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CMML: GM-CSF inhibitor lenzilumab shows early promise
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
There is currently no international standard of care for patients with CMML, but given its overlap with other myelodysplastic and myeloproliferative syndromes, CMML is usually treated with the hypomethylating agent azacitidine (Vidaza, Onureg), which is associated with objective response rates of 40%-50% and a complete response rate of less than 20%. Alternatively, some patients are treated with the antimetabolite hydroxurea in the palliative setting.
CMML is “insidious, it’s rare, but we think the incidence is increasing because more patients are now getting sequencing done by their doctors, and therapy [related] cases, patients that have survived chemo in the last 10 years, can also develop this disease,” said Daniel Thomas, MD, PhD, from the South Australian Health and Medical Research Institute, Adelaide, in an interview.
Dr. Thomas is a co-investigator of the ongoing phase 2/3 PREACH-M trial, which is testing a novel strategy of treating CMML with mutations in the RAS pathway with a combination of azacitidine and the investigational antibody lenzilumab, which is a targeted inhibitor of granulocyte-macrophage colony-stimulating factor (GM-CSF).
Preliminary results from the trial, reported at the European Hematology Association (EHA) annual meeting, showed that among 10 patients with CMML bearing mutations in the RAS pathway, the combination was associated with durable decreases in monocyte counts, increases in platelet counts and hemoglobin levels, and reductions in both spleen size and C-reactive protein level.
Targeting GM-CSF
More than 90% of cases of CMML carry somatic mutations that are thought to be leukemogenic, with an estimated 46%-60% of cases having mutations in TET2, a tumor suppressor, and an estimated 40% having mutations in KRAS, NRAS, or CBL, all of which are involved in cellular proliferation, and which, research suggests, are sensitive to GM-CSF inhibition.
“I was very surprised that the RAS-mutant arm – so, patients that have KRAS, NRAS, or CBL mutations – are just responding beautifully to [lenzilumab], ” Dr. Thomas said.
“It’s [in the] early days, but if what we’re seeing is durable across the next 10 patients, then I think we’re looking at a game changer,” he added.
Cameron Durrant, MD, DRCOG, MRCGP, chairman and CEO of lenzilumab’s maker Humanigen, said in an interview that the development of the antibody for CMML was spurred in part by research from investigators at the Mayo Clinic, showing that patients with mutations that increased sensitivity to GM-CSF seemed to have better clinical outcomes when the growth factor was blocked.
In addition, Dr. Durrant said, preclinical research from investigators at the Moffitt Cancer Center, Tampa, found that myeloid and monocytic progenitors “fed” on GM-CSF and were sensitive to GM-CSF signal inhibition.
“The biological idea that’s being explored here in the clinic in this study is that by blocking, or starving, if you will, those cells of that food, then you can prevent this overgrowth of certain blood cells that lead to chronic myelomonocytic leukemia,” he said.
PREACH-M details
Lenzilumab is an engineered human immunoglobulin G1-kappa monoclonal antibody with high affinity for human GM-CSF.
In the open label, nonrandomized PREACH-M trial, 72 patients with CMML were enrolled and were assigned to receive 24 monthly cycles of therapy depending on mutational status.
Patients with RAS pathway mutations were assigned to receive azacitidine delivered subcutaneously 75 mg/m2 for 7 days, plus intravenous lenzilumab 552 mg on days 1 and 15 of cycle 1 and on day 1 only of all subsequent cycles.
Patients with TET2 mutations only were assigned to receive azacitidine on the same schedule, plus IV sodium ascorbate 30 g for 7 days, with the first dose 15 g, and subsequent doses 30 g if there is no evidence of tumor lysis syndrome. Following IV administration, patients continue on oral sodium ascorbate 1.1 g on all other days.
The primary endpoint of complete and partial responses any time during the first 12 cycles is planned for reporting at the annual meeting of the American Society of Hematology in December, Dr. Thomas said.
