while collaborative follow-up may ease access to more distant treatments for some patients, the lesser willingness among Black participants to travel for cancer therapy – regardless of follow-up arrangement – means that attention must be paid to unintended consequences, to avoid worsening the existing disparities in access to cellular therapies.

These data represent a step toward better understanding of how patients considering whether or not to travel for specialized cancer care weigh trade-offs, he said.

“However, we need to dig deeper into the issues we uncovered in future research, he added. “Our findings suggest that collaborative follow-up between the hospitals that offer these treatments and the oncologists in patients’ own communities could improve access to specialized cancer treatments. But I also think it’s important to understand that this may not be the solution for everyone, and so multiple and individualized strategies are going to be needed.”
 

Personalized treatment strategies

The findings provide important perspective on the need to address patients’ concerns and circumstances to improve access to cellular therapies, said Ankit Kansagra, MD, the Eugene P. Frenkel, M.D. Scholar in Clinical Medicine at the University of Texas Southwestern Medical Center, Dallas.

The unique focus by Dr. Frosch and his associates on the patient perspective versus the health care system perspective underscores the need to be patient-focused, and serves as a reminder that different strategies are needed for different patients, Dr. Kansagra, who has also conducted research on access to CAR T therapies, said in an interview.

For some patients, a shared model of care is much more important than a 5% improvement in survival, he said, adding that providers shouldn’t assume that they understand a patient’s perspective.

Devising hybrid solutions that take community and individual needs into consideration would be preferable to seeking one national solution for care access, he added.

“It’s also pretty clear from this that it can be a shared model versus just an academic center or community center doing everything,” he said. “I think that’s going to be the next frontier – [determining] how we can hand over a patient, once CAR T is done, back to the community oncologist so he or she can continue following the patient and knows the survivorship plan – and keeping that model in place.”

Next steps

Further work is needed to determine the mechanisms driving the differences observed between Black and White patients in this study, the authors said, explaining that “[a]lthough the differences observed by race may reflect structural racism-driven access inequities, the relatively small subsample of Black patients and model complexity constraints limited our ability to analyze multiple factors.

“A prospective validation study to demonstrate the association of stated preferences with real-world decisions would further support our findings,” they wrote.

Dr. Frosch reported having no conflicts of interest. Dr. Kansagra is on advisory boards for Alnylam, Bristol Myers Squibb, Cota Healthcare, GSK, Janssen, Oncopeptides, and Takeda.

[email protected]

Collaboration between specialized centers and local oncologists could improve equitable access to cellular therapies for patients with diffuse, large B-cell lymphoma (DLBCL), but other “multifaceted and personalized” strategies are also needed, a new study shows.

Fox Chase Cancer Center, Philadelphia

The findings, from a survey focused on patients’ willingness to travel for treatment, offer valuable insights on DLBCL patients’ perspectives and care needs, and on racial and sociodemographic variations among their perspectives and needs, the investigators said.
 

Treatment decision factors

They used a choice-based conjoint analysis to assess the relative value that 302 patients with DLBCL place on clinical factors, continuity of care, and travel time. Patients were asked to select treatment plans, choosing between pairs of hypothetical options that varied in travel time, follow-up arrangement, oncologist continuity, 2-year overall survival, and intensive care unit admission rate, the authors explained.

When all follow-up care in the hypothetical scenario was provided at the treatment center, plans requiring travel time of longer than 30 minutes were less attractive, Zachary A. K. Frosch, MD, and colleagues reported in the Journal of Clinical Oncology.

Importance weights, when compared with 30-minute travel time, were –0.54, –0.57, and –0.17 for 60, 90, and 120 minute travel time, they found.

However, scenarios involving shared follow-up by the treatment center and patients’ local providers mitigated the negative impact of travel on treatment plan choice, they noted (importance weights, 0.63, 0.32, and 0.26 at 60, 90, and 120-minute travel times).

Importantly, an analysis of responses based on sociodemographic factors showed that Black participants were less likely to choose plans requiring longer travel, regardless of follow-up arrangement, the authors said.

“Black patients were also less likely than White patients to choose treatment plans that offered lower continuity with their current oncologist (importance weights, 2.50 to vs. 1.09, respectively),” they wrote.

Further, when making choices that required trade-offs, treatment efficacy was a weaker driver of treatment plan preferences for Black patient than for White patients (importance weights, 0.34 vs. 0.75 per 5% point increase in overall survival, respectively).
 

