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ASCO honors Hagop Kantarjian, MD, for leukemia research
This award is the society’s “highest scientific honor, and I am extremely happy and honored to receive it,” Dr. Kantarjian commented in an interview with this news organization.
Dr. Kantarjian serves as the chair of the department of leukemia and currently holds the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston.
“No doubt that this is not an individual award. It represents an award for the accomplishments of all the leukemia faculty at MD Anderson across 4 decades. It’s really a teamwork effort that led to so many discoveries and improvements in treatment and care of patients with leukemia,” he commented.
The David A. Karnofsky Memorial Award has been presented annually since 1970 to recognize oncologists who have made outstanding contributions to cancer research, diagnosis, or treatment, ASCO noted.
From Lebanon to Texas
Dr. Kantarjian received his medical degree from the American University of Beirut, in Lebanon, in 1979 and completed his residency in internal medicine at the same institution in 1981.
It was his experience at MD Anderson as a young medical student and later as a fellow that fueled his interest and career in leukemia, he said.
“In 1978, I took a 4-month elective at MD Anderson, and I soon realized how different and innovative the atmosphere at MD Anderson was, compared to where I was training in Lebanon,” Dr. Kantarjian told this news organization.
Working with mentors that included MD Anderson heavyweights Emil Freireich, MD, Kenneth McCredie, MD, and Michael Keating, MD, helped shape his career and guide his leukemia research, he said.
Transformative impact on leukemia outcomes
The award citation notes that over the past 4 decades, Dr. Kantarjian’s research has transformed some standards of care and has dramatically improved survival in several leukemia subtypes, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphocytic leukemia (ALL).
“Four decades ago, most of the leukemias were incurable. Today, most of the leukemias are potentially curable with targeted therapies. That’s what I am most proud of,” Dr. Kantarjian told this news organization.
Among Dr. Kantarjian’s contributions to the field of leukemia:
- Developing the HYPER-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) as a standard-of-care, frontline therapy for adults with ALL.
- Establishing clinical biology parameters of CML, including definitions of CML phases and cytogenetic responses, and establishing new prognostic factors that were subsequently adopted in studies of tyrosine kinase inhibitors.
- Leading the development of decitabine and epigenetic hypomethylation therapy for MDS and for older/unfit patients with AML.
- Pioneering research with hypomethylating agents (HMAs) in combination with venetoclax, which led to FDA approval of HMA-venetoclax combinations for older/unfit patients with AML.
- Championing the development of clofarabine, conducting animal toxicology studies, and leading subsequent phase 1 and 2 trials and pivotal phase 3 and 4 trials that led to FDA approval of clofarabine for pediatric ALL.
- Developing several FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and venetoclax, which all received FDA approval for the treatment of AML and its subsets.
- Developing regimens for inotuzumab and blinatumomab combined with chemotherapy for adults with pre-B ALL.
- Working on the development of imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and omacetaxine, which all received FDA approval for CML therapy.
“Dr. Kantarjian’s long list of accomplishments and groundbreaking discoveries are a testament to his lifelong commitment to impactful cancer research and patient care,” Giulio Draetta, MD, PhD, chief scientific officer at MD Anderson, said in a statement.
Giving back
Dr. Kantarjian has written more than 2,200 peer-reviewed articles and more than 100 book chapters. In 2012, he cofounded the Society of Hematologic Oncology, which has now expanded worldwide.
He has served on multiple ASCO committees throughout the years and served on the ASCO board of directors from 2010 to 2015.
Dr. Kantarjian is passionately involved in mentoring and education. In 2000 he created the MD Anderson Leukemia Fellowship, which now trains about 10 fellows in leukemia annually.
He is a nonresident fellow in health care at the Rice Baker Institute and has written extensively on important health care issues in cancer, including the importance of universal equitable health care, health care safety nets, health care as a human right, and the problem of drug shortages.
Dr. Kantarjian is a strong advocate for more affordable drug therapies. For years he has been outspoken about the high price of leukemia drugs and has written high-profile articles in medical journals. He has even appeared on a popular television program to publicize the issue.
“Drug costs have been increasing over time. If you think about it, even if you discover a drug that cures cancer, but the drug is affordable for the 1% of the patients, then you have no cure for cancer,” Dr. Kantarjian told this news organization.
“I started speaking about the issue of the cancer drug costs in 2012. Unfortunately, we have not made progress simply because of the for-profit nature of health care and the strong lobbying by drug companies,” he added. Dr. Kantarjian hopes new legislation will eventually turn the tide.
Dr. Kantarjian has received many other honors throughout his distinguished career, including the American Lebanese Medical Association’s Lifetime Achievement Award, the American Association for Cancer Research’s Joseph H. Burchenal Memorial Award, and the Leukemia Society of America’s Outstanding Service to Mankind Award. He also was named an ASCO Fellow and a Leukemia Society of America Special Fellow and Scholar.
Dr. Kantarjian will be presented with the 2023 David A. Karnofsky Memorial Award, which includes a $25,000 honorarium, and will give a scientific lecture about his research at the ASCO annual meeting in Chicago in early June.
A version of this article originally appeared on Medscape.com.
This award is the society’s “highest scientific honor, and I am extremely happy and honored to receive it,” Dr. Kantarjian commented in an interview with this news organization.
Dr. Kantarjian serves as the chair of the department of leukemia and currently holds the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston.
“No doubt that this is not an individual award. It represents an award for the accomplishments of all the leukemia faculty at MD Anderson across 4 decades. It’s really a teamwork effort that led to so many discoveries and improvements in treatment and care of patients with leukemia,” he commented.
The David A. Karnofsky Memorial Award has been presented annually since 1970 to recognize oncologists who have made outstanding contributions to cancer research, diagnosis, or treatment, ASCO noted.
From Lebanon to Texas
Dr. Kantarjian received his medical degree from the American University of Beirut, in Lebanon, in 1979 and completed his residency in internal medicine at the same institution in 1981.
It was his experience at MD Anderson as a young medical student and later as a fellow that fueled his interest and career in leukemia, he said.
“In 1978, I took a 4-month elective at MD Anderson, and I soon realized how different and innovative the atmosphere at MD Anderson was, compared to where I was training in Lebanon,” Dr. Kantarjian told this news organization.
Working with mentors that included MD Anderson heavyweights Emil Freireich, MD, Kenneth McCredie, MD, and Michael Keating, MD, helped shape his career and guide his leukemia research, he said.
Transformative impact on leukemia outcomes
The award citation notes that over the past 4 decades, Dr. Kantarjian’s research has transformed some standards of care and has dramatically improved survival in several leukemia subtypes, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphocytic leukemia (ALL).
“Four decades ago, most of the leukemias were incurable. Today, most of the leukemias are potentially curable with targeted therapies. That’s what I am most proud of,” Dr. Kantarjian told this news organization.
Among Dr. Kantarjian’s contributions to the field of leukemia:
- Developing the HYPER-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) as a standard-of-care, frontline therapy for adults with ALL.
- Establishing clinical biology parameters of CML, including definitions of CML phases and cytogenetic responses, and establishing new prognostic factors that were subsequently adopted in studies of tyrosine kinase inhibitors.
- Leading the development of decitabine and epigenetic hypomethylation therapy for MDS and for older/unfit patients with AML.
- Pioneering research with hypomethylating agents (HMAs) in combination with venetoclax, which led to FDA approval of HMA-venetoclax combinations for older/unfit patients with AML.
- Championing the development of clofarabine, conducting animal toxicology studies, and leading subsequent phase 1 and 2 trials and pivotal phase 3 and 4 trials that led to FDA approval of clofarabine for pediatric ALL.
- Developing several FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and venetoclax, which all received FDA approval for the treatment of AML and its subsets.
- Developing regimens for inotuzumab and blinatumomab combined with chemotherapy for adults with pre-B ALL.
- Working on the development of imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and omacetaxine, which all received FDA approval for CML therapy.
“Dr. Kantarjian’s long list of accomplishments and groundbreaking discoveries are a testament to his lifelong commitment to impactful cancer research and patient care,” Giulio Draetta, MD, PhD, chief scientific officer at MD Anderson, said in a statement.
Giving back
Dr. Kantarjian has written more than 2,200 peer-reviewed articles and more than 100 book chapters. In 2012, he cofounded the Society of Hematologic Oncology, which has now expanded worldwide.
He has served on multiple ASCO committees throughout the years and served on the ASCO board of directors from 2010 to 2015.
Dr. Kantarjian is passionately involved in mentoring and education. In 2000 he created the MD Anderson Leukemia Fellowship, which now trains about 10 fellows in leukemia annually.
He is a nonresident fellow in health care at the Rice Baker Institute and has written extensively on important health care issues in cancer, including the importance of universal equitable health care, health care safety nets, health care as a human right, and the problem of drug shortages.
Dr. Kantarjian is a strong advocate for more affordable drug therapies. For years he has been outspoken about the high price of leukemia drugs and has written high-profile articles in medical journals. He has even appeared on a popular television program to publicize the issue.
“Drug costs have been increasing over time. If you think about it, even if you discover a drug that cures cancer, but the drug is affordable for the 1% of the patients, then you have no cure for cancer,” Dr. Kantarjian told this news organization.