At EHA 2023, the investigators reported available data on 10 patients enrolled in the lenzilumab arm and one enrolled in the azacitidine-sodium ascorbate arm.
Among patients in the lenzilumab arm there was a 5.1-fold decrease in monocyte counts (P = .03) and 2.4-fold decrease in blast counts (P = .04) at 12 months of follow-up.
In addition there was a trend toward increased platelet counts over baseline at 12 months, a significant increase in blood hemoglobin concentration (P = .024), a significant reduction in spleen size (P = .03) and a trend toward lower levels of the inflammatory marker C-reactive protein.
There were 21 grade 3 or 4 adverse events reported, of which 5 were deemed to be possibly related to lenzilumab.
Dr. Thomas told this news organization that the investigators have been “pleasantly surprised” at how well patients tolerated the monoclonal antibody.
“We haven’t had any infusion reactions, we haven’t had any pulmonary alveolar proteinosis, [and] we haven’t had any fevers from the infusion, from the antibody,” he said.
There were some instances of neutropenia and thrombocytopenia that the investigators think may have been related to azacitidine, he noted.
The study is sponsored by the National Health and Medical Research Council of Australia. Dr. Thomas reported no relevant financial relationships. Dr. Durrant is an employee and director of Humanigen.
A version of this article first appeared on Medscape.com.
FROM EHA 2023
‘Best’ for most APL patients: Chemo-free regimen
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.
APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.
However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.
They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.
The median duration of follow-up was 5.66 years, with a range of 0-14 years.
The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.
Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).
Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.
The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).
Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).
In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).
Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).
Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.
Age was not a significant factor in terms of the incidence of relapse (P = .159).
Clinical trial versus real-world outcomes
Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).
Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).
Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.
The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.
“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.
“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.
“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”
Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.
“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.
The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
ATRA/ATO ‘gold standard’ for low/intermediate risk
Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.
“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”
“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.
Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.
“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.
Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.
“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”
Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
FROM EHA 2023
Widespread carboplatin, cisplatin shortages: NCCN survey
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
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.
Number of cancer survivors with functional limitations doubled in 20 years
Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.
Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.
The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.
For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
Patients surveyed on function
Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.
Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
Not just a result of living longer
Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.
“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.
Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.
Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.
“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
Quality of life beyond survivorship
Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.
“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.
The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.
There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”
Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.
“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.
A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.
Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.
Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.
The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.
For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
Patients surveyed on function
Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.
Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
Not just a result of living longer
Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.
“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.
Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.
Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.
“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
Quality of life beyond survivorship
Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.
“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.
The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.
There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”
Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.
“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.
A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.
Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.
Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.
The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.
For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
Patients surveyed on function
Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.
Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
Not just a result of living longer
Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.
“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.
Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.
Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.
“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
Quality of life beyond survivorship
Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.
“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.
The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.
There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”
Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.
“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.
A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.
FROM JAMA ONCOLOGY
AFib risk with cancer drugs underestimated
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Venetoclax shows promise for r/r hairy cell leukemia
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
Venetoclax is already approved for adults with chronic lymphocytic leukemia, small lymphocytic leukemia, and as part of a treatment combination in certain patients with acute myeloid leukemia.
The new findings suggest that the drug could also be a chemotherapy-free treatment option for HCL patients after the failure of multiple prior lines of therapy, including vemurafenib plus rituximab, the investigators wrote in a letter to the editor published in the New England Journal of Medicine.
Treatment options for such patients are limited, they noted.
Enrico Tiacci, MD, of the University of Perugia (Italy), and colleagues decided to explore the use of venetoclax in this patient population after reports of in vitro findings showing a possible benefit.
The investigators administered the drug off-label to six patients who had received vemurafenib plus rituximab as their most recent prior therapy; one was resistant and five relapsed after that therapy, they reported. Venetoclax was delivered in 29-day cycles.
After 6 or 12 cycles, two patients experienced complete remission with minimal residual disease (MRD), and one had partial remission, although each had incomplete platelet recovery.
