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Ex–hospital porter a neglected giant of cancer research
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
DKMS: Small nonprofit to world’s largest stem cell donor registry
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.
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,
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.
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,
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.
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,
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.
Pfizer offers refund if drug ‘doesn’t work’
The high cost of new cancer drugs has been the subject of many debates and discussions, but the issue remains largely unresolved.
Now, one pharmaceutical company is offering a refund if its drug “doesn’t work.”
For what it says is the first time in the industry,
“Through this pilot program, Pfizer will offer a warranty to patients and health plans -- Medicare Part D, commercial and those who pay cash -- who are prescribed Xalkori for an FDA [US Food and Drug Administration]–approved indication,” said a company spokesperson.
Although Pfizer claims that its pilot program is a first in the industry, there have been others that are similar.
In 2017, Novartis offered something similar for tisagenlecleucel (Kymriah), the CAR T-cell therapy that launched with a daunting price tag of $475,000. After receiving backlash over the cost, Novartis announced that if the drug does not work after the first month, patients pay nothing.
Italy has been using this system for several years. Pharmaceutical companies must refund money if the drug fails to work. In 2015, the state-run healthcare system collected €200 million ($220 million) in refunds.
Pfizer pledge
Crizotinib is a selective tyrosine kinase inhibitor used mainly in the treatment of metastatic non–small cell lung cancer for patients whose tumors are positive for ALK or ROS1, as detected by an FDA-approved test. This indication was approved a decade ago. Another indication, ALK-positive anaplastic large cell lymphoma, was added earlier this year.
Details of the Pfizer Pledge are posted on Pfizer’s website. Eligible patients are those for whom crizotinib is discontinued before the fourth 30-day supply is dispensed by the patient’s pharmacy.
“The warranty will reimburse an amount equal to the cost paid for the medicine,” the spokesperson added. “The insurance-backed warranty pilot program will be insured and managed by AIG.”
This program is only available for patients who reside in the United States.
If use of crizotinib is discontinued and documentation of ineffectiveness is provided, Pfizer will refund the out-of-pocket amount that was paid for up to the first three bottles (30-day supply) of crizotinib, up to a maximum of $19,144 for each month’s supply, or a total of $57,432. Pfizer will also refund the cost that was paid by Medicare or a commercial insurer.
“Also, we have made sure to develop a program that also allows for Medicare patients to be eligible, since they are exempt from copay cards and at risk for significant financial burden when starting an oncology treatment,” said the spokesperson.
The pilot program is available to patients who began taking crizotinib from June 1, 2021, through December 31, 2021.
So far, Pfizer is offering this warranty only for crizotinib, but that may change in the future.
“Once the pilot is complete, we will assess learnings and consider whether to build a more robust, scalable program capable of supporting multiple products,” the Pfizer spokesperson commented.
Previous scheme ended in court
Pfizer had previously tried a different approach to reducing drug costs: it had attempted to offer copay support programs to Medicare patients who were prescribed its cardiac drug tafamidis (Vyndaqe, Vyndamax).
Tafamidis, launched in 2019, is used for patients with transthyretin amyloid cardiomyopathy. For those patients, it has been shown to reduce all-cause mortality and cardiovascular hospitalizations. It costs about $225,000 a year and has been described as the most expensive cardiovascular drug in the United States.
Earlier this month, a court dismissed Pfizer’s challenge to an anti-kickback law that prevented the company from offering copay support programs to Medicare patients.
The judge ruled that Pfizer’s plan to offer direct payments to patients violated a federal ban on “knowingly or willfully” providing financial support to induce drug purchases, even in the absence of corrupt intent.
Pharmaceutical manufacturers are forbidden from subsidizing copayments for Medicare beneficiaries but are allowed to donate to independent nonprofit organizations that offer copay assistance. Pfizer sued the U.S. Department of Health and Human Services in June 2020 to get a court ruling that their proposed programs were legal.
The new pledge program for crizotinib operates from a different premise, the Pfizer spokesperson commented.
A version of this article first appeared on Medscape.com.
The high cost of new cancer drugs has been the subject of many debates and discussions, but the issue remains largely unresolved.
Now, one pharmaceutical company is offering a refund if its drug “doesn’t work.”
For what it says is the first time in the industry,
“Through this pilot program, Pfizer will offer a warranty to patients and health plans -- Medicare Part D, commercial and those who pay cash -- who are prescribed Xalkori for an FDA [US Food and Drug Administration]–approved indication,” said a company spokesperson.
Although Pfizer claims that its pilot program is a first in the industry, there have been others that are similar.
In 2017, Novartis offered something similar for tisagenlecleucel (Kymriah), the CAR T-cell therapy that launched with a daunting price tag of $475,000. After receiving backlash over the cost, Novartis announced that if the drug does not work after the first month, patients pay nothing.
Italy has been using this system for several years. Pharmaceutical companies must refund money if the drug fails to work. In 2015, the state-run healthcare system collected €200 million ($220 million) in refunds.