“I started speaking about the issue of the cancer drug costs in 2012. Unfortunately, we have not made progress simply because of the for-profit nature of health care and the strong lobbying by drug companies,” he added. Dr. Kantarjian hopes new legislation will eventually turn the tide.
Dr. Kantarjian has received many other honors throughout his distinguished career, including the American Lebanese Medical Association’s Lifetime Achievement Award, the American Association for Cancer Research’s Joseph H. Burchenal Memorial Award, and the Leukemia Society of America’s Outstanding Service to Mankind Award. He also was named an ASCO Fellow and a Leukemia Society of America Special Fellow and Scholar.
Dr. Kantarjian will be presented with the 2023 David A. Karnofsky Memorial Award, which includes a $25,000 honorarium, and will give a scientific lecture about his research at the ASCO annual meeting in Chicago in early June.
A version of this article originally appeared on Medscape.com.
This award is the society’s “highest scientific honor, and I am extremely happy and honored to receive it,” Dr. Kantarjian commented in an interview with this news organization.
Dr. Kantarjian serves as the chair of the department of leukemia and currently holds the Samsung Distinguished University Chair in Cancer Medicine at the University of Texas MD Anderson Cancer Center, Houston.
“No doubt that this is not an individual award. It represents an award for the accomplishments of all the leukemia faculty at MD Anderson across 4 decades. It’s really a teamwork effort that led to so many discoveries and improvements in treatment and care of patients with leukemia,” he commented.
The David A. Karnofsky Memorial Award has been presented annually since 1970 to recognize oncologists who have made outstanding contributions to cancer research, diagnosis, or treatment, ASCO noted.
From Lebanon to Texas
Dr. Kantarjian received his medical degree from the American University of Beirut, in Lebanon, in 1979 and completed his residency in internal medicine at the same institution in 1981.
It was his experience at MD Anderson as a young medical student and later as a fellow that fueled his interest and career in leukemia, he said.
“In 1978, I took a 4-month elective at MD Anderson, and I soon realized how different and innovative the atmosphere at MD Anderson was, compared to where I was training in Lebanon,” Dr. Kantarjian told this news organization.
Working with mentors that included MD Anderson heavyweights Emil Freireich, MD, Kenneth McCredie, MD, and Michael Keating, MD, helped shape his career and guide his leukemia research, he said.
Transformative impact on leukemia outcomes
The award citation notes that over the past 4 decades, Dr. Kantarjian’s research has transformed some standards of care and has dramatically improved survival in several leukemia subtypes, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphocytic leukemia (ALL).
“Four decades ago, most of the leukemias were incurable. Today, most of the leukemias are potentially curable with targeted therapies. That’s what I am most proud of,” Dr. Kantarjian told this news organization.
Among Dr. Kantarjian’s contributions to the field of leukemia:
- Developing the HYPER-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) as a standard-of-care, frontline therapy for adults with ALL.
- Establishing clinical biology parameters of CML, including definitions of CML phases and cytogenetic responses, and establishing new prognostic factors that were subsequently adopted in studies of tyrosine kinase inhibitors.
- Leading the development of decitabine and epigenetic hypomethylation therapy for MDS and for older/unfit patients with AML.
- Pioneering research with hypomethylating agents (HMAs) in combination with venetoclax, which led to FDA approval of HMA-venetoclax combinations for older/unfit patients with AML.
- Championing the development of clofarabine, conducting animal toxicology studies, and leading subsequent phase 1 and 2 trials and pivotal phase 3 and 4 trials that led to FDA approval of clofarabine for pediatric ALL.
- Developing several FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and venetoclax, which all received FDA approval for the treatment of AML and its subsets.
- Developing regimens for inotuzumab and blinatumomab combined with chemotherapy for adults with pre-B ALL.
- Working on the development of imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and omacetaxine, which all received FDA approval for CML therapy.
“Dr. Kantarjian’s long list of accomplishments and groundbreaking discoveries are a testament to his lifelong commitment to impactful cancer research and patient care,” Giulio Draetta, MD, PhD, chief scientific officer at MD Anderson, said in a statement.
Giving back
Dr. Kantarjian has written more than 2,200 peer-reviewed articles and more than 100 book chapters. In 2012, he cofounded the Society of Hematologic Oncology, which has now expanded worldwide.
He has served on multiple ASCO committees throughout the years and served on the ASCO board of directors from 2010 to 2015.
Dr. Kantarjian is passionately involved in mentoring and education. In 2000 he created the MD Anderson Leukemia Fellowship, which now trains about 10 fellows in leukemia annually.
He is a nonresident fellow in health care at the Rice Baker Institute and has written extensively on important health care issues in cancer, including the importance of universal equitable health care, health care safety nets, health care as a human right, and the problem of drug shortages.
Dr. Kantarjian is a strong advocate for more affordable drug therapies. For years he has been outspoken about the high price of leukemia drugs and has written high-profile articles in medical journals. He has even appeared on a popular television program to publicize the issue.
“Drug costs have been increasing over time. If you think about it, even if you discover a drug that cures cancer, but the drug is affordable for the 1% of the patients, then you have no cure for cancer,” Dr. Kantarjian told this news organization.
“I started speaking about the issue of the cancer drug costs in 2012. Unfortunately, we have not made progress simply because of the for-profit nature of health care and the strong lobbying by drug companies,” he added. Dr. Kantarjian hopes new legislation will eventually turn the tide.
Dr. Kantarjian has received many other honors throughout his distinguished career, including the American Lebanese Medical Association’s Lifetime Achievement Award, the American Association for Cancer Research’s Joseph H. Burchenal Memorial Award, and the Leukemia Society of America’s Outstanding Service to Mankind Award. He also was named an ASCO Fellow and a Leukemia Society of America Special Fellow and Scholar.
Dr. Kantarjian will be presented with the 2023 David A. Karnofsky Memorial Award, which includes a $25,000 honorarium, and will give a scientific lecture about his research at the ASCO annual meeting in Chicago in early June.
A version of this article originally appeared on Medscape.com.
Red-cell donor’s sex does not affect transfusion survival
In a randomized clinical trial with almost 9,000 patients, the adjusted hazard ratio of death among recipients of female donors’ blood, compared with recipients of male donors’ blood, was 0.98. The data contradict the finding of previous observational studies that donor sex is associated with recipient outcomes.
“The key finding was that we actually had a null result,” study author Dean Fergusson, MD, PhD, senior scientist at the Ottawa Hospital Research Institute, said in an interview. “We went in thinking that male donor blood would confer a benefit over female donor blood, and we found that there’s absolutely no difference between the donor sexes on recipient outcomes – mortality and other major secondary outcomes,” Dr. Fergusson added.
The study was published in the New England Journal of Medicine.
Differences ‘don’t matter’
A 2015 article from the National Heart, Lung, and Blood Institute identified a potential effect of donor sex on transfusion recipient survival. Since then, several observational studies have suggested that donor sex may influence survival after transfusion. This research includes two large studies, one from Canada and one from the Netherlands, that reported a heightened risk of death among recipients of red-cell units from female donors or donors who had been pregnant. Other studies, however, yielded conflicting results.
“The rationale was that female blood, because of biochemical properties, different hormones, exposure to babies and other males, all led to a different product, if you will, and these subtle changes could affect the blood product in terms of shelf life and potency,” said Dr. Fergusson. “That itself would have downstream effects on the recipient.”
The current double-blind study included 8,719 patients who received transfusions from September 2018 to December 2020 at three academic medical centers in Canada. Of this group, 5,190 received male donor blood, and 3,529 received blood from female donors.
The researchers randomly assigned patients in a 60:40 ratio to male and female donor groups. Data collection and follow-up were performed by the Ottawa Hospital Data Warehouse, Canadian Blood Services, and ICES, an independent research institute. Patient characteristics were similar in both trial groups at baseline.
After an average follow-up of 11.2 months, with a maximum follow-up of 29 months, 1,141 patients in the female donor group and 1,712 in the male donor group died. The study found no statistically significant difference in overall survival between the two groups. The unadjusted HR for death, with the male group as the reference, was 0.97, and the adjusted HR was 0.98. The rates of overall survival were 58% and 56.1% in the female and male donor groups, respectively.
The study did not prove that differences in outcome based on donor sex do not exist, said Dr. Fergusson. “But those differences really don’t matter in the recipient.”
The design of the trial itself was unique, Dr. Fergusson said. After patients consented to participate and underwent randomization, the study used routinely collected data from the participating hospitals’ electronic medical records rather than collect data anew for each patient. “That had a profound effect on the efficiency of the trial. We did this trial for a cost of less than $300,000, and typically it would cost $9 million by using high-quality electronic health data.”
The study also evaluated several secondary outcomes. Recipients of female donor blood had twice the incidence of MRSA infection. In addition, an unadjusted subgroup analysis suggested a 10% lower risk of death among male patients assigned to the female donor group, compared with those assigned to the male donor group.
The risk of death was almost three times higher among patients in the female donor group who received units from donors aged 20-29.9 years (HR, 2.93). “The inconsistency of the point estimates across groups and the multiplicity of analyses increase the risk that those findings were due to chance,” according to the authors.
Big data
Commenting on the study, Jeannie Callum, MD, professor and director of transfusion medicine at Queen’s University, Kingston, Ont., said that the use of routinely collected data from the participating hospitals’ electronic medical records was “one of the really great things about this paper.”