Adding rituximab at a dose of 375 mg per square meter of body-surface area for three to eight cycles improved the depth of response in a patient who had a previous minor response, further reduced MRD in one who had a complete remission to venetoclax, and led to hematologic remission in one who had no response to venetoclax, they noted.
Progression-free survival ranged from 23 to 53-plus months in all five patients who did not have early progression and was similar or better than PFS seen after vemurafenib plus rituximab.
The main toxic effect of venetoclax was worsening of baseline neutropenia, which was sometimes complicated by infections or febrile neutropenia and was managed by dose reductions and granulocyte colony-stimulating factor.
“Thus, venetoclax with or without rituximab may serve as a safe and effective salvage option after failure of vemurafenib plus rituximab treatment, especially in patients who do not require a rapid recovery of blood count,” they concluded.
The study was supported by grants from Fondazione Associazione Italiana per la Ricerca sul Cancro and the Italian Ministry of Health.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Transplant vs. chemo: Similar AML survival rates
Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.
“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.
However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.
The study was published online in JAMA Oncology.
Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.
While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.
However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.
To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.
The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.
Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).
The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).
In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).
Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”
In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
Results ‘may not translate to real-life clinical practice’
An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.
“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.
“However, risk stratification strategies currently used were not followed,” he said.
For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.
In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.
“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.
Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.
“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”
The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.
In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.
“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”
Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”
The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.
“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.
However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.
The study was published online in JAMA Oncology.
Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.
While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.
However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.
To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.
The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.
Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).
The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).
In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).
Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”
In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
Results ‘may not translate to real-life clinical practice’
An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.
“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.
“However, risk stratification strategies currently used were not followed,” he said.
For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.
In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.
“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.
Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.
“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”
The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.
In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.
“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”
Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”
The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.
“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.
However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.
The study was published online in JAMA Oncology.
Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.
While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.
However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.
To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.
The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.
Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).
The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).
In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).
Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”
In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
Results ‘may not translate to real-life clinical practice’
An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.
“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.
“However, risk stratification strategies currently used were not followed,” he said.
For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.
In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.
“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.
Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.
“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”
The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.
In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.
“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”
Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”
The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
‘Astonishing’ results: Skip salvage chemo, proceed to HSCT
NEW ORLEANS –
The results come from the phase 3 ASAP Trial and were presented at the annual meeting of the American Society of Hematology.
“We selected this to be in the plenary because it completely changes how we’ve traditionally thought about acute myeloid leukemia,” commented press briefing moderator Mikkael A. Sekeres, MD, from the University of Miami, who also serves as chair of the ASH Committee on Communications.
“When we have a patient who has relapsed or refractory AML, that person is in a very, very difficult situation, and the mortality among those sort of patients is incredibly high,” Dr. Sekeres commented. “So traditionally we’ve given them very high doses of chemotherapy to try to reduce the tumor burden – at least that’s been the theory – to then get them successfully to a transplant.”
This new finding “completely upends that, if these results hold,” he said. The clinical implication is that “we no longer have to hospitalize these patients and give them very aggressive chemotherapy ... [and] we don’t introduce all the morbidity from giving them very high dose chemotherapy, which can actually prevent a transplant from happening if they get sick enough, and we can get them to a transplant quicker.”
The ASAP trial was conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or a relapse after first induction therapy.
They were randomly assigned to either a remission-induction strategy aiming for a better response prior to an allogeneic hematopoietic stem cell transplant (alloHCT), or a disease-control strategy consisting primarily of watchful waiting with low-dose cytarabine and single doses of mitoxantrone as needed, followed by sequential conditioning and alloHCT.
The results after 4 years of follow-up showed no differences in either leukemia-free survival or overall survival between patients who underwent additional chemotherapy with the remission-induction strategy and those who went straight to transplant, reported Johannes Schetelig, MD, MSc, from the Clinical Trials Unit at DKMS, Dresden, Germany.