Pfizer pledge
Crizotinib is a selective tyrosine kinase inhibitor used mainly in the treatment of metastatic non–small cell lung cancer for patients whose tumors are positive for ALK or ROS1, as detected by an FDA-approved test. This indication was approved a decade ago. Another indication, ALK-positive anaplastic large cell lymphoma, was added earlier this year.
Details of the Pfizer Pledge are posted on Pfizer’s website. Eligible patients are those for whom crizotinib is discontinued before the fourth 30-day supply is dispensed by the patient’s pharmacy.
“The warranty will reimburse an amount equal to the cost paid for the medicine,” the spokesperson added. “The insurance-backed warranty pilot program will be insured and managed by AIG.”
This program is only available for patients who reside in the United States.
If use of crizotinib is discontinued and documentation of ineffectiveness is provided, Pfizer will refund the out-of-pocket amount that was paid for up to the first three bottles (30-day supply) of crizotinib, up to a maximum of $19,144 for each month’s supply, or a total of $57,432. Pfizer will also refund the cost that was paid by Medicare or a commercial insurer.
“Also, we have made sure to develop a program that also allows for Medicare patients to be eligible, since they are exempt from copay cards and at risk for significant financial burden when starting an oncology treatment,” said the spokesperson.
The pilot program is available to patients who began taking crizotinib from June 1, 2021, through December 31, 2021.
So far, Pfizer is offering this warranty only for crizotinib, but that may change in the future.
“Once the pilot is complete, we will assess learnings and consider whether to build a more robust, scalable program capable of supporting multiple products,” the Pfizer spokesperson commented.
Previous scheme ended in court
Pfizer had previously tried a different approach to reducing drug costs: it had attempted to offer copay support programs to Medicare patients who were prescribed its cardiac drug tafamidis (Vyndaqe, Vyndamax).
Tafamidis, launched in 2019, is used for patients with transthyretin amyloid cardiomyopathy. For those patients, it has been shown to reduce all-cause mortality and cardiovascular hospitalizations. It costs about $225,000 a year and has been described as the most expensive cardiovascular drug in the United States.
Earlier this month, a court dismissed Pfizer’s challenge to an anti-kickback law that prevented the company from offering copay support programs to Medicare patients.
The judge ruled that Pfizer’s plan to offer direct payments to patients violated a federal ban on “knowingly or willfully” providing financial support to induce drug purchases, even in the absence of corrupt intent.
Pharmaceutical manufacturers are forbidden from subsidizing copayments for Medicare beneficiaries but are allowed to donate to independent nonprofit organizations that offer copay assistance. Pfizer sued the U.S. Department of Health and Human Services in June 2020 to get a court ruling that their proposed programs were legal.
The new pledge program for crizotinib operates from a different premise, the Pfizer spokesperson commented.
A version of this article first appeared on Medscape.com.
The high cost of new cancer drugs has been the subject of many debates and discussions, but the issue remains largely unresolved.
Now, one pharmaceutical company is offering a refund if its drug “doesn’t work.”
For what it says is the first time in the industry,
“Through this pilot program, Pfizer will offer a warranty to patients and health plans -- Medicare Part D, commercial and those who pay cash -- who are prescribed Xalkori for an FDA [US Food and Drug Administration]–approved indication,” said a company spokesperson.
Although Pfizer claims that its pilot program is a first in the industry, there have been others that are similar.
In 2017, Novartis offered something similar for tisagenlecleucel (Kymriah), the CAR T-cell therapy that launched with a daunting price tag of $475,000. After receiving backlash over the cost, Novartis announced that if the drug does not work after the first month, patients pay nothing.
Italy has been using this system for several years. Pharmaceutical companies must refund money if the drug fails to work. In 2015, the state-run healthcare system collected €200 million ($220 million) in refunds.
Pfizer pledge
Crizotinib is a selective tyrosine kinase inhibitor used mainly in the treatment of metastatic non–small cell lung cancer for patients whose tumors are positive for ALK or ROS1, as detected by an FDA-approved test. This indication was approved a decade ago. Another indication, ALK-positive anaplastic large cell lymphoma, was added earlier this year.
Details of the Pfizer Pledge are posted on Pfizer’s website. Eligible patients are those for whom crizotinib is discontinued before the fourth 30-day supply is dispensed by the patient’s pharmacy.
“The warranty will reimburse an amount equal to the cost paid for the medicine,” the spokesperson added. “The insurance-backed warranty pilot program will be insured and managed by AIG.”
This program is only available for patients who reside in the United States.
If use of crizotinib is discontinued and documentation of ineffectiveness is provided, Pfizer will refund the out-of-pocket amount that was paid for up to the first three bottles (30-day supply) of crizotinib, up to a maximum of $19,144 for each month’s supply, or a total of $57,432. Pfizer will also refund the cost that was paid by Medicare or a commercial insurer.
“Also, we have made sure to develop a program that also allows for Medicare patients to be eligible, since they are exempt from copay cards and at risk for significant financial burden when starting an oncology treatment,” said the spokesperson.
The pilot program is available to patients who began taking crizotinib from June 1, 2021, through December 31, 2021.