This use of Big Data “allows you to do a trial like this with almost 9,000 patients without spending millions and millions of dollars to have people go through charts and record data,” she added.
Dr. Callum also pointed out some of the trial’s limitations. “One of the things that kind of detracts from the study in my mind is that they randomized everybody that was getting a transfusion, but outpatients getting a transfusion have a very low mortality rate. So, you have a group of patients that are never going to have that endpoint being included in the study, and that might’ve diluted the findings.”
About 11.4% of participants received blood from a donor group other than the one to which they had been assigned, and this factor may further dilute the findings, said Dr. Callum. “That’s a difficult thing to avoid.” She noted that a trial in which she is collaborating, called Sex Matters, may answer some of these questions about the use of female versus male donor blood.
The investigators also noted that the findings may not be generalizable to other countries. “Just because we didn’t find something in Canada with our blood production system doesn’t mean that the United States might not find it different, because how they manufacture their red blood cells for transfusion is different than how we do them in Canada,” said Dr. Callum.
Nonetheless, this study shows the potential of using Big Data in medicine. “This is the future of large randomized clinical trials to quickly answer questions,” said Dr. Callum. “In the United States, Canada, and other countries that have these large electronic medical records systems, this kind of trial would be able to be done in other centers.”
The study was funded by the Canadian Institutes of Health Research. Dr. Fergusson and Dr. Callum disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a randomized clinical trial with almost 9,000 patients, the adjusted hazard ratio of death among recipients of female donors’ blood, compared with recipients of male donors’ blood, was 0.98. The data contradict the finding of previous observational studies that donor sex is associated with recipient outcomes.
“The key finding was that we actually had a null result,” study author Dean Fergusson, MD, PhD, senior scientist at the Ottawa Hospital Research Institute, said in an interview. “We went in thinking that male donor blood would confer a benefit over female donor blood, and we found that there’s absolutely no difference between the donor sexes on recipient outcomes – mortality and other major secondary outcomes,” Dr. Fergusson added.
The study was published in the New England Journal of Medicine.
Differences ‘don’t matter’
A 2015 article from the National Heart, Lung, and Blood Institute identified a potential effect of donor sex on transfusion recipient survival. Since then, several observational studies have suggested that donor sex may influence survival after transfusion. This research includes two large studies, one from Canada and one from the Netherlands, that reported a heightened risk of death among recipients of red-cell units from female donors or donors who had been pregnant. Other studies, however, yielded conflicting results.
“The rationale was that female blood, because of biochemical properties, different hormones, exposure to babies and other males, all led to a different product, if you will, and these subtle changes could affect the blood product in terms of shelf life and potency,” said Dr. Fergusson. “That itself would have downstream effects on the recipient.”
The current double-blind study included 8,719 patients who received transfusions from September 2018 to December 2020 at three academic medical centers in Canada. Of this group, 5,190 received male donor blood, and 3,529 received blood from female donors.
The researchers randomly assigned patients in a 60:40 ratio to male and female donor groups. Data collection and follow-up were performed by the Ottawa Hospital Data Warehouse, Canadian Blood Services, and ICES, an independent research institute. Patient characteristics were similar in both trial groups at baseline.
After an average follow-up of 11.2 months, with a maximum follow-up of 29 months, 1,141 patients in the female donor group and 1,712 in the male donor group died. The study found no statistically significant difference in overall survival between the two groups. The unadjusted HR for death, with the male group as the reference, was 0.97, and the adjusted HR was 0.98. The rates of overall survival were 58% and 56.1% in the female and male donor groups, respectively.
The study did not prove that differences in outcome based on donor sex do not exist, said Dr. Fergusson. “But those differences really don’t matter in the recipient.”
The design of the trial itself was unique, Dr. Fergusson said. After patients consented to participate and underwent randomization, the study used routinely collected data from the participating hospitals’ electronic medical records rather than collect data anew for each patient. “That had a profound effect on the efficiency of the trial. We did this trial for a cost of less than $300,000, and typically it would cost $9 million by using high-quality electronic health data.”
The study also evaluated several secondary outcomes. Recipients of female donor blood had twice the incidence of MRSA infection. In addition, an unadjusted subgroup analysis suggested a 10% lower risk of death among male patients assigned to the female donor group, compared with those assigned to the male donor group.
The risk of death was almost three times higher among patients in the female donor group who received units from donors aged 20-29.9 years (HR, 2.93). “The inconsistency of the point estimates across groups and the multiplicity of analyses increase the risk that those findings were due to chance,” according to the authors.
Big data
Commenting on the study, Jeannie Callum, MD, professor and director of transfusion medicine at Queen’s University, Kingston, Ont., said that the use of routinely collected data from the participating hospitals’ electronic medical records was “one of the really great things about this paper.”
This use of Big Data “allows you to do a trial like this with almost 9,000 patients without spending millions and millions of dollars to have people go through charts and record data,” she added.
Dr. Callum also pointed out some of the trial’s limitations. “One of the things that kind of detracts from the study in my mind is that they randomized everybody that was getting a transfusion, but outpatients getting a transfusion have a very low mortality rate. So, you have a group of patients that are never going to have that endpoint being included in the study, and that might’ve diluted the findings.”
About 11.4% of participants received blood from a donor group other than the one to which they had been assigned, and this factor may further dilute the findings, said Dr. Callum. “That’s a difficult thing to avoid.” She noted that a trial in which she is collaborating, called Sex Matters, may answer some of these questions about the use of female versus male donor blood.
The investigators also noted that the findings may not be generalizable to other countries. “Just because we didn’t find something in Canada with our blood production system doesn’t mean that the United States might not find it different, because how they manufacture their red blood cells for transfusion is different than how we do them in Canada,” said Dr. Callum.
Nonetheless, this study shows the potential of using Big Data in medicine. “This is the future of large randomized clinical trials to quickly answer questions,” said Dr. Callum. “In the United States, Canada, and other countries that have these large electronic medical records systems, this kind of trial would be able to be done in other centers.”
The study was funded by the Canadian Institutes of Health Research. Dr. Fergusson and Dr. Callum disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a randomized clinical trial with almost 9,000 patients, the adjusted hazard ratio of death among recipients of female donors’ blood, compared with recipients of male donors’ blood, was 0.98. The data contradict the finding of previous observational studies that donor sex is associated with recipient outcomes.
“The key finding was that we actually had a null result,” study author Dean Fergusson, MD, PhD, senior scientist at the Ottawa Hospital Research Institute, said in an interview. “We went in thinking that male donor blood would confer a benefit over female donor blood, and we found that there’s absolutely no difference between the donor sexes on recipient outcomes – mortality and other major secondary outcomes,” Dr. Fergusson added.
The study was published in the New England Journal of Medicine.
Differences ‘don’t matter’
A 2015 article from the National Heart, Lung, and Blood Institute identified a potential effect of donor sex on transfusion recipient survival. Since then, several observational studies have suggested that donor sex may influence survival after transfusion. This research includes two large studies, one from Canada and one from the Netherlands, that reported a heightened risk of death among recipients of red-cell units from female donors or donors who had been pregnant. Other studies, however, yielded conflicting results.
“The rationale was that female blood, because of biochemical properties, different hormones, exposure to babies and other males, all led to a different product, if you will, and these subtle changes could affect the blood product in terms of shelf life and potency,” said Dr. Fergusson. “That itself would have downstream effects on the recipient.”
The current double-blind study included 8,719 patients who received transfusions from September 2018 to December 2020 at three academic medical centers in Canada. Of this group, 5,190 received male donor blood, and 3,529 received blood from female donors.
The researchers randomly assigned patients in a 60:40 ratio to male and female donor groups. Data collection and follow-up were performed by the Ottawa Hospital Data Warehouse, Canadian Blood Services, and ICES, an independent research institute. Patient characteristics were similar in both trial groups at baseline.
After an average follow-up of 11.2 months, with a maximum follow-up of 29 months, 1,141 patients in the female donor group and 1,712 in the male donor group died. The study found no statistically significant difference in overall survival between the two groups. The unadjusted HR for death, with the male group as the reference, was 0.97, and the adjusted HR was 0.98. The rates of overall survival were 58% and 56.1% in the female and male donor groups, respectively.
The study did not prove that differences in outcome based on donor sex do not exist, said Dr. Fergusson. “But those differences really don’t matter in the recipient.”
The design of the trial itself was unique, Dr. Fergusson said. After patients consented to participate and underwent randomization, the study used routinely collected data from the participating hospitals’ electronic medical records rather than collect data anew for each patient. “That had a profound effect on the efficiency of the trial. We did this trial for a cost of less than $300,000, and typically it would cost $9 million by using high-quality electronic health data.”
The study also evaluated several secondary outcomes. Recipients of female donor blood had twice the incidence of MRSA infection. In addition, an unadjusted subgroup analysis suggested a 10% lower risk of death among male patients assigned to the female donor group, compared with those assigned to the male donor group.
The risk of death was almost three times higher among patients in the female donor group who received units from donors aged 20-29.9 years (HR, 2.93). “The inconsistency of the point estimates across groups and the multiplicity of analyses increase the risk that those findings were due to chance,” according to the authors.