“We expected non-inferiority – this was what we tested, and of course this was based on an assumption that we could get close or even somewhat better with respect to the primary endpoint, disease-free survival, after transplantation,” he said.
“What we did not expect is that the early success, [complete response] on day 56 after transplantation, also translates into equal long-term benefit, so this is what I was really astonished about,” Dr. Schetelig said at a press briefing prior to his presentation.
Less intensive approach
Dr. Schetelig explained that the rationale for the study was previous work by his group and others showing that alloHCT in patients with residual aplasia after first induction is feasible, with favorable outcomes, compared with standard of care. Additionally, the impetus for the research was evidence that sequential conditioning based on high-dose cytarabine or melphalan plus reduced-intensity conditioning and alloHCT resulted in long-term control for relapsed or refractory AML.
Dr. Schetelig also gave details of the two treatment arms of the ASAP trial. The remission-inducing arm consisted of cytarabine (3 g/m2 for younger patients or 1 g/m2 for patients over age 60) twice daily on days 1-3 plus 10 mitoxantrone mg/m2 on days 3-5 and subsequent alloHCT. In the other group – disease control prior to sequential conditioning and alloHCT – watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease control.
Although, as Dr. Schetelig noted, the statistical goal of the study was to show non-inferiority of the disease control arm, this less intensive strategy exceeded expectations for meeting the primary endpoint of disease-free survival (DFS; a maintained complete response) by day 56 after alloHCT.
In an intention-to-treat and per-protocol analysis, the respective rates of DFS at 56 days in the disease control group were 83.5% and 84.1%. In comparison, the respective rates in the remission-induction group were 81% and 81.3%.
Further, after a median follow-up from randomization of 37 months, there were no differences in either leukemia-free survival or overall survival out to 4 years after DFS at day 56.
The disease-control strategy was also associated with significantly fewer adverse events grade 3 or greater (23% vs. 64%, P < .001), and fewer days in hospital prior to transplant (mean 19 vs. 42, P < .001). There were no significant differences between the trial arms in either deaths within 28 days of randomization or time to discharge from hospital (28 days in each arm).
“These data support sequential conditioning and alloHCT without prior remission-induction chemotherapy whenever a stem cell donor is readily available,” the researchers concluded.
“These results underline the importance of facilitating alloHCT as [the] most effective anti-leukemic therapy in patients with [relapsed or refractory] AML and stress the need for starting donor search at diagnosis,” they added.
The study was sponsored by DKMS gemeinnützige GmbH. Dr. Schetelig disclosed honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Sekkeres reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
The results come from the phase 3 ASAP Trial and were presented at the annual meeting of the American Society of Hematology.
“We selected this to be in the plenary because it completely changes how we’ve traditionally thought about acute myeloid leukemia,” commented press briefing moderator Mikkael A. Sekeres, MD, from the University of Miami, who also serves as chair of the ASH Committee on Communications.
“When we have a patient who has relapsed or refractory AML, that person is in a very, very difficult situation, and the mortality among those sort of patients is incredibly high,” Dr. Sekeres commented. “So traditionally we’ve given them very high doses of chemotherapy to try to reduce the tumor burden – at least that’s been the theory – to then get them successfully to a transplant.”
This new finding “completely upends that, if these results hold,” he said. The clinical implication is that “we no longer have to hospitalize these patients and give them very aggressive chemotherapy ... [and] we don’t introduce all the morbidity from giving them very high dose chemotherapy, which can actually prevent a transplant from happening if they get sick enough, and we can get them to a transplant quicker.”
The ASAP trial was conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or a relapse after first induction therapy.
They were randomly assigned to either a remission-induction strategy aiming for a better response prior to an allogeneic hematopoietic stem cell transplant (alloHCT), or a disease-control strategy consisting primarily of watchful waiting with low-dose cytarabine and single doses of mitoxantrone as needed, followed by sequential conditioning and alloHCT.