So far, Pfizer is offering this warranty only for crizotinib, but that may change in the future.
“Once the pilot is complete, we will assess learnings and consider whether to build a more robust, scalable program capable of supporting multiple products,” the Pfizer spokesperson commented.
Previous scheme ended in court
Pfizer had previously tried a different approach to reducing drug costs: it had attempted to offer copay support programs to Medicare patients who were prescribed its cardiac drug tafamidis (Vyndaqe, Vyndamax).
Tafamidis, launched in 2019, is used for patients with transthyretin amyloid cardiomyopathy. For those patients, it has been shown to reduce all-cause mortality and cardiovascular hospitalizations. It costs about $225,000 a year and has been described as the most expensive cardiovascular drug in the United States.
Earlier this month, a court dismissed Pfizer’s challenge to an anti-kickback law that prevented the company from offering copay support programs to Medicare patients.
The judge ruled that Pfizer’s plan to offer direct payments to patients violated a federal ban on “knowingly or willfully” providing financial support to induce drug purchases, even in the absence of corrupt intent.
Pharmaceutical manufacturers are forbidden from subsidizing copayments for Medicare beneficiaries but are allowed to donate to independent nonprofit organizations that offer copay assistance. Pfizer sued the U.S. Department of Health and Human Services in June 2020 to get a court ruling that their proposed programs were legal.
The new pledge program for crizotinib operates from a different premise, the Pfizer spokesperson commented.
A version of this article first appeared on Medscape.com.
Blacks and Hispanics have higher inpatient use for mycosis fungoides
according to an analysis of the 2012-2017 National Inpatient Sample (NIS).
The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.
Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.
Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.
Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).
Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).
In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.
The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.
Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.
according to an analysis of the 2012-2017 National Inpatient Sample (NIS).
The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.
Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.
Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.
Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).
Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).
In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.
The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.
Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.
according to an analysis of the 2012-2017 National Inpatient Sample (NIS).
The findings are consistent with prior studies implicating earlier and more severe disease in Black and Hispanic patients, and reinforce the importance of accurate diagnosis and early treatment.
Dermatologists should maintain “a higher index of suspicion for MF in patients with skin of color, as early diagnosis may help mitigate the downstream costs of management,” Justin Choi, BA, a medical student at the University of Illinois at Chicago, said at the annual Skin of Color Society symposium.
Mr. Choi and coinvestigators, led by Shawn Kwatra, MD, of Johns Hopkins University, Baltimore, identified hospital admissions for MF in the NIS for 10,790 White patients, 4,020 Black patients, and 1,615 Hispanic patients over the 5-year period. The inpatient prevalence of MF – the most common variant of primary cutaneous T-cell lymphoma – was highest in these groups.
Black and Hispanic patients who were hospitalized for MF were significantly younger than White patients, with a mean age of 51.7 years and 48.5 years, respectively, compared with 59.9 years (P < .001 in each case). They also had longer lengths of stay: 8.34 days on average for Black patients and 8.88 for Hispanic patients, compared with 6.66 days for White patients (P < .001 and P = .001, respectively).
Hispanic patients accrued the highest costs of care (a mean of $107,242 vs. $64,049, P =.003) and underwent more procedures (a mean of 2.43 vs. 1.93, P = .004) than White patients. Black patients similarly had higher costs associated with their hospital stay (a mean of $75,053 vs. $64,049, P =.042).
In a multivariate linear regression adjusted for age, sex and insurance type, Black race remained significantly associated with a longer LOS than White race, and Hispanic ethnicity with a longer LOS, increased costs, and more procedures than White race.
The NIS is a publicly available, all-payer inpatient care database developed for the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project.
Mr. Choi is a dermatology research fellow working under the guidance of Dr. Kwatra.
FROM SOC SOCIETY 2021
Don’t delay: Cancer patients need both doses of COVID vaccine
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Why a mycosis fungoides diagnosis takes so long
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
FROM THE CUTANEOUS MALIGNANCIES FORUM
Phase 1 study shows feasibility, safety, efficacy of STAR T cells for ALL
A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
Remission can be improved
While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.
The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.
The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m2 per day) and cyclophosphamide (250mg/m2 per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
100% MRD negative
On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.
Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.
Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 104 copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
STAR holds promise
Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.
Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”
Dr. Lu reported that she had no relevant disclosures.
SOURCE: Lu P et al. ASH 2020, Abstract 270.
A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
Remission can be improved
While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.
The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.
The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m2 per day) and cyclophosphamide (250mg/m2 per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
100% MRD negative
On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.
Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.
Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 104 copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
STAR holds promise
Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.
Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”
Dr. Lu reported that she had no relevant disclosures.
SOURCE: Lu P et al. ASH 2020, Abstract 270.
A phase 1 first-in-human study demonstrated synthetic T-cell receptor and antigen receptor (STAR) technical feasibility, clinical safety and efficacy in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), according to senior study author Peihua Lu, MD, Beijing Lu Daopei Institute of Hematology, Beijing, China. STAR T cells were found to be superior to conventional chimeric antigen receptor (CAR) T cells with respect to signaling capacity, cytokine production and antitumor potency in an animal model study, according to Dr. Lu’s presentation at the annual meeting of the American Society of Hematology.