Big data
Commenting on the study, Jeannie Callum, MD, professor and director of transfusion medicine at Queen’s University, Kingston, Ont., said that the use of routinely collected data from the participating hospitals’ electronic medical records was “one of the really great things about this paper.”
This use of Big Data “allows you to do a trial like this with almost 9,000 patients without spending millions and millions of dollars to have people go through charts and record data,” she added.
Dr. Callum also pointed out some of the trial’s limitations. “One of the things that kind of detracts from the study in my mind is that they randomized everybody that was getting a transfusion, but outpatients getting a transfusion have a very low mortality rate. So, you have a group of patients that are never going to have that endpoint being included in the study, and that might’ve diluted the findings.”
About 11.4% of participants received blood from a donor group other than the one to which they had been assigned, and this factor may further dilute the findings, said Dr. Callum. “That’s a difficult thing to avoid.” She noted that a trial in which she is collaborating, called Sex Matters, may answer some of these questions about the use of female versus male donor blood.
The investigators also noted that the findings may not be generalizable to other countries. “Just because we didn’t find something in Canada with our blood production system doesn’t mean that the United States might not find it different, because how they manufacture their red blood cells for transfusion is different than how we do them in Canada,” said Dr. Callum.
Nonetheless, this study shows the potential of using Big Data in medicine. “This is the future of large randomized clinical trials to quickly answer questions,” said Dr. Callum. “In the United States, Canada, and other countries that have these large electronic medical records systems, this kind of trial would be able to be done in other centers.”
The study was funded by the Canadian Institutes of Health Research. Dr. Fergusson and Dr. Callum disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
New hope for MDS, with AML treatments
Until just over a year ago, Pat Trueman, an 82-year-old in New Hampshire, had always been a “go-go-go” kind of person. Then she started feeling tired easily, even while doing basic housework.
“I had no stamina,” Ms. Trueman said. “I didn’t feel that bad, but I just couldn’t do anything.” She had also begun noticing black and blue bruises appearing on her body, so she met with her cardiologist. But when switching medications and getting a pacemaker didn’t rid Ms. Trueman of the symptoms, her doctor referred her to a hematologist oncologist.
A bone marrow biopsy eventually revealed that Ms. Trueman had myelodysplastic neoplasms, or MDS, a blood cancer affecting an estimated 60,000-170,000 people in the United States, mostly over age 60. MDS includes several bone marrow disorders in which the bone marrow does not produce enough healthy, normal blood cells. Cytopenias are therefore a key feature of MDS, whether it’s anemia (in Ms. Trueman’s case), neutropenia, or thrombocytopenia.
Jamie Koprivnikar, MD, a hematologist oncologist at Hackensack (N.J) University Medical Center, describes the condition to her patients using a factory metaphor: “Our bone marrow is the factory where the red blood cells, white blood cells, and platelets are made, and MDS is where the machinery of the factory is broken, so the factory is making defective parts and not enough parts.”
The paradox of MDS is that too many cells are in the bone marrow while too few are in the blood, since most in the marrow die before reaching the blood, explained Azra Raza, MD, a professor of medicine and director of the MDS Center at Columbia University Medical Center, New York, and author of The First Cell (New York: Basic Books, 2019).
“We’re looking at taking a lot of the therapies that we’ve used to treat AML and then trying to apply them to MDS,” Dr. Koprivnikar said. “With all the improvement that we’re seeing there with leukemia, we’re definitely expecting this trickle-down effect to also help our high-risk MDS patients.”
Workup begins with risk stratification
While different types of MDS exist, based on morphology of the blood cells, after diagnosis the most important determination to make is of the patient’s risk level, based on the International Prognostic Scoring System–Revised (IPSS-R), updated in 2022.
While there are six MDS risk levels, patients generally fall into the high-risk and low-risk categories. The risk-level workup includes “a bone marrow biopsy with morphology, looking at how many blasts they have, looking for dysplasia, cytogenetics, and a full spectrum myeloid mutation testing, or molecular testing,” according to Anna Halpern, MD, an assistant professor of hematology in the clinical research division at Fred Hutchinson Cancer Center, Seattle. ”I use that information and along with their age, in some cases to calculate an IPSS-M or IPPS-R score, and what goes into that risk stratification includes how low their blood counts are as well as any adverse risks features we might see in their marrow, like adverse risk genetics, adverse risk mutations or increased blasts.”
Treatment decisions then turn on whether a patient is high risk – about a third of MDS patients – or low risk, because those treatment goals differ.
“With low-risk, the goal is to improve quality of life,” Dr. Raza said. “For higher-risk MDS, the goal is to prolong survival and delay progression to acute leukemia” since nearly a third of MDS patients will eventually develop AML.
More specifically, the aim with low-risk MDS is “to foster transfusion independence, either to prevent transfusions or to decrease the need for transfusions in people already receiving them,” explained Ellen Ritchie, MD, an assistant professor of medicine and hematologist-oncologist at Weill Cornell Medicine, New York. “We’re not hoping so much to cure the myelofibrosis at that point, but rather to improve blood counts.”
Sometimes, Dr. Halpern said, such treatment means active surveillance monitoring of blood counts, and at other times, it means treating cytopenia – most often anemia. The erythropoiesis-stimulating agents used to treat anemia are epoetin alfa (Epogen/Procrit) or darbepoetin alfa (Aranesp).
Ms. Trueman, whose MDS is low risk, started taking Aranesp, but she didn’t feel well on the drug and didn’t think it was helping much. She was taken off that drug and now relies only on transfusions for treatment, when her blood counts fall too low.
A newer anemia medication, luspatercept (Reblozyl), was approved in 2020 but is reserved primarily for those who fail one of the other erythropoiesis-stimulating agents and have a subtype of MDS with ring sideroblasts. Although white blood cell and platelet growth factors exist for other cytopenias, they’re rarely used because they offer little survival benefit and carry risks, Dr. Halpern said. The only other medication typically used for low-risk MDS is lenalidomide (Revlimid), which is reserved only for those with 5q-deletion syndrome.
The goal of treating high-risk MDS, on the other hand, is to cure it – when possible.
“The only curative approach for MDS is an allogeneic stem cell transplant or bone marrow transplant,” Dr. Halpern said, but transplants carry high rates of morbidity and mortality and therefore require a base level of physical fitness for a patient to consider it.
Dr. Koprivnikar observed that “MDS is certainly a disease of the elderly, and with each increasing decade of life, incidence increases. So there are a lot of patients who do not qualify for transplant.”
Age is not the sole determining factor, however. Dr. Ritchie noted that transplants can be offered to patients up to age 75 and sometimes older, depending on their physical condition. “It all depends upon the patient, their fitness, how much caretaker support they have, and what their comorbid illnesses are.”
If a transplant isn’t an option, Dr. Halpern and Dr. Raza said, they steer patients toward clinical trial participation. Otherwise, the first-line treatment is chemotherapy with hypomethylating agents to hopefully put patients in remission, Dr. Ritchie said.
The main chemo agents for high-risk patients ineligible for transplant are azacitidine (Vidaza) or decitabine (Dacogen), offered indefinitely until patients stop responding or experience progression or intolerance, Dr. Koprivnikar said. The only recently approved drug in this space is Inqovi, which is not a new agent, but it provides decitabine and cedazuridine in an oral pill form, so that patients can avoid infusions.
Treatment gaps
Few treatments options currently exist for patients with MDS, beyond erythropoiesis-stimulating agents for low-risk MDS and chemotherapy or transplant for high-risk MDS, as well as lenalidomide and luspatercept for specific subpopulations. With few breakthroughs occurring, Dr. Halpern expects that progress will only happen gradually, with new treatments coming primarily in the form of AML therapies.
“The biggest gap in our MDS regimen is treatment that can successfully treat or alter the natural history of TP53-mutated disease,” said Dr. Halpern, referring to an adverse risk mutation that can occur spontaneously or as a result of exposure to chemotherapy or radiation. “TP53-mutated MDS is very challenging to treat, and we have not had any successful therapy, so that is the biggest area of need.”
The most promising possibility in that area is an anti-CD47 drug called magrolimab, a drug being tested in a trial of which Dr. Halpern is a principal investigator. Not yet approved, magrolimab has been showing promise for AML when given with azacitidine (Vidaza) and venetoclax (Venclexta).
Venetoclax, currently used for AML, is another drug that Dr. Halpern expects to be approved for MDS soon. A phase 1b trial presented at the 2021 annual meeting of the American Hematology Society found that more than three-quarters of patients with high-risk MDS responded to the combination of venetoclax and azacitidine.
Unlike so many other cancers, MDS has seen little success with immunotherapy, which tends to have too much toxicity for patients with MDS. While Dr. Halpern sees potential for more exploration in this realm, she doesn’t anticipate immunotherapy or chimeric antigen receptor T-cell therapy becoming treatments for MDS in the near future.
“What I do think is, hopefully, we will have better treatment for TP53-mutated disease,” she said, while adding that there are currently no standard options for patients who stopped responding or don’t respond to hypomethylating agents.
Similarly, few new treatments have emerged for low-risk MDS, but there a couple of possibilities on the horizon.