The results after 4 years of follow-up showed no differences in either leukemia-free survival or overall survival between patients who underwent additional chemotherapy with the remission-induction strategy and those who went straight to transplant, reported Johannes Schetelig, MD, MSc, from the Clinical Trials Unit at DKMS, Dresden, Germany.
“We expected non-inferiority – this was what we tested, and of course this was based on an assumption that we could get close or even somewhat better with respect to the primary endpoint, disease-free survival, after transplantation,” he said.
“What we did not expect is that the early success, [complete response] on day 56 after transplantation, also translates into equal long-term benefit, so this is what I was really astonished about,” Dr. Schetelig said at a press briefing prior to his presentation.
Less intensive approach
Dr. Schetelig explained that the rationale for the study was previous work by his group and others showing that alloHCT in patients with residual aplasia after first induction is feasible, with favorable outcomes, compared with standard of care. Additionally, the impetus for the research was evidence that sequential conditioning based on high-dose cytarabine or melphalan plus reduced-intensity conditioning and alloHCT resulted in long-term control for relapsed or refractory AML.
Dr. Schetelig also gave details of the two treatment arms of the ASAP trial. The remission-inducing arm consisted of cytarabine (3 g/m2 for younger patients or 1 g/m2 for patients over age 60) twice daily on days 1-3 plus 10 mitoxantrone mg/m2 on days 3-5 and subsequent alloHCT. In the other group – disease control prior to sequential conditioning and alloHCT – watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease control.
Although, as Dr. Schetelig noted, the statistical goal of the study was to show non-inferiority of the disease control arm, this less intensive strategy exceeded expectations for meeting the primary endpoint of disease-free survival (DFS; a maintained complete response) by day 56 after alloHCT.
In an intention-to-treat and per-protocol analysis, the respective rates of DFS at 56 days in the disease control group were 83.5% and 84.1%. In comparison, the respective rates in the remission-induction group were 81% and 81.3%.
Further, after a median follow-up from randomization of 37 months, there were no differences in either leukemia-free survival or overall survival out to 4 years after DFS at day 56.
The disease-control strategy was also associated with significantly fewer adverse events grade 3 or greater (23% vs. 64%, P < .001), and fewer days in hospital prior to transplant (mean 19 vs. 42, P < .001). There were no significant differences between the trial arms in either deaths within 28 days of randomization or time to discharge from hospital (28 days in each arm).
“These data support sequential conditioning and alloHCT without prior remission-induction chemotherapy whenever a stem cell donor is readily available,” the researchers concluded.
“These results underline the importance of facilitating alloHCT as [the] most effective anti-leukemic therapy in patients with [relapsed or refractory] AML and stress the need for starting donor search at diagnosis,” they added.
The study was sponsored by DKMS gemeinnützige GmbH. Dr. Schetelig disclosed honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Sekkeres reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS –
The results come from the phase 3 ASAP Trial and were presented at the annual meeting of the American Society of Hematology.
“We selected this to be in the plenary because it completely changes how we’ve traditionally thought about acute myeloid leukemia,” commented press briefing moderator Mikkael A. Sekeres, MD, from the University of Miami, who also serves as chair of the ASH Committee on Communications.
“When we have a patient who has relapsed or refractory AML, that person is in a very, very difficult situation, and the mortality among those sort of patients is incredibly high,” Dr. Sekeres commented. “So traditionally we’ve given them very high doses of chemotherapy to try to reduce the tumor burden – at least that’s been the theory – to then get them successfully to a transplant.”
This new finding “completely upends that, if these results hold,” he said. The clinical implication is that “we no longer have to hospitalize these patients and give them very aggressive chemotherapy ... [and] we don’t introduce all the morbidity from giving them very high dose chemotherapy, which can actually prevent a transplant from happening if they get sick enough, and we can get them to a transplant quicker.”
The ASAP trial was conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or a relapse after first induction therapy.