Remission can be improved
While CAR T-cell therapy has demonstrated high response rates in patients with B-cell malignancies, remission durability and safety can be improved, Dr Lu said. Her team developed STAR, a novel double-chain chimeric receptor consisting of two protein modules, each containing an antibody light or heavy chain variable region, the T cell receptor (TCR) alpha or beta chain constant region fused to the OX-40 costimulatory domain. The 2 modules are linked by a self-cleaving Furin-p2A sequence that allows the modules to be proteolytically separated and reconstituted. In preclinical in vitro research, STAR-T-cells showed a much faster and stronger cell activation, compared with CAR T cells and superior target cell–killing ability, and higher levels of interferon-y after coculture with the CD19+ Raji cell. In a murine in vivo study, STAR-T cells had higher antileukemia activity, compared with CAR-T cells, and significantly inhibited tumor cell growth, Dr. Lu stated. All animals were sustainably tumor free 5 days after STAR-T cell injection.
The first-in-human study included 18 CD19+ relapsed/refractory B-cell ALL (median age 22.5 years) patients, with a median bone marrow blast level pre–CAR T of 15.3%.
The manufacture success rate was 100% and took about 9 days (7-13). Transduction efficacy was 57.4% (41.0%-78.2%). Subjects received a conditioning regimen of intravenous fludarabine (25mg/m2 per day) and cyclophosphamide (250mg/m2 per day) for 3 days followed by a single STAR T-cell infusion. Patients were given the option, after they achieved complete remission (CR), of proceeding to consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT).
100% MRD negative
On day 14 following transplant, 18/18 had achieved minimal residual disease–negative complete response/CRi (with incomplete hematologic recovery). One patient relapsed after allogeneic transplant, becoming minimal residual disease positive on day 28. After a median follow-up of 105 days, 11/18 bridged into allo-HSCT without relapse. Among the seven patients who did not undergo allo-HSCT, one relapsed on day 58 and died on day 63. The patient had CNS leukemia and 87% bone marrow blasts before receiving STAR T. The others, Dr. Lu said, remain in CR.
Mild cytokine release syndrome (CRS) occurred in only 10 patients (55.6%), with grade 1 CRS in 8 patients and grade 2 in 2 patients. Grade 3 neurotoxicity occurred in two patients.
Reporting cellular kinetics of STAR T cells in peripheral blood by fluorescence-activated cell sorting (FACS)/quantitative PCR showed the highest STAR-T proliferation ratio (STAR/CD3) of 88.1%. Median peak level was 4.9 x 104 copies number/mcg genomic DNA. The peak time was day 8.5 and the longest detection time was 6 months after STAR T infusion (STAR T ratio, 0.46%-1.85%). High in vivo proliferation and persistence was observed regardless of infusion dose.
STAR holds promise
Dr. Lu concluded: “The phase 1 first-in-human study demonstrated technical feasibility, clinical safety and efficacy of STAR T in treating CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia.” She noted also that long-term observation of these patients and studies of larger patient cohorts are warranted to evaluate a beneficial advantage of the STAR T over the conventional CAR T product.
Asked about future directions in the discussion period, Dr. Lu responded that “this product holds great promise, No. 1 because it is actually between a T-cell receptor and a CAR T, and so clearly has fewer side effects. It potentially can recognize and target the tumor intracellular antigen better than a conventional CAR T. It is easier to construct – and holds great promise for treating solid tumors.”
Dr. Lu reported that she had no relevant disclosures.
SOURCE: Lu P et al. ASH 2020, Abstract 270.
FROM ASH 2020
Duvelisib response rate encouraging in phase 2 PRIMO trial of patients with r/r PTCL
Duvelisib is demonstrating encouraging activity and manageable toxicities among patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) in a phase 2 trial, an investigator said.
The overall response rate in the dose-optimization phase of the PRIMO trial was more than 60% among patients receiving 75 mg of duvelisib twice daily, with a median duration of response exceeding 12 months, said investigator Barbara Pro, MD, of Northwestern University, Chicago.
In the ongoing dose-expansion phase, in which patients start on 75 mg twice daily and then transition to a lower dose, the ORR is over 50%, including complete responses (CRs) in about one-third of patients, Dr. Pro reported at the annual meeting of the American Society of Hematology.
Most previously approved treatments for relapsed/refractory PTCL are associated with ORRs of less than 30%, low rates of CR, and median progression-free survival of less than 4 months, Dr. Pro said in her presentation.
There have been no unexpected toxicities in the dose-expansion phase, and the adverse event profile is consistent with what has been observed previously for this oral phosphatidylinositol 3-kinase (PI3K) inhibitor, according to Dr. Pro.
Based on results to date, Dr. Pro said she and coinvestigators are hopeful that duvelisib will have a place in the treatment armamentarium for relapsed/refractory PTCL in the future.