“For a while, low-risk, transfusion-dependent MDS was an area that was being overlooked, and we are starting to see more activity in that area as well, with more drugs being developed,” Dr. Koprivnikar said. Drugs showing promise include imetelstat – an investigative telomerase inhibitor – and IRAK inhibitors. A phase 3 trial of imetelstat recently met its primary endpoint of 8 weeks of transfusion independence in low-risk MDS patients who aren’t responding to or cannot take erythropoiesis-stimulating agents, like Ms. Trueman. If effective and approved, a drug like imetelstat may allow patients like Ms. Trueman to resume some activities that she misses now.
“I have so much energy in my head, and I want to do so much, but I can’t,” Ms. Trueman said. “Now I think I’m getting lazy and I don’t like it because I’m not that kind of person. It’s pretty hard.”
Dr. Raza disclosed relationships with Epizyme, Grail, Vor, Taiho, RareCells, and TFC Therapeutics. Dr Ritchie reported ties with Jazz Pharmaceuticals, Novartis, Takeda, Incyte, AbbVie, Astellas, and Imago Biosciences. Dr. Halpern disclosed relationships with AbbVie, Notable Labs, Imago, Bayer, Gilead, Jazz, Incyte, Karyopharm, and Disc Medicine.
Until just over a year ago, Pat Trueman, an 82-year-old in New Hampshire, had always been a “go-go-go” kind of person. Then she started feeling tired easily, even while doing basic housework.
“I had no stamina,” Ms. Trueman said. “I didn’t feel that bad, but I just couldn’t do anything.” She had also begun noticing black and blue bruises appearing on her body, so she met with her cardiologist. But when switching medications and getting a pacemaker didn’t rid Ms. Trueman of the symptoms, her doctor referred her to a hematologist oncologist.
A bone marrow biopsy eventually revealed that Ms. Trueman had myelodysplastic neoplasms, or MDS, a blood cancer affecting an estimated 60,000-170,000 people in the United States, mostly over age 60. MDS includes several bone marrow disorders in which the bone marrow does not produce enough healthy, normal blood cells. Cytopenias are therefore a key feature of MDS, whether it’s anemia (in Ms. Trueman’s case), neutropenia, or thrombocytopenia.
Jamie Koprivnikar, MD, a hematologist oncologist at Hackensack (N.J) University Medical Center, describes the condition to her patients using a factory metaphor: “Our bone marrow is the factory where the red blood cells, white blood cells, and platelets are made, and MDS is where the machinery of the factory is broken, so the factory is making defective parts and not enough parts.”
The paradox of MDS is that too many cells are in the bone marrow while too few are in the blood, since most in the marrow die before reaching the blood, explained Azra Raza, MD, a professor of medicine and director of the MDS Center at Columbia University Medical Center, New York, and author of The First Cell (New York: Basic Books, 2019).
“We’re looking at taking a lot of the therapies that we’ve used to treat AML and then trying to apply them to MDS,” Dr. Koprivnikar said. “With all the improvement that we’re seeing there with leukemia, we’re definitely expecting this trickle-down effect to also help our high-risk MDS patients.”
Workup begins with risk stratification
While different types of MDS exist, based on morphology of the blood cells, after diagnosis the most important determination to make is of the patient’s risk level, based on the International Prognostic Scoring System–Revised (IPSS-R), updated in 2022.
While there are six MDS risk levels, patients generally fall into the high-risk and low-risk categories. The risk-level workup includes “a bone marrow biopsy with morphology, looking at how many blasts they have, looking for dysplasia, cytogenetics, and a full spectrum myeloid mutation testing, or molecular testing,” according to Anna Halpern, MD, an assistant professor of hematology in the clinical research division at Fred Hutchinson Cancer Center, Seattle. ”I use that information and along with their age, in some cases to calculate an IPSS-M or IPPS-R score, and what goes into that risk stratification includes how low their blood counts are as well as any adverse risks features we might see in their marrow, like adverse risk genetics, adverse risk mutations or increased blasts.”
Treatment decisions then turn on whether a patient is high risk – about a third of MDS patients – or low risk, because those treatment goals differ.
“With low-risk, the goal is to improve quality of life,” Dr. Raza said. “For higher-risk MDS, the goal is to prolong survival and delay progression to acute leukemia” since nearly a third of MDS patients will eventually develop AML.
More specifically, the aim with low-risk MDS is “to foster transfusion independence, either to prevent transfusions or to decrease the need for transfusions in people already receiving them,” explained Ellen Ritchie, MD, an assistant professor of medicine and hematologist-oncologist at Weill Cornell Medicine, New York. “We’re not hoping so much to cure the myelofibrosis at that point, but rather to improve blood counts.”
Sometimes, Dr. Halpern said, such treatment means active surveillance monitoring of blood counts, and at other times, it means treating cytopenia – most often anemia. The erythropoiesis-stimulating agents used to treat anemia are epoetin alfa (Epogen/Procrit) or darbepoetin alfa (Aranesp).
Ms. Trueman, whose MDS is low risk, started taking Aranesp, but she didn’t feel well on the drug and didn’t think it was helping much. She was taken off that drug and now relies only on transfusions for treatment, when her blood counts fall too low.
A newer anemia medication, luspatercept (Reblozyl), was approved in 2020 but is reserved primarily for those who fail one of the other erythropoiesis-stimulating agents and have a subtype of MDS with ring sideroblasts. Although white blood cell and platelet growth factors exist for other cytopenias, they’re rarely used because they offer little survival benefit and carry risks, Dr. Halpern said. The only other medication typically used for low-risk MDS is lenalidomide (Revlimid), which is reserved only for those with 5q-deletion syndrome.
The goal of treating high-risk MDS, on the other hand, is to cure it – when possible.
“The only curative approach for MDS is an allogeneic stem cell transplant or bone marrow transplant,” Dr. Halpern said, but transplants carry high rates of morbidity and mortality and therefore require a base level of physical fitness for a patient to consider it.
Dr. Koprivnikar observed that “MDS is certainly a disease of the elderly, and with each increasing decade of life, incidence increases. So there are a lot of patients who do not qualify for transplant.”
Age is not the sole determining factor, however. Dr. Ritchie noted that transplants can be offered to patients up to age 75 and sometimes older, depending on their physical condition. “It all depends upon the patient, their fitness, how much caretaker support they have, and what their comorbid illnesses are.”
If a transplant isn’t an option, Dr. Halpern and Dr. Raza said, they steer patients toward clinical trial participation. Otherwise, the first-line treatment is chemotherapy with hypomethylating agents to hopefully put patients in remission, Dr. Ritchie said.
The main chemo agents for high-risk patients ineligible for transplant are azacitidine (Vidaza) or decitabine (Dacogen), offered indefinitely until patients stop responding or experience progression or intolerance, Dr. Koprivnikar said. The only recently approved drug in this space is Inqovi, which is not a new agent, but it provides decitabine and cedazuridine in an oral pill form, so that patients can avoid infusions.
Treatment gaps
Few treatments options currently exist for patients with MDS, beyond erythropoiesis-stimulating agents for low-risk MDS and chemotherapy or transplant for high-risk MDS, as well as lenalidomide and luspatercept for specific subpopulations. With few breakthroughs occurring, Dr. Halpern expects that progress will only happen gradually, with new treatments coming primarily in the form of AML therapies.
“The biggest gap in our MDS regimen is treatment that can successfully treat or alter the natural history of TP53-mutated disease,” said Dr. Halpern, referring to an adverse risk mutation that can occur spontaneously or as a result of exposure to chemotherapy or radiation. “TP53-mutated MDS is very challenging to treat, and we have not had any successful therapy, so that is the biggest area of need.”
The most promising possibility in that area is an anti-CD47 drug called magrolimab, a drug being tested in a trial of which Dr. Halpern is a principal investigator. Not yet approved, magrolimab has been showing promise for AML when given with azacitidine (Vidaza) and venetoclax (Venclexta).
Venetoclax, currently used for AML, is another drug that Dr. Halpern expects to be approved for MDS soon. A phase 1b trial presented at the 2021 annual meeting of the American Hematology Society found that more than three-quarters of patients with high-risk MDS responded to the combination of venetoclax and azacitidine.
Unlike so many other cancers, MDS has seen little success with immunotherapy, which tends to have too much toxicity for patients with MDS. While Dr. Halpern sees potential for more exploration in this realm, she doesn’t anticipate immunotherapy or chimeric antigen receptor T-cell therapy becoming treatments for MDS in the near future.
“What I do think is, hopefully, we will have better treatment for TP53-mutated disease,” she said, while adding that there are currently no standard options for patients who stopped responding or don’t respond to hypomethylating agents.
Similarly, few new treatments have emerged for low-risk MDS, but there a couple of possibilities on the horizon.
“For a while, low-risk, transfusion-dependent MDS was an area that was being overlooked, and we are starting to see more activity in that area as well, with more drugs being developed,” Dr. Koprivnikar said. Drugs showing promise include imetelstat – an investigative telomerase inhibitor – and IRAK inhibitors. A phase 3 trial of imetelstat recently met its primary endpoint of 8 weeks of transfusion independence in low-risk MDS patients who aren’t responding to or cannot take erythropoiesis-stimulating agents, like Ms. Trueman. If effective and approved, a drug like imetelstat may allow patients like Ms. Trueman to resume some activities that she misses now.