They were randomly assigned to either a remission-induction strategy aiming for a better response prior to an allogeneic hematopoietic stem cell transplant (alloHCT), or a disease-control strategy consisting primarily of watchful waiting with low-dose cytarabine and single doses of mitoxantrone as needed, followed by sequential conditioning and alloHCT.
The results after 4 years of follow-up showed no differences in either leukemia-free survival or overall survival between patients who underwent additional chemotherapy with the remission-induction strategy and those who went straight to transplant, reported Johannes Schetelig, MD, MSc, from the Clinical Trials Unit at DKMS, Dresden, Germany.
“We expected non-inferiority – this was what we tested, and of course this was based on an assumption that we could get close or even somewhat better with respect to the primary endpoint, disease-free survival, after transplantation,” he said.
“What we did not expect is that the early success, [complete response] on day 56 after transplantation, also translates into equal long-term benefit, so this is what I was really astonished about,” Dr. Schetelig said at a press briefing prior to his presentation.
Less intensive approach
Dr. Schetelig explained that the rationale for the study was previous work by his group and others showing that alloHCT in patients with residual aplasia after first induction is feasible, with favorable outcomes, compared with standard of care. Additionally, the impetus for the research was evidence that sequential conditioning based on high-dose cytarabine or melphalan plus reduced-intensity conditioning and alloHCT resulted in long-term control for relapsed or refractory AML.
Dr. Schetelig also gave details of the two treatment arms of the ASAP trial. The remission-inducing arm consisted of cytarabine (3 g/m2 for younger patients or 1 g/m2 for patients over age 60) twice daily on days 1-3 plus 10 mitoxantrone mg/m2 on days 3-5 and subsequent alloHCT. In the other group – disease control prior to sequential conditioning and alloHCT – watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were permitted for disease control.
Although, as Dr. Schetelig noted, the statistical goal of the study was to show non-inferiority of the disease control arm, this less intensive strategy exceeded expectations for meeting the primary endpoint of disease-free survival (DFS; a maintained complete response) by day 56 after alloHCT.
In an intention-to-treat and per-protocol analysis, the respective rates of DFS at 56 days in the disease control group were 83.5% and 84.1%. In comparison, the respective rates in the remission-induction group were 81% and 81.3%.
Further, after a median follow-up from randomization of 37 months, there were no differences in either leukemia-free survival or overall survival out to 4 years after DFS at day 56.
The disease-control strategy was also associated with significantly fewer adverse events grade 3 or greater (23% vs. 64%, P < .001), and fewer days in hospital prior to transplant (mean 19 vs. 42, P < .001). There were no significant differences between the trial arms in either deaths within 28 days of randomization or time to discharge from hospital (28 days in each arm).
“These data support sequential conditioning and alloHCT without prior remission-induction chemotherapy whenever a stem cell donor is readily available,” the researchers concluded.
“These results underline the importance of facilitating alloHCT as [the] most effective anti-leukemic therapy in patients with [relapsed or refractory] AML and stress the need for starting donor search at diagnosis,” they added.
The study was sponsored by DKMS gemeinnützige GmbH. Dr. Schetelig disclosed honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Dr. Sekkeres reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASH 2022
Global effort needed to widen access to HSCT
The use of HSCT, the main curative option for AML, “remains unacceptably low,” commented Molly Tokaz, MD, a hematology/oncology fellow at the Fred Hutchinson Cancer Center, Seattle.
She was presenting the findings from a study of worldwide HSCT utilization at the annual meeting of the American Society of Hematology.
Globally, the incidence of AML has increased 16.2% – from 101,867 cases in 2009 to 118,404 in 2016, she noted. This in turn has led to a 54.9% increase in the worldwide use of HSCT for AML, from 9,659 to 14,965 transplants per year over the same period.
North America and Europe have the highest utilization rates of allogeneic HSCT for AML, but even so, fewer than 40% of patients have the procedure, raising a “question of how [well] we are prioritizing the use of HSCT, even in these resource-abundant health systems,” Dr. Tokaz said.