“This is one of the most effective agents in T-cell lymphoma, and hopefully will be approved and available for treatment soon,” she said in remarks following her presentation of PRIMO study data.
“The next question would be how to try to move this agent up front,” she added. “We’ll have to try to see what could be the possible combinations and evaluate the possible overlapping toxicity with alternative treatments.”
The PRIMO trial provides “very exciting numbers” that include roughly half of relapsed/refractory PTCL patients are responding to the oral therapy, said Andrei R. Shustov, MD, professor of medicine in the division of hematology at the University of Washington, Seattle.
Perhaps more importantly, at least half of those responses have been CRs, Dr. Shustov noted in an interview: “We haven’t seen this yet in T-cell lymphomas, short of brentuximab vedotin targeting CD30,” he said, referring to the 2018 Food and Drug Administration approval of brentuximab vedotin for previously untreated CD30-expressing PTCL.
If duvelisib is approved, it would be the first oral agent with an indication for relapsed/refractory PTCL, which could have important implications for patient quality of life, Dr. Shustov added.
“The fact that you can take a pill at home, and don’t have to be in clinic once a week, or have the port device, or be infused every week would be an incredible change in quality of life,” he said, “and this is really amplified in the older population where quality of life is so important.”
Duvelisib was FDA approved in 2018, at a dose of 25 mg orally twice daily, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma, following at least two previous treatments.
In relapsed/refractory PTCL, results of a phase 1 study previously published in Blood showed that duvelisib demonstrated an ORR of 50%, or 8 out of 16 patients treated with 25 or 75 mg twice daily continuously.
The phase 2 study described by Dr. Pro at this year’s ASH meeting included 33 patients with relapsed/refractory PTCL treated with duvelisib 25 mg or 75 mg twice daily as part of a dose-optimization phase, and 25 patients treated in an expansion phase at 75 mg twice daily for two 28-day cycles, followed by treatment at 25 mg twice daily.
Starting at the higher dose of 75 mg twice daily is intended to achieve rapid tumor control, while switching to the lower 25-mg twice-daily dose is to maintain long-term control of the disease while mitigating potential for later toxicities, according to the published abstract for the PRIMO trial.
Results of the dose-optimization phase included an ORR by independent review committee of 62% for patients treated at the 75-mg twice-daily dose, and 40% for those treated at 25 mg twice daily. The median duration of response in the 75-mg twice-daily group was 12.2 months, which Dr. Pro said was significantly higher than what was observed for the lower dose.
In the ongoing dose-expansion phase, the ORR by investigator was 52% (13 of 25 patients), with a CR rate of 36% (9 of 25 patients). The reported data show that with a median duration of follow-up of 3.78 months, the median duration of response thus far is 4.1 months.
The most common grade 3 or higher adverse events were increases in ALT and AST, seen in 24% and 20% of patients, respectively. The most common grade 3 or greater hematologic toxicity was decreased lymphocyte count, seen in 16%.
Three serious treatment-emergent adverse events thought to be related to duvelisib occurred in two patients, including grade 5 pneumonitis in one patient, and skin lesion plus posttransplant lymphoproliferative disorder in the other patient, according to Dr. Pro. Serious treatment-emergent adverse events leading to duvelisib discontinuation included increased ALT/AST in 2 patients and pneumonitis in one patient.
Grade 1-2 adverse events reported at ASH included hypertension, nausea, anemia, fatigue, diarrhea, constipation and pyrexia, among others.
Enrollment in the dose-expansion phase of PRIMO is ongoing and should be complete in February, according to Dr. Pro.
Support for the study came from Verastem Oncology and Secura Bio. Dr. Pro reported research funding from Verastem Oncology, Takeda, and other pharmaceutical companies and honoraria from Takeda and Seattle Genetics.
SOURCE: Pro B et al. ASH 2020, Abstract 44.
Duvelisib is demonstrating encouraging activity and manageable toxicities among patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) in a phase 2 trial, an investigator said.
The overall response rate in the dose-optimization phase of the PRIMO trial was more than 60% among patients receiving 75 mg of duvelisib twice daily, with a median duration of response exceeding 12 months, said investigator Barbara Pro, MD, of Northwestern University, Chicago.
In the ongoing dose-expansion phase, in which patients start on 75 mg twice daily and then transition to a lower dose, the ORR is over 50%, including complete responses (CRs) in about one-third of patients, Dr. Pro reported at the annual meeting of the American Society of Hematology.
Most previously approved treatments for relapsed/refractory PTCL are associated with ORRs of less than 30%, low rates of CR, and median progression-free survival of less than 4 months, Dr. Pro said in her presentation.
There have been no unexpected toxicities in the dose-expansion phase, and the adverse event profile is consistent with what has been observed previously for this oral phosphatidylinositol 3-kinase (PI3K) inhibitor, according to Dr. Pro.
Based on results to date, Dr. Pro said she and coinvestigators are hopeful that duvelisib will have a place in the treatment armamentarium for relapsed/refractory PTCL in the future.