“I have so much energy in my head, and I want to do so much, but I can’t,” Ms. Trueman said. “Now I think I’m getting lazy and I don’t like it because I’m not that kind of person. It’s pretty hard.”
Dr. Raza disclosed relationships with Epizyme, Grail, Vor, Taiho, RareCells, and TFC Therapeutics. Dr Ritchie reported ties with Jazz Pharmaceuticals, Novartis, Takeda, Incyte, AbbVie, Astellas, and Imago Biosciences. Dr. Halpern disclosed relationships with AbbVie, Notable Labs, Imago, Bayer, Gilead, Jazz, Incyte, Karyopharm, and Disc Medicine.
Until just over a year ago, Pat Trueman, an 82-year-old in New Hampshire, had always been a “go-go-go” kind of person. Then she started feeling tired easily, even while doing basic housework.
“I had no stamina,” Ms. Trueman said. “I didn’t feel that bad, but I just couldn’t do anything.” She had also begun noticing black and blue bruises appearing on her body, so she met with her cardiologist. But when switching medications and getting a pacemaker didn’t rid Ms. Trueman of the symptoms, her doctor referred her to a hematologist oncologist.
A bone marrow biopsy eventually revealed that Ms. Trueman had myelodysplastic neoplasms, or MDS, a blood cancer affecting an estimated 60,000-170,000 people in the United States, mostly over age 60. MDS includes several bone marrow disorders in which the bone marrow does not produce enough healthy, normal blood cells. Cytopenias are therefore a key feature of MDS, whether it’s anemia (in Ms. Trueman’s case), neutropenia, or thrombocytopenia.
Jamie Koprivnikar, MD, a hematologist oncologist at Hackensack (N.J) University Medical Center, describes the condition to her patients using a factory metaphor: “Our bone marrow is the factory where the red blood cells, white blood cells, and platelets are made, and MDS is where the machinery of the factory is broken, so the factory is making defective parts and not enough parts.”
The paradox of MDS is that too many cells are in the bone marrow while too few are in the blood, since most in the marrow die before reaching the blood, explained Azra Raza, MD, a professor of medicine and director of the MDS Center at Columbia University Medical Center, New York, and author of The First Cell (New York: Basic Books, 2019).
“We’re looking at taking a lot of the therapies that we’ve used to treat AML and then trying to apply them to MDS,” Dr. Koprivnikar said. “With all the improvement that we’re seeing there with leukemia, we’re definitely expecting this trickle-down effect to also help our high-risk MDS patients.”
Workup begins with risk stratification
While different types of MDS exist, based on morphology of the blood cells, after diagnosis the most important determination to make is of the patient’s risk level, based on the International Prognostic Scoring System–Revised (IPSS-R), updated in 2022.
While there are six MDS risk levels, patients generally fall into the high-risk and low-risk categories. The risk-level workup includes “a bone marrow biopsy with morphology, looking at how many blasts they have, looking for dysplasia, cytogenetics, and a full spectrum myeloid mutation testing, or molecular testing,” according to Anna Halpern, MD, an assistant professor of hematology in the clinical research division at Fred Hutchinson Cancer Center, Seattle. ”I use that information and along with their age, in some cases to calculate an IPSS-M or IPPS-R score, and what goes into that risk stratification includes how low their blood counts are as well as any adverse risks features we might see in their marrow, like adverse risk genetics, adverse risk mutations or increased blasts.”
Treatment decisions then turn on whether a patient is high risk – about a third of MDS patients – or low risk, because those treatment goals differ.
“With low-risk, the goal is to improve quality of life,” Dr. Raza said. “For higher-risk MDS, the goal is to prolong survival and delay progression to acute leukemia” since nearly a third of MDS patients will eventually develop AML.
More specifically, the aim with low-risk MDS is “to foster transfusion independence, either to prevent transfusions or to decrease the need for transfusions in people already receiving them,” explained Ellen Ritchie, MD, an assistant professor of medicine and hematologist-oncologist at Weill Cornell Medicine, New York. “We’re not hoping so much to cure the myelofibrosis at that point, but rather to improve blood counts.”
Sometimes, Dr. Halpern said, such treatment means active surveillance monitoring of blood counts, and at other times, it means treating cytopenia – most often anemia. The erythropoiesis-stimulating agents used to treat anemia are epoetin alfa (Epogen/Procrit) or darbepoetin alfa (Aranesp).
Ms. Trueman, whose MDS is low risk, started taking Aranesp, but she didn’t feel well on the drug and didn’t think it was helping much. She was taken off that drug and now relies only on transfusions for treatment, when her blood counts fall too low.
A newer anemia medication, luspatercept (Reblozyl), was approved in 2020 but is reserved primarily for those who fail one of the other erythropoiesis-stimulating agents and have a subtype of MDS with ring sideroblasts. Although white blood cell and platelet growth factors exist for other cytopenias, they’re rarely used because they offer little survival benefit and carry risks, Dr. Halpern said. The only other medication typically used for low-risk MDS is lenalidomide (Revlimid), which is reserved only for those with 5q-deletion syndrome.
The goal of treating high-risk MDS, on the other hand, is to cure it – when possible.
“The only curative approach for MDS is an allogeneic stem cell transplant or bone marrow transplant,” Dr. Halpern said, but transplants carry high rates of morbidity and mortality and therefore require a base level of physical fitness for a patient to consider it.
Dr. Koprivnikar observed that “MDS is certainly a disease of the elderly, and with each increasing decade of life, incidence increases. So there are a lot of patients who do not qualify for transplant.”
Age is not the sole determining factor, however. Dr. Ritchie noted that transplants can be offered to patients up to age 75 and sometimes older, depending on their physical condition. “It all depends upon the patient, their fitness, how much caretaker support they have, and what their comorbid illnesses are.”
If a transplant isn’t an option, Dr. Halpern and Dr. Raza said, they steer patients toward clinical trial participation. Otherwise, the first-line treatment is chemotherapy with hypomethylating agents to hopefully put patients in remission, Dr. Ritchie said.
The main chemo agents for high-risk patients ineligible for transplant are azacitidine (Vidaza) or decitabine (Dacogen), offered indefinitely until patients stop responding or experience progression or intolerance, Dr. Koprivnikar said. The only recently approved drug in this space is Inqovi, which is not a new agent, but it provides decitabine and cedazuridine in an oral pill form, so that patients can avoid infusions.
Treatment gaps
Few treatments options currently exist for patients with MDS, beyond erythropoiesis-stimulating agents for low-risk MDS and chemotherapy or transplant for high-risk MDS, as well as lenalidomide and luspatercept for specific subpopulations. With few breakthroughs occurring, Dr. Halpern expects that progress will only happen gradually, with new treatments coming primarily in the form of AML therapies.
“The biggest gap in our MDS regimen is treatment that can successfully treat or alter the natural history of TP53-mutated disease,” said Dr. Halpern, referring to an adverse risk mutation that can occur spontaneously or as a result of exposure to chemotherapy or radiation. “TP53-mutated MDS is very challenging to treat, and we have not had any successful therapy, so that is the biggest area of need.”
The most promising possibility in that area is an anti-CD47 drug called magrolimab, a drug being tested in a trial of which Dr. Halpern is a principal investigator. Not yet approved, magrolimab has been showing promise for AML when given with azacitidine (Vidaza) and venetoclax (Venclexta).
Venetoclax, currently used for AML, is another drug that Dr. Halpern expects to be approved for MDS soon. A phase 1b trial presented at the 2021 annual meeting of the American Hematology Society found that more than three-quarters of patients with high-risk MDS responded to the combination of venetoclax and azacitidine.
Unlike so many other cancers, MDS has seen little success with immunotherapy, which tends to have too much toxicity for patients with MDS. While Dr. Halpern sees potential for more exploration in this realm, she doesn’t anticipate immunotherapy or chimeric antigen receptor T-cell therapy becoming treatments for MDS in the near future.
“What I do think is, hopefully, we will have better treatment for TP53-mutated disease,” she said, while adding that there are currently no standard options for patients who stopped responding or don’t respond to hypomethylating agents.
Similarly, few new treatments have emerged for low-risk MDS, but there a couple of possibilities on the horizon.
“For a while, low-risk, transfusion-dependent MDS was an area that was being overlooked, and we are starting to see more activity in that area as well, with more drugs being developed,” Dr. Koprivnikar said. Drugs showing promise include imetelstat – an investigative telomerase inhibitor – and IRAK inhibitors. A phase 3 trial of imetelstat recently met its primary endpoint of 8 weeks of transfusion independence in low-risk MDS patients who aren’t responding to or cannot take erythropoiesis-stimulating agents, like Ms. Trueman. If effective and approved, a drug like imetelstat may allow patients like Ms. Trueman to resume some activities that she misses now.
“I have so much energy in my head, and I want to do so much, but I can’t,” Ms. Trueman said. “Now I think I’m getting lazy and I don’t like it because I’m not that kind of person. It’s pretty hard.”
Dr. Raza disclosed relationships with Epizyme, Grail, Vor, Taiho, RareCells, and TFC Therapeutics. Dr Ritchie reported ties with Jazz Pharmaceuticals, Novartis, Takeda, Incyte, AbbVie, Astellas, and Imago Biosciences. Dr. Halpern disclosed relationships with AbbVie, Notable Labs, Imago, Bayer, Gilead, Jazz, Incyte, Karyopharm, and Disc Medicine.