Why the findings matter

“Certain cancer treatments aren’t offered everywhere. Examples of this are the bone marrow transplants and [chimeric antigen receptor T-cell] therapies used to treat patients with blood cancers such as lymphoma,” Dr. Frosch said in an interview, adding that the limited geographic availability of these treatments means that patients who need them may have to travel farther and also to establish care with a new oncologist.

“These are both things that some patients may be reluctant to do,” added Dr. Frosch, who was with the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, at the time of the study, but is now assistant professor at Fox Chase Cancer Center in Philadelphia.

“We wanted to better understand how patients think about these trade-offs,” he said. “We found that they were less likely to choose treatments requiring more travel, or treatments that required them to transfer care to a new oncologist. This was the case, even if it meant choosing a treatment that might be less effective against their cancer. But when patients were offered a chance to have half of their follow-up appointments locally, travel was less of a barrier.”

Importantly, not all participants valued each aspect of treatments equally, Dr. Frosch noted, referencing the responses of Black versus White patients.

He and his colleagues stressed that while collaborative follow-up may ease access to more distant treatments for some patients, the lesser willingness among Black participants to travel for cancer therapy – regardless of follow-up arrangement – means that attention must be paid to unintended consequences, to avoid worsening the existing disparities in access to cellular therapies.

These data represent a step toward better understanding of how patients considering whether or not to travel for specialized cancer care weigh trade-offs, he said.

“However, we need to dig deeper into the issues we uncovered in future research, he added. “Our findings suggest that collaborative follow-up between the hospitals that offer these treatments and the oncologists in patients’ own communities could improve access to specialized cancer treatments. But I also think it’s important to understand that this may not be the solution for everyone, and so multiple and individualized strategies are going to be needed.”
 

Personalized treatment strategies

The findings provide important perspective on the need to address patients’ concerns and circumstances to improve access to cellular therapies, said Ankit Kansagra, MD, the Eugene P. Frenkel, M.D. Scholar in Clinical Medicine at the University of Texas Southwestern Medical Center, Dallas.

The unique focus by Dr. Frosch and his associates on the patient perspective versus the health care system perspective underscores the need to be patient-focused, and serves as a reminder that different strategies are needed for different patients, Dr. Kansagra, who has also conducted research on access to CAR T therapies, said in an interview.

For some patients, a shared model of care is much more important than a 5% improvement in survival, he said, adding that providers shouldn’t assume that they understand a patient’s perspective.

Devising hybrid solutions that take community and individual needs into consideration would be preferable to seeking one national solution for care access, he added.

“It’s also pretty clear from this that it can be a shared model versus just an academic center or community center doing everything,” he said. “I think that’s going to be the next frontier – [determining] how we can hand over a patient, once CAR T is done, back to the community oncologist so he or she can continue following the patient and knows the survivorship plan – and keeping that model in place.”

Next steps

Further work is needed to determine the mechanisms driving the differences observed between Black and White patients in this study, the authors said, explaining that “[a]lthough the differences observed by race may reflect structural racism-driven access inequities, the relatively small subsample of Black patients and model complexity constraints limited our ability to analyze multiple factors.

“A prospective validation study to demonstrate the association of stated preferences with real-world decisions would further support our findings,” they wrote.

Dr. Frosch reported having no conflicts of interest. Dr. Kansagra is on advisory boards for Alnylam, Bristol Myers Squibb, Cota Healthcare, GSK, Janssen, Oncopeptides, and Takeda.

[email protected]

Collaboration between specialized centers and local oncologists could improve equitable access to cellular therapies for patients with diffuse, large B-cell lymphoma (DLBCL), but other “multifaceted and personalized” strategies are also needed, a new study shows.

Fox Chase Cancer Center, Philadelphia

The findings, from a survey focused on patients’ willingness to travel for treatment, offer valuable insights on DLBCL patients’ perspectives and care needs, and on racial and sociodemographic variations among their perspectives and needs, the investigators said.
 

Treatment decision factors

They used a choice-based conjoint analysis to assess the relative value that 302 patients with DLBCL place on clinical factors, continuity of care, and travel time. Patients were asked to select treatment plans, choosing between pairs of hypothetical options that varied in travel time, follow-up arrangement, oncologist continuity, 2-year overall survival, and intensive care unit admission rate, the authors explained.

When all follow-up care in the hypothetical scenario was provided at the treatment center, plans requiring travel time of longer than 30 minutes were less attractive, Zachary A. K. Frosch, MD, and colleagues reported in the Journal of Clinical Oncology.