Meanwhile, in Africa, South America, and the Eastern Mediterranean, fewer than 5% of AML patients undergo transplant. Although “resource-constrained regions have the largest growth in HSCT use” in recent years, utilization rates remain abysmally low, “which has profound effects on the expected outcomes for patients in these regions,” she said.
Overall, “patients from lower- and middle-income countries face substantial barriers to accessing stem cell transplantation for AML,” commented Chancellor Donald, MD, a hematologist/oncologist at Tulane University, New Orleans, who moderated the session.
The “stark regional differences” illustrate “inequities in the delivery of stem cell transplants” but also opportunities “to improve access to this potentially curative treatment,” he said.
The goal of the study was to establish a global baseline of HSCT utilization to help focus future expansion efforts aimed at closing regional access gaps. It shows there is much work to be done, Dr. Tokaz said.
An international effort is needed to address the issue, including better data collection, implementation of regional HSCT programs, increased representation of ethnic and racial minorities in international donor registries, and other measures. In many cases, telemedicine can help with sharing cross-border expertise.
In short, what’s needed is a “comprehensive global effort to improve outcomes for patients with AML” worldwide, Dr. Tokaz said.
Timing of transplant is similar across regions, generally coming during the first complete remission, and there’s also been a global shift toward collecting stem cells from peripheral blood.
There has also been a marked shift away from autologous procedures and toward allogeneic transplants, she said.
A key difference between regions, however, is that while more than half of transplants are from unrelated donors in Europe and North America, almost all are from related donors in Africa and the Eastern Mediterranean, with an increasing proportion of haploidentical donors. In addition, the majority of transplants in Asia, the western Pacific, and South America are from related donors.
The use of related donors has implications for HSCT treatment algorithms and outcomes, Dr. Tokaz said.
The estimates of AML incidence were obtained from the 2019 Global Burden of Disease study. Data on HSCT utilization came from the Worldwide Network for Blood and Marrow Transplantation. No funding source was reported. Dr. Tokaz reports no relevant financial relationships, but some co-authors had numerous industry ties. Dr. Donald reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The use of HSCT, the main curative option for AML, “remains unacceptably low,” commented Molly Tokaz, MD, a hematology/oncology fellow at the Fred Hutchinson Cancer Center, Seattle.
She was presenting the findings from a study of worldwide HSCT utilization at the annual meeting of the American Society of Hematology.
Globally, the incidence of AML has increased 16.2% – from 101,867 cases in 2009 to 118,404 in 2016, she noted. This in turn has led to a 54.9% increase in the worldwide use of HSCT for AML, from 9,659 to 14,965 transplants per year over the same period.
North America and Europe have the highest utilization rates of allogeneic HSCT for AML, but even so, fewer than 40% of patients have the procedure, raising a “question of how [well] we are prioritizing the use of HSCT, even in these resource-abundant health systems,” Dr. Tokaz said.
Meanwhile, in Africa, South America, and the Eastern Mediterranean, fewer than 5% of AML patients undergo transplant. Although “resource-constrained regions have the largest growth in HSCT use” in recent years, utilization rates remain abysmally low, “which has profound effects on the expected outcomes for patients in these regions,” she said.
Overall, “patients from lower- and middle-income countries face substantial barriers to accessing stem cell transplantation for AML,” commented Chancellor Donald, MD, a hematologist/oncologist at Tulane University, New Orleans, who moderated the session.
The “stark regional differences” illustrate “inequities in the delivery of stem cell transplants” but also opportunities “to improve access to this potentially curative treatment,” he said.
The goal of the study was to establish a global baseline of HSCT utilization to help focus future expansion efforts aimed at closing regional access gaps. It shows there is much work to be done, Dr. Tokaz said.
An international effort is needed to address the issue, including better data collection, implementation of regional HSCT programs, increased representation of ethnic and racial minorities in international donor registries, and other measures. In many cases, telemedicine can help with sharing cross-border expertise.