“This is one of the most effective agents in T-cell lymphoma, and hopefully will be approved and available for treatment soon,” she said in remarks following her presentation of PRIMO study data.
“The next question would be how to try to move this agent up front,” she added. “We’ll have to try to see what could be the possible combinations and evaluate the possible overlapping toxicity with alternative treatments.”
The PRIMO trial provides “very exciting numbers” that include roughly half of relapsed/refractory PTCL patients are responding to the oral therapy, said Andrei R. Shustov, MD, professor of medicine in the division of hematology at the University of Washington, Seattle.
Perhaps more importantly, at least half of those responses have been CRs, Dr. Shustov noted in an interview: “We haven’t seen this yet in T-cell lymphomas, short of brentuximab vedotin targeting CD30,” he said, referring to the 2018 Food and Drug Administration approval of brentuximab vedotin for previously untreated CD30-expressing PTCL.
If duvelisib is approved, it would be the first oral agent with an indication for relapsed/refractory PTCL, which could have important implications for patient quality of life, Dr. Shustov added.
“The fact that you can take a pill at home, and don’t have to be in clinic once a week, or have the port device, or be infused every week would be an incredible change in quality of life,” he said, “and this is really amplified in the older population where quality of life is so important.”
Duvelisib was FDA approved in 2018, at a dose of 25 mg orally twice daily, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma, following at least two previous treatments.
In relapsed/refractory PTCL, results of a phase 1 study previously published in Blood showed that duvelisib demonstrated an ORR of 50%, or 8 out of 16 patients treated with 25 or 75 mg twice daily continuously.
The phase 2 study described by Dr. Pro at this year’s ASH meeting included 33 patients with relapsed/refractory PTCL treated with duvelisib 25 mg or 75 mg twice daily as part of a dose-optimization phase, and 25 patients treated in an expansion phase at 75 mg twice daily for two 28-day cycles, followed by treatment at 25 mg twice daily.
Starting at the higher dose of 75 mg twice daily is intended to achieve rapid tumor control, while switching to the lower 25-mg twice-daily dose is to maintain long-term control of the disease while mitigating potential for later toxicities, according to the published abstract for the PRIMO trial.
Results of the dose-optimization phase included an ORR by independent review committee of 62% for patients treated at the 75-mg twice-daily dose, and 40% for those treated at 25 mg twice daily. The median duration of response in the 75-mg twice-daily group was 12.2 months, which Dr. Pro said was significantly higher than what was observed for the lower dose.
In the ongoing dose-expansion phase, the ORR by investigator was 52% (13 of 25 patients), with a CR rate of 36% (9 of 25 patients). The reported data show that with a median duration of follow-up of 3.78 months, the median duration of response thus far is 4.1 months.
The most common grade 3 or higher adverse events were increases in ALT and AST, seen in 24% and 20% of patients, respectively. The most common grade 3 or greater hematologic toxicity was decreased lymphocyte count, seen in 16%.
Three serious treatment-emergent adverse events thought to be related to duvelisib occurred in two patients, including grade 5 pneumonitis in one patient, and skin lesion plus posttransplant lymphoproliferative disorder in the other patient, according to Dr. Pro. Serious treatment-emergent adverse events leading to duvelisib discontinuation included increased ALT/AST in 2 patients and pneumonitis in one patient.
Grade 1-2 adverse events reported at ASH included hypertension, nausea, anemia, fatigue, diarrhea, constipation and pyrexia, among others.
Enrollment in the dose-expansion phase of PRIMO is ongoing and should be complete in February, according to Dr. Pro.
Support for the study came from Verastem Oncology and Secura Bio. Dr. Pro reported research funding from Verastem Oncology, Takeda, and other pharmaceutical companies and honoraria from Takeda and Seattle Genetics.
SOURCE: Pro B et al. ASH 2020, Abstract 44.
Duvelisib is demonstrating encouraging activity and manageable toxicities among patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) in a phase 2 trial, an investigator said.
The overall response rate in the dose-optimization phase of the PRIMO trial was more than 60% among patients receiving 75 mg of duvelisib twice daily, with a median duration of response exceeding 12 months, said investigator Barbara Pro, MD, of Northwestern University, Chicago.
In the ongoing dose-expansion phase, in which patients start on 75 mg twice daily and then transition to a lower dose, the ORR is over 50%, including complete responses (CRs) in about one-third of patients, Dr. Pro reported at the annual meeting of the American Society of Hematology.
Most previously approved treatments for relapsed/refractory PTCL are associated with ORRs of less than 30%, low rates of CR, and median progression-free survival of less than 4 months, Dr. Pro said in her presentation.
There have been no unexpected toxicities in the dose-expansion phase, and the adverse event profile is consistent with what has been observed previously for this oral phosphatidylinositol 3-kinase (PI3K) inhibitor, according to Dr. Pro.
Based on results to date, Dr. Pro said she and coinvestigators are hopeful that duvelisib will have a place in the treatment armamentarium for relapsed/refractory PTCL in the future.