Importance weights, when compared with 30-minute travel time, were –0.54, –0.57, and –0.17 for 60, 90, and 120 minute travel time, they found.

However, scenarios involving shared follow-up by the treatment center and patients’ local providers mitigated the negative impact of travel on treatment plan choice, they noted (importance weights, 0.63, 0.32, and 0.26 at 60, 90, and 120-minute travel times).

Importantly, an analysis of responses based on sociodemographic factors showed that Black participants were less likely to choose plans requiring longer travel, regardless of follow-up arrangement, the authors said.

“Black patients were also less likely than White patients to choose treatment plans that offered lower continuity with their current oncologist (importance weights, 2.50 to vs. 1.09, respectively),” they wrote.

Further, when making choices that required trade-offs, treatment efficacy was a weaker driver of treatment plan preferences for Black patient than for White patients (importance weights, 0.34 vs. 0.75 per 5% point increase in overall survival, respectively).
 

Why the findings matter

“Certain cancer treatments aren’t offered everywhere. Examples of this are the bone marrow transplants and [chimeric antigen receptor T-cell] therapies used to treat patients with blood cancers such as lymphoma,” Dr. Frosch said in an interview, adding that the limited geographic availability of these treatments means that patients who need them may have to travel farther and also to establish care with a new oncologist.

“These are both things that some patients may be reluctant to do,” added Dr. Frosch, who was with the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, at the time of the study, but is now assistant professor at Fox Chase Cancer Center in Philadelphia.

“We wanted to better understand how patients think about these trade-offs,” he said. “We found that they were less likely to choose treatments requiring more travel, or treatments that required them to transfer care to a new oncologist. This was the case, even if it meant choosing a treatment that might be less effective against their cancer. But when patients were offered a chance to have half of their follow-up appointments locally, travel was less of a barrier.”

Importantly, not all participants valued each aspect of treatments equally, Dr. Frosch noted, referencing the responses of Black versus White patients.

He and his colleagues stressed that while collaborative follow-up may ease access to more distant treatments for some patients, the lesser willingness among Black participants to travel for cancer therapy – regardless of follow-up arrangement – means that attention must be paid to unintended consequences, to avoid worsening the existing disparities in access to cellular therapies.

These data represent a step toward better understanding of how patients considering whether or not to travel for specialized cancer care weigh trade-offs, he said.

“However, we need to dig deeper into the issues we uncovered in future research, he added. “Our findings suggest that collaborative follow-up between the hospitals that offer these treatments and the oncologists in patients’ own communities could improve access to specialized cancer treatments. But I also think it’s important to understand that this may not be the solution for everyone, and so multiple and individualized strategies are going to be needed.”
 

Personalized treatment strategies

The findings provide important perspective on the need to address patients’ concerns and circumstances to improve access to cellular therapies, said Ankit Kansagra, MD, the Eugene P. Frenkel, M.D. Scholar in Clinical Medicine at the University of Texas Southwestern Medical Center, Dallas.

The unique focus by Dr. Frosch and his associates on the patient perspective versus the health care system perspective underscores the need to be patient-focused, and serves as a reminder that different strategies are needed for different patients, Dr. Kansagra, who has also conducted research on access to CAR T therapies, said in an interview.

For some patients, a shared model of care is much more important than a 5% improvement in survival, he said, adding that providers shouldn’t assume that they understand a patient’s perspective.

Devising hybrid solutions that take community and individual needs into consideration would be preferable to seeking one national solution for care access, he added.

“It’s also pretty clear from this that it can be a shared model versus just an academic center or community center doing everything,” he said. “I think that’s going to be the next frontier – [determining] how we can hand over a patient, once CAR T is done, back to the community oncologist so he or she can continue following the patient and knows the survivorship plan – and keeping that model in place.”

Next steps

Further work is needed to determine the mechanisms driving the differences observed between Black and White patients in this study, the authors said, explaining that “[a]lthough the differences observed by race may reflect structural racism-driven access inequities, the relatively small subsample of Black patients and model complexity constraints limited our ability to analyze multiple factors.

“A prospective validation study to demonstrate the association of stated preferences with real-world decisions would further support our findings,” they wrote.

Dr. Frosch reported having no conflicts of interest. Dr. Kansagra is on advisory boards for Alnylam, Bristol Myers Squibb, Cota Healthcare, GSK, Janssen, Oncopeptides, and Takeda.

[email protected]