In short, what’s needed is a “comprehensive global effort to improve outcomes for patients with AML” worldwide, Dr. Tokaz said.
Timing of transplant is similar across regions, generally coming during the first complete remission, and there’s also been a global shift toward collecting stem cells from peripheral blood.
There has also been a marked shift away from autologous procedures and toward allogeneic transplants, she said.
A key difference between regions, however, is that while more than half of transplants are from unrelated donors in Europe and North America, almost all are from related donors in Africa and the Eastern Mediterranean, with an increasing proportion of haploidentical donors. In addition, the majority of transplants in Asia, the western Pacific, and South America are from related donors.
The use of related donors has implications for HSCT treatment algorithms and outcomes, Dr. Tokaz said.
The estimates of AML incidence were obtained from the 2019 Global Burden of Disease study. Data on HSCT utilization came from the Worldwide Network for Blood and Marrow Transplantation. No funding source was reported. Dr. Tokaz reports no relevant financial relationships, but some co-authors had numerous industry ties. Dr. Donald reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The use of HSCT, the main curative option for AML, “remains unacceptably low,” commented Molly Tokaz, MD, a hematology/oncology fellow at the Fred Hutchinson Cancer Center, Seattle.
She was presenting the findings from a study of worldwide HSCT utilization at the annual meeting of the American Society of Hematology.
Globally, the incidence of AML has increased 16.2% – from 101,867 cases in 2009 to 118,404 in 2016, she noted. This in turn has led to a 54.9% increase in the worldwide use of HSCT for AML, from 9,659 to 14,965 transplants per year over the same period.
North America and Europe have the highest utilization rates of allogeneic HSCT for AML, but even so, fewer than 40% of patients have the procedure, raising a “question of how [well] we are prioritizing the use of HSCT, even in these resource-abundant health systems,” Dr. Tokaz said.
Meanwhile, in Africa, South America, and the Eastern Mediterranean, fewer than 5% of AML patients undergo transplant. Although “resource-constrained regions have the largest growth in HSCT use” in recent years, utilization rates remain abysmally low, “which has profound effects on the expected outcomes for patients in these regions,” she said.
Overall, “patients from lower- and middle-income countries face substantial barriers to accessing stem cell transplantation for AML,” commented Chancellor Donald, MD, a hematologist/oncologist at Tulane University, New Orleans, who moderated the session.
The “stark regional differences” illustrate “inequities in the delivery of stem cell transplants” but also opportunities “to improve access to this potentially curative treatment,” he said.
The goal of the study was to establish a global baseline of HSCT utilization to help focus future expansion efforts aimed at closing regional access gaps. It shows there is much work to be done, Dr. Tokaz said.
An international effort is needed to address the issue, including better data collection, implementation of regional HSCT programs, increased representation of ethnic and racial minorities in international donor registries, and other measures. In many cases, telemedicine can help with sharing cross-border expertise.
In short, what’s needed is a “comprehensive global effort to improve outcomes for patients with AML” worldwide, Dr. Tokaz said.
Timing of transplant is similar across regions, generally coming during the first complete remission, and there’s also been a global shift toward collecting stem cells from peripheral blood.
There has also been a marked shift away from autologous procedures and toward allogeneic transplants, she said.
A key difference between regions, however, is that while more than half of transplants are from unrelated donors in Europe and North America, almost all are from related donors in Africa and the Eastern Mediterranean, with an increasing proportion of haploidentical donors. In addition, the majority of transplants in Asia, the western Pacific, and South America are from related donors.
The use of related donors has implications for HSCT treatment algorithms and outcomes, Dr. Tokaz said.
The estimates of AML incidence were obtained from the 2019 Global Burden of Disease study. Data on HSCT utilization came from the Worldwide Network for Blood and Marrow Transplantation. No funding source was reported. Dr. Tokaz reports no relevant financial relationships, but some co-authors had numerous industry ties. Dr. Donald reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ASH 2022