“This is one of the most effective agents in T-cell lymphoma, and hopefully will be approved and available for treatment soon,” she said in remarks following her presentation of PRIMO study data.
“The next question would be how to try to move this agent up front,” she added. “We’ll have to try to see what could be the possible combinations and evaluate the possible overlapping toxicity with alternative treatments.”
The PRIMO trial provides “very exciting numbers” that include roughly half of relapsed/refractory PTCL patients are responding to the oral therapy, said Andrei R. Shustov, MD, professor of medicine in the division of hematology at the University of Washington, Seattle.
Perhaps more importantly, at least half of those responses have been CRs, Dr. Shustov noted in an interview: “We haven’t seen this yet in T-cell lymphomas, short of brentuximab vedotin targeting CD30,” he said, referring to the 2018 Food and Drug Administration approval of brentuximab vedotin for previously untreated CD30-expressing PTCL.
If duvelisib is approved, it would be the first oral agent with an indication for relapsed/refractory PTCL, which could have important implications for patient quality of life, Dr. Shustov added.
“The fact that you can take a pill at home, and don’t have to be in clinic once a week, or have the port device, or be infused every week would be an incredible change in quality of life,” he said, “and this is really amplified in the older population where quality of life is so important.”
Duvelisib was FDA approved in 2018, at a dose of 25 mg orally twice daily, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular lymphoma, following at least two previous treatments.
In relapsed/refractory PTCL, results of a phase 1 study previously published in Blood showed that duvelisib demonstrated an ORR of 50%, or 8 out of 16 patients treated with 25 or 75 mg twice daily continuously.
The phase 2 study described by Dr. Pro at this year’s ASH meeting included 33 patients with relapsed/refractory PTCL treated with duvelisib 25 mg or 75 mg twice daily as part of a dose-optimization phase, and 25 patients treated in an expansion phase at 75 mg twice daily for two 28-day cycles, followed by treatment at 25 mg twice daily.
Starting at the higher dose of 75 mg twice daily is intended to achieve rapid tumor control, while switching to the lower 25-mg twice-daily dose is to maintain long-term control of the disease while mitigating potential for later toxicities, according to the published abstract for the PRIMO trial.
Results of the dose-optimization phase included an ORR by independent review committee of 62% for patients treated at the 75-mg twice-daily dose, and 40% for those treated at 25 mg twice daily. The median duration of response in the 75-mg twice-daily group was 12.2 months, which Dr. Pro said was significantly higher than what was observed for the lower dose.
In the ongoing dose-expansion phase, the ORR by investigator was 52% (13 of 25 patients), with a CR rate of 36% (9 of 25 patients). The reported data show that with a median duration of follow-up of 3.78 months, the median duration of response thus far is 4.1 months.
The most common grade 3 or higher adverse events were increases in ALT and AST, seen in 24% and 20% of patients, respectively. The most common grade 3 or greater hematologic toxicity was decreased lymphocyte count, seen in 16%.
Three serious treatment-emergent adverse events thought to be related to duvelisib occurred in two patients, including grade 5 pneumonitis in one patient, and skin lesion plus posttransplant lymphoproliferative disorder in the other patient, according to Dr. Pro. Serious treatment-emergent adverse events leading to duvelisib discontinuation included increased ALT/AST in 2 patients and pneumonitis in one patient.
Grade 1-2 adverse events reported at ASH included hypertension, nausea, anemia, fatigue, diarrhea, constipation and pyrexia, among others.
Enrollment in the dose-expansion phase of PRIMO is ongoing and should be complete in February, according to Dr. Pro.
Support for the study came from Verastem Oncology and Secura Bio. Dr. Pro reported research funding from Verastem Oncology, Takeda, and other pharmaceutical companies and honoraria from Takeda and Seattle Genetics.
SOURCE: Pro B et al. ASH 2020, Abstract 44.
FROM ASH 2020
Allogeneic transplant leads to durable remissions in T-cell lymphomas
, results of a large retrospective observational study suggest.
Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.
“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.
“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.
Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.
Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.
Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.
Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.
“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.
“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.
The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.
At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.
Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.
Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.
There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.
Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.
Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.
While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.
“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.
“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”
Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.
Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.
, results of a large retrospective observational study suggest.
Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.
“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.
“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.
Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.
Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.
Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.
Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.
“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.
“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.
The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.
At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.
Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.
Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.
There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.
Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.
Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.
While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.
“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.
“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”
Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.
Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.
, results of a large retrospective observational study suggest.
Five-year progression-free survival (PFS) approached 40% and 5-year overall survival (OS) was over 50% in the study, which according to an investigator is the largest-ever reported patient series of allogeneic stem cell transplantation in T-cell lymphomas.
“We believe that eligible patients with relapsed/refractory T-cell lymphomas should be considered for consultation for allogeneic transplant by an expert clinician,” said investigator Neha Mehta-Shah, MD, of Washington University in St. Louis.
“These decisions should occur on a patient by patient level – but it’s important to consider this,” Dr. Mehta-Shah said at the annual meeting of the American Society of Hematology, held virtually this year.