VEXAS syndrome: More common, variable, and severe than expected
A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.
“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”
Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.
“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”
According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.
For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.
Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).
Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.
Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.
Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”
In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”
Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”
As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”
The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.
In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.
“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”
The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”
The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.
A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.
“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”
Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.
“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”
According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.
For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.
Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).
Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.
Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.
Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”
In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”
Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”
As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”
The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.
In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.
“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”
The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”
The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.
A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable, and dangerous than previously understood, according to results of a retrospective observational study of a large health care system database. The findings, published in JAMA, found that it struck 1 in 4,269 men over the age of 50 in a largely White population and caused a wide variety of symptoms.
“The disease is quite severe,” study lead author David Beck, MD, PhD, of the department of medicine at NYU Langone Health, said in an interview. Patients with the condition “have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”
Dr. Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020. They linked it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.
“VEXAS syndrome is characterized by anemia and inflammation in the skin, lungs, cartilage, and joints,” Dr. Beck said. “These symptoms are frequently mistaken for other rheumatic or hematologic diseases. However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”
According to him, hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was 9 years among patients with a certain variant; that was significantly less than patients with two other variants.
For the new study, researchers searched for UBA1 variants in genetic data from 163,096 subjects (mean age, 52.8 years; 94% White, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data comes from patients at 10 Pennsylvania hospitals.
Eleven people (9 males, 2 females) had likely UBA1 variants, and all had anemia. The cases accounted for 1 in 13,591 unrelated people (95% confidence interval, 1:7,775-1:23,758), 1 in 4,269 men older than 50 years (95% CI, 1:2,319-1:7,859), and 1 in 26,238 women older than 50 years (95% CI, 1:7,196-1:147,669).
Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.
Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering that it hadn’t been discovered and described until recently.
Just over half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome. “This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Dr. Beck said. “The lack of associated clinical diagnoses may be due to the variety of nonspecific clinical characteristics that span different subspecialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”
In the future, “professionals should look out for patients with unexplained inflammation – and some combination of hematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies,” Dr. Beck said. “These patients will also frequently be anemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”
Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels.”
As for treatment, Dr. Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics. However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents [DMARDs]. In addition, bone marrow transplantation has shown signs of being a highly effective therapy.”
The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.
In an interview, Matthew J. Koster, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., who’s studied the disease but didn’t take part in this research project, said the findings are valid and “highly important.
“The findings of this study highlight what many academic and quaternary referral centers were wondering: Is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said. “Currently, there are less than 400 cases reported in the literature of VEXAS, but large centers are diagnosing this condition with some frequency. For example, at Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every 7-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed approximately 250 patients over that same time frame when pooling patients nationwide.”
The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases that are not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”
The National Institute of Health funded the study. Dr. Beck, the other authors, and Dr. Koster report no disclosures.
FROM JAMA
Bias and other barriers to HSCT access
For example, at the June 5 plenary session of the American Society of Clinical Oncology, Paul Richardson, MD, presented results of the DETERMINATION trial. More than 40,000 attendees heard his message that, in patients with newly diagnosed multiple myeloma (MM), up-front high-dose melphalan with autologous hematopoietic stem cell transplant (HSCT) support is associated with a significantly longer median progression-free survival of 67 months, compared with 46 months for patients randomized to delayed transplantation. The 5-year overall survival is similar for both arms.
While I and many of my colleagues in the field of transplantation used this data to strongly encourage MM patients to undergo HSCT as consolidation of their initial remission, others – including many investigators on the DETERMINATION trial – reached a starkly different conclusion. They suggested that delaying transplant was a valid option, since no survival benefit was observed.
Bias, when defined as a prejudice in favor of or against a specific treatment on the part of physicians and patients, has not been carefully studied in the realm of cellular therapies. However, physician and patient perceptions or misperceptions about the value or toxicity of a specific therapy are probably major drivers of whether a patient is referred for and accepts a particular form of treatment. In my specialization, that would mean either a stem cell transplant or other forms of cell therapy.
As with other medical procedures, in my field there are significant disparities in the use of transplantation among patients of different racial, ethnic, and age groups. Rates of both auto- and allo-HSCT are significantly higher for Whites than for African Americans. Hispanic patients have the lowest rates of utilization of auto-HSCT. Patients over the age of 60 have an eightfold risk of nonreferral to an HSCT center. Obviously, these nonreferrals reduce access to HSCT for older patients, particularly if they are seen at nonacademic centers.
One must question whether these disparities are caused by the physicians not believing in the value of transplantation, or simply not understanding its value? Or do they just lack the time to refer patients to a transplant center?
Socioeconomic factors, insurance status, age, and psychosocial characteristics all impact access to HSCT, yet some older patients with fewer economic resources and less insurance coverage still undergo the procedure. Is that because their physicians spent time educating these patients about the potential value of this treatment? Is it because the physicians went the extra mile to get these patients access to HSCT?
Physician preference also plays a significant role in whether a patient receives an allo-HSCT for acute myeloid leukemia and myelodysplastic syndrome. In a large survey of hematologists and oncologists performed by Pidala and colleagues, half of those surveyed agreed with the statement: “I feel the risk (morbidity and mortality) after HSCT is very high.” Most indicated that they “feel outcomes of unrelated donor HCT are much worse than matched sibling HCT.”
More importantly, more than one-third of those surveyed agreed that, “because of the high risks of allogeneic HSCT, I refer only after failure of conventional chemotherapy.” They voiced this opinion despite the fact that mortality rates after HSCT have been reduced significantly. With modern techniques, outcomes of unrelated donors are as good as with sibling donor transplants, and national guidelines strongly recommend that patients get referred before they become refractory to chemotherapy.
What can we do about this problem? Obviously, physician and provider education is important, but primary care physicians and general oncologists are already bombarded daily with new information. Relatively rare conditions like those we treat simply may not get their attention.
Personally, I think one of the most effective ways to overcome bias among physicians would be to target patients through a direct advertising campaign and public service announcements. Only by getting the attention of patients can they be directed to current, accurate information.
This solution could reduce the impact of physician biases or misperceptions and provide patients with greater access to lifesaving cell therapies.
Dr. Giralt is deputy division head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center in New York.
For example, at the June 5 plenary session of the American Society of Clinical Oncology, Paul Richardson, MD, presented results of the DETERMINATION trial. More than 40,000 attendees heard his message that, in patients with newly diagnosed multiple myeloma (MM), up-front high-dose melphalan with autologous hematopoietic stem cell transplant (HSCT) support is associated with a significantly longer median progression-free survival of 67 months, compared with 46 months for patients randomized to delayed transplantation. The 5-year overall survival is similar for both arms.
While I and many of my colleagues in the field of transplantation used this data to strongly encourage MM patients to undergo HSCT as consolidation of their initial remission, others – including many investigators on the DETERMINATION trial – reached a starkly different conclusion. They suggested that delaying transplant was a valid option, since no survival benefit was observed.
Bias, when defined as a prejudice in favor of or against a specific treatment on the part of physicians and patients, has not been carefully studied in the realm of cellular therapies. However, physician and patient perceptions or misperceptions about the value or toxicity of a specific therapy are probably major drivers of whether a patient is referred for and accepts a particular form of treatment. In my specialization, that would mean either a stem cell transplant or other forms of cell therapy.
As with other medical procedures, in my field there are significant disparities in the use of transplantation among patients of different racial, ethnic, and age groups. Rates of both auto- and allo-HSCT are significantly higher for Whites than for African Americans. Hispanic patients have the lowest rates of utilization of auto-HSCT. Patients over the age of 60 have an eightfold risk of nonreferral to an HSCT center. Obviously, these nonreferrals reduce access to HSCT for older patients, particularly if they are seen at nonacademic centers.
One must question whether these disparities are caused by the physicians not believing in the value of transplantation, or simply not understanding its value? Or do they just lack the time to refer patients to a transplant center?
Socioeconomic factors, insurance status, age, and psychosocial characteristics all impact access to HSCT, yet some older patients with fewer economic resources and less insurance coverage still undergo the procedure. Is that because their physicians spent time educating these patients about the potential value of this treatment? Is it because the physicians went the extra mile to get these patients access to HSCT?
Physician preference also plays a significant role in whether a patient receives an allo-HSCT for acute myeloid leukemia and myelodysplastic syndrome. In a large survey of hematologists and oncologists performed by Pidala and colleagues, half of those surveyed agreed with the statement: “I feel the risk (morbidity and mortality) after HSCT is very high.” Most indicated that they “feel outcomes of unrelated donor HCT are much worse than matched sibling HCT.”
More importantly, more than one-third of those surveyed agreed that, “because of the high risks of allogeneic HSCT, I refer only after failure of conventional chemotherapy.” They voiced this opinion despite the fact that mortality rates after HSCT have been reduced significantly. With modern techniques, outcomes of unrelated donors are as good as with sibling donor transplants, and national guidelines strongly recommend that patients get referred before they become refractory to chemotherapy.
What can we do about this problem? Obviously, physician and provider education is important, but primary care physicians and general oncologists are already bombarded daily with new information. Relatively rare conditions like those we treat simply may not get their attention.