Notably, patients with cutaneous T-cell lymphoma (CTCL) had a higher rate of relapse yet similar overall survival (OS) compared to patients with common peripheral T-cell lymphoma (PTCL) subtypes, according to Dr. Mehta-Shah.
Among PTCL subtypes, there was a trend toward improved PFS and OS for angioimmunoblastic T-cell lymphoma (AITL), compared with PTCL not otherwise specified (PTCL-NOS) and anaplastic large-cell lymphoma (ALCL), she added.
Catherine M. Diefenbach, MD, director of the clinical lymphoma program at NYU Langone’s Perlmutter Cancer Center, said the results of this retrospective study need to considered in light of the treatment-related risks associated with allogeneic transplantation.
Treatment-related mortality in the study ranged from about 8% to 24%, depending on the donor type, while acute and chronic graft-versus-host-disease (GvHD) was seen in more than 40% of patients, the reported data show.
“If I have a relapsed patient with AITL, I would look to this data and say that patients with AITL appear in a retrospective study to have a strong benefit,” Dr. Diefenbach said in an interview.
“For the other patients, you would describe both potential benefits and also discuss the treatment-associated risks – both the chronic GvHD and transplant-related mortality – and you’d have to balance the risk with the benefits for each individual case,” Dr. Diefenbach added.
The retrospective analysis by Dr. Mehta-Shah and colleagues included 508 consecutive T-cell lymphoma patients receiving allogeneic transplants at 12 academic centers between 2000 and 2019. The most common subtypes were PTCL-NOS in 26%, AITL in 16%, CTCL in 13%, and hepatosplenic T-cell lymphoma (HSTCL) in 7%. About 40% had a matched related donor (MRD) and 39% had a matched unrelated donor (MUD). The conditioning regimen was myeloablative in about a third of patients and nonmyeloablative in two-thirds.
At 5 years, PFS was 39.4% and OS was 50.8% for the overall study cohort, Dr. Mehta-Shah reported, noting that the median time from relapse to death post allogeneic transplant was 10.2 months.
Patients in complete remission at the time of transplant fared better than others, with a median PFS of 44.6 months vs. 8.5 months for those in partial remission, 21.0 months in those with stable disease, and 3.5 months for those with progressive disease at time of transplant, data show.
Patients with common PTCL subtypes had better PFS compared to patients with CTCL, yet OS was similar, according to the investigator. At 5 years, PFS was 43.7% and 18.6%, respectively, for PTCL and CTCL, while OS was 53.1% and 44.0%, respectively.
There was a trend toward improved outcomes for AITL relative to PTCL-NOS and ALCL, with a median PFS of 51.4 months for AITL versus 18.3 months those other subtypes. Similarly, median OS was not reached for AITL versus 73.1 months in the other subtypes.
Treatment-related mortality was lowest for patients with MRDs, or 8.2% at 12 months, Dr. Mehta-Shah reported, while patients with MUDs, mismatched donors, or haploidentical donors had treatment-related mortality of 13% to 16% at 12 months, and those with cord blood donors had treatment-related mortality of nearly 24% at 12 months.
Acute GvHD was observed in 46% of patients and chronic GvHD was seen in nearly 41%, the investigator added.
While these findings are important to consider in individual patient consultations, the study is nevertheless subject to limitations including patient selection and referral bias, according to Dr. Mehta-Shah.
“This was a retrospective analysis of patients who underwent transplant,” she said in a question-and-answer period. “Of course, that is heavily biased by who got to a transplant center, who was well enough to achieve transplant, and who had a donor or donor options, as well as their overall health and depth of remission,” the researcher said.
“I think this just represents what we could tell patients about what may happen to them once they embark on a transplant,” she added, “but really, there would be more prospective work needed to be done for what happens to patients overarching, and how many of them even get to a transplant consultation.”
Further studies should be done to develop predictive tools or biomarkers to determine who benefits from an allogeneic transplant, if there are predictors of relapse following allogeneic transplant, and what are the mechanisms of relapse following allogeneic transplant, according to Dr. Mehta-Shah.
Dr. Mehta-Shah reported research funding from Bristol Myers-Squibb, Celgene, Verastem, Corvus, Innate Pharmaceuticals, and Genentech/Roche. She reported consultancy with Kyowa Hakko Kirin, C4 Therapeutics, and Karyopharm Therapeutics.
SOURCE: Mehta-Shah N et al. ASH 2020, Abstract 41.
FROM ASH 2020
Pigment traits, sun sensitivity associated with risk of non-Hodgkin lymphomas and chronic lymphocytic leukemia
Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.
The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.
Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
Common etiology?
Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.
The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.
Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.
These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.
“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.
The study was sponsored by the French government. The authors stated that they had no conflicts of interest.
SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.
Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.
The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.
Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
Common etiology?
Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.
The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.
Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.
These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.
“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.
The study was sponsored by the French government. The authors stated that they had no conflicts of interest.
SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.
Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.
The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.
Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
Common etiology?
Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.
The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.
Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.
These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.
“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.
The study was sponsored by the French government. The authors stated that they had no conflicts of interest.
SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.
FROM CANCER MEDICINE