Personally, I think one of the most effective ways to overcome bias among physicians would be to target patients through a direct advertising campaign and public service announcements. Only by getting the attention of patients can they be directed to current, accurate information.
This solution could reduce the impact of physician biases or misperceptions and provide patients with greater access to lifesaving cell therapies.
Dr. Giralt is deputy division head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center in New York.
For example, at the June 5 plenary session of the American Society of Clinical Oncology, Paul Richardson, MD, presented results of the DETERMINATION trial. More than 40,000 attendees heard his message that, in patients with newly diagnosed multiple myeloma (MM), up-front high-dose melphalan with autologous hematopoietic stem cell transplant (HSCT) support is associated with a significantly longer median progression-free survival of 67 months, compared with 46 months for patients randomized to delayed transplantation. The 5-year overall survival is similar for both arms.
While I and many of my colleagues in the field of transplantation used this data to strongly encourage MM patients to undergo HSCT as consolidation of their initial remission, others – including many investigators on the DETERMINATION trial – reached a starkly different conclusion. They suggested that delaying transplant was a valid option, since no survival benefit was observed.
Bias, when defined as a prejudice in favor of or against a specific treatment on the part of physicians and patients, has not been carefully studied in the realm of cellular therapies. However, physician and patient perceptions or misperceptions about the value or toxicity of a specific therapy are probably major drivers of whether a patient is referred for and accepts a particular form of treatment. In my specialization, that would mean either a stem cell transplant or other forms of cell therapy.
As with other medical procedures, in my field there are significant disparities in the use of transplantation among patients of different racial, ethnic, and age groups. Rates of both auto- and allo-HSCT are significantly higher for Whites than for African Americans. Hispanic patients have the lowest rates of utilization of auto-HSCT. Patients over the age of 60 have an eightfold risk of nonreferral to an HSCT center. Obviously, these nonreferrals reduce access to HSCT for older patients, particularly if they are seen at nonacademic centers.
One must question whether these disparities are caused by the physicians not believing in the value of transplantation, or simply not understanding its value? Or do they just lack the time to refer patients to a transplant center?
Socioeconomic factors, insurance status, age, and psychosocial characteristics all impact access to HSCT, yet some older patients with fewer economic resources and less insurance coverage still undergo the procedure. Is that because their physicians spent time educating these patients about the potential value of this treatment? Is it because the physicians went the extra mile to get these patients access to HSCT?
Physician preference also plays a significant role in whether a patient receives an allo-HSCT for acute myeloid leukemia and myelodysplastic syndrome. In a large survey of hematologists and oncologists performed by Pidala and colleagues, half of those surveyed agreed with the statement: “I feel the risk (morbidity and mortality) after HSCT is very high.” Most indicated that they “feel outcomes of unrelated donor HCT are much worse than matched sibling HCT.”
More importantly, more than one-third of those surveyed agreed that, “because of the high risks of allogeneic HSCT, I refer only after failure of conventional chemotherapy.” They voiced this opinion despite the fact that mortality rates after HSCT have been reduced significantly. With modern techniques, outcomes of unrelated donors are as good as with sibling donor transplants, and national guidelines strongly recommend that patients get referred before they become refractory to chemotherapy.
What can we do about this problem? Obviously, physician and provider education is important, but primary care physicians and general oncologists are already bombarded daily with new information. Relatively rare conditions like those we treat simply may not get their attention.
Personally, I think one of the most effective ways to overcome bias among physicians would be to target patients through a direct advertising campaign and public service announcements. Only by getting the attention of patients can they be directed to current, accurate information.
This solution could reduce the impact of physician biases or misperceptions and provide patients with greater access to lifesaving cell therapies.
Dr. Giralt is deputy division head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center in New York.
‘Superior’ CLL regimen cuts chemo in half
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
“Overall, our data suggests that [the chemoimmunotherapy] regimen is very effective and appears superior to published six cycles of chemotherapy regimen for the same favorable risk features,” first author Dr. Nitin Jain, an associate professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston, told MDedge.
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) has been a standard frontline treatment for young, fit patients with CLL, resulting in 10-year PFS rates above 55% in patients with mutated IGHV status, said coauthor Dr. Alessandra Ferrajoli, also of the MD Anderson Cancer Center, in presenting the findings at the European Hematology Association annual congress.
The authors sought to investigate the efficacy of a targeted therapy combination of ibrutinib and obinutuzumab with fludarabine and cyclophosphamide (iFCG). They also sought to determine whether a three-cycle regimen of the chemotherapy, as compared to six cycles, could reduce the risk of myelodysplastic syndrome (MDS), which increases with chemotherapy in CLL patients who have mutated IGHV status.
For the phase 2 study, 45 previously untreated patients with CLL, who had mutated IGHV and an absence of del(17p)/TP53 mutation (both of which are associated with more favorable outcomes in CLL) were enrolled between March 2016 and August 2018. The patients were deemed fit for chemotherapy and had a median age of 60.
All patients were initially treated with three cycles of the iFCG regimen, and among them, 39 (87%) achieved undetectable measurable residual disease (MRD) in their bone marrow.
After the three cycles, an MRD-driven strategy was then used to determine subsequent treatment: All patients received nine courses of ibrutinib, and for those achieving complete remission (CR) or CR with incomplete count recovery (CRi) and undetectable MRD, three cycles of obinutuzumab were administered, while all others received nine additional cycles of obinutuzumab.
At completion of the 12 courses, those who still had MRD positivity continued on ibrutinib, while those with undetectable MRD discontinued ibrutinib.
By cycle six of iFCG, 40 (89%) of the patients achieved undetectable MRD. Overall, 44 of the 45 patients (98%) achieved undetectable MRD as their best response at any time during the study, with 69% of patients achieving CR/CRi. Four patients came off the study prior to cycle 12, including one death, one infection, and one patient who opted to pursue treatment locally. With a median follow-up of 59.6 months, there were no cases of CLL progression or Richter transformation and the lone death was from heart failure.
One patient developed treatment-related myelodysplastic syndrome (MDS), and that patient has maintained normal blood counts over 38 months of monitoring and has not required MDS therapy, Dr. Ferrajoli reported.
Over the follow-up, the six patients who were MRD positive after the completion of three cycles experienced a recurrence of MRD, defined as two consecutive values of 0.01% or higher in peripheral blood by flow cytometry, at a median of 27.2 months after stopping all therapy.
“Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity during therapy,” Dr. Ferrajoli said.
She noted that all six of the patients were being monitored, with no clinical progression or active therapy. However, with a median follow-up of 5 years, the progression-free survival (PFS) rate among the 45 patients was 97.7%, and the overall survival (OS) rate was 97.8%. Dr. Ferrajoli noted that, while the study population was clearly different, the results compare favorably with CLL clinical trial results that have previously shown a 5-year PFS of approximately 65% with FCR alone; approximately 70% with ibrutinib; and 81% with ibrutinib among patients with mutated IGHV status.
Furthermore, the rate of undetectable MRD status in mutated IGHV patients being 95% in evaluable patients in the current study is notably higher than rates of 51% through 67% reported in five other trials of CLL treatment with six cycles of FCR and with a rate of 79% in the DFCI trial of six-cycle chemotherapy plus ibrutinib.
And the current study’s undetectable MRD rate of 89% in the intention-to-treat population compares with just 13% though 40% in the five other chemotherapy trials and 79% in the DFCI trial, the authors note.
The current trial was the only one of any of their comparisons to utilize the three-cycle regimen.
Asked at the meeting about concerns of toxicities reported with obinutuzumab and chemotherapy, Dr. Ferrajoli said “the treatment was very well tolerated.”
“Myelosuppression is a concern with this combination, but we did make the use of prophylactic growth-factor mandatory in the study, so we were able to control that,” she said.
Dr. Jain noted that, while treatment trends have moved largely to chemo-free regimens, particularly in the United States because of concerns about the MDS, the current study’s results importantly shed light on a potentially beneficial approach of just three cycles of chemotherapy.
“In Europe and the rest of the world where chemo use is still common, this regimen could be considered,” he told MDedge. “The findings show that if you still use chemo in your practice, this regimen uses 50% less chemotherapy, yet seems to give higher response rates.”
“While MDS and acute myeloid leukemia (AML) remain a concern with any chemotherapy regimen, it is possible that 50% less chemo will lead to less risk of MDS AML, but longer-term follow-up [is needed],” he said.
Dr. Ferrajoli reported that she has received research support from Astra-Zeneca and Beigene. Dr. Jain has received research funding and honoraria from Genentech and Pharmacyclics.
FROM EHA 2022
‘Extremely exciting’ study results guide MM treatment options
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.
Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.
However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.
In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.
The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.
“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.
Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.
“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
Study details
In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.
At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.
The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).
The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.
“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.
Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.
“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.
When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).
However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.
“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”
He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.
“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
Lack of difference in overall survival
These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.
“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.”
Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.
The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.”
Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASCO 2022
Precision medicine: A new approach to AML, other blood cancers
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
Myeloid patients respond robustly to Moderna COVID vaccine
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
aotto@mdedge.com
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
aotto@mdedge.com
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
aotto@mdedge.com
FROM ASH 2021
For leukemias, COVID-19 death risks tied to poor prognoses, ICU deferrals
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
FROM ASH 2021