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Clozapine and cancer risk in schizophrenia patients: New data
Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.
The study was published online in The Lancet Psychiatry.
An unresolved issue
Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.
Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.
Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.
“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen.
Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.
To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.
“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.
The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.
Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
Patient education, vigilant monitoring
The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.
Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.
Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.
Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).
Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.
Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.
The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.
These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
A ‘vital’ medication
Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.
“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.
In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.
The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.
“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.
“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.
The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.
The study was published online in The Lancet Psychiatry.
An unresolved issue
Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.
Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.
Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.
“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen.
Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.
To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.
“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.
The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.
Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
Patient education, vigilant monitoring
The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.
Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.
Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.
Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).
Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.
Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.
The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.
These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
A ‘vital’ medication
Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.
“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.
In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.
The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.
“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.
“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.
The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.
The study was published online in The Lancet Psychiatry.
An unresolved issue
Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.
Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.
Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.
“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen.
Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.
To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.
“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.
The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.
Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
Patient education, vigilant monitoring
The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.
Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.
Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.
Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).
Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.
Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.
The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.
These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
A ‘vital’ medication
Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.
“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.
In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.
The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.
“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.
“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.
The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET PSYCHIATRY
Surrogate endpoints acceptable in AML trials, says FDA
The Food and Drug Administration has been harshly criticized for using surrogate endpoints in clinical trials in its approval of new drugs, and especially so in oncology, where critics have argued that the only truly meaningful endpoint is overall survival (OS).
But the FDA is now fighting back and is arguing that in certain cases surrogate endpoints do translate to overall survival benefits. A case in point is in clinical trials of new treatments being investigated in patients newly diagnosed with acute myeloid leukemia (AML).
The results show that these particular surrogate endpoints do have real value in predicting the efficacy of drugs for the treatment of newly diagnosed AML, they concluded.
“To our knowledge, our results represent the first direct examination of the relationship of response rate and EFS to OS using trial-level and patient-level data in patients with newly diagnosed AML treated with intensive induction chemotherapy,” the FDA investigators commented.
“The results support the FDA’s acceptance of EFS as a clinical benefit endpoint supportive of traditional approval for treatments with curative intent,” they added.
The analysis was published online on Dec. 10, 2021, in the Journal of Clinical Oncology.
“The central finding of the article, that both EFS and the CR rate are reliably associated with improved OS, is of immediate relevance and indicates that these parameters represent acceptable and appropriate surrogate endpoints for clinical trials of AML,” Courtney DiNardo, MD, University of Texas MD Anderson Cancer Center, Houston, and Daniel Pollyea, MD, University of Colorado at Denver, Aurora, wrote in an accompanying editorial.
“The establishment of CR and EFS as appropriate surrogate endpoints for patients with newly diagnosed AML receiving intensive chemotherapy will allow earlier evaluation of novel therapies and speed the delivery of safe and effective therapies to our patients,” they added.
Analysis of clinical trials submitted for approval
The FDA investigators conducted an analysis of eight trials that had been submitted to the agency for licensing approval between 2007 and 2011. Together, the trials included a total of 4,482 patients with newly diagnosed AML.
Five trials evaluated gemtuzumab ozogamicin (Mylotarg), while two trials evaluated a daunorubicin and cytarabine liposome injection, also known as CPX-351 (Vyxeos), and one trial evaluated midostaurin (RYDAPT).
“All were approved in combination with, or for use as, intensive induction chemotherapy in patients with newly diagnosed AML,” the team wrote. Both trial-level and patient-level associations between responses, EFS, and OS were evaluated.
The association between the hazard ratio for OS and the odds ratio for CR at the trial level was “moderate.” The association between the HR for OS and the OR for lesser response rates – namely, CR with incomplete hematologic recovery (CRi) and CR with incomplete platelet recovery (CRp) – was similarly moderate, as investigators note.
On the other hand, while the associations between the HR for OS and the HR for EFS were again moderate, “on the basis of the harmonized primary definition of EFS across trials, the association became stronger,” the authors reported. The harmonized definition of EFS across the trials included time from random assignment to treatment failure, relapse from CR, or death from any cause, whichever occurred earlier.
The FDA authors cautioned that a significant number of patients who relapsed did not die during the course of the clinical trial, resulting in a considerably longer OS, compared with EFS in some patients. However, to further explore the relationship between response and survival, a patient-level analysis of response – namely, CR versus CRi or CRp versus no response – was performed.”Patients who achieved a CR had a [27%] better OS, compared with patients whose best response was CRi or CRp,” the authors noted.
Patients who achieved a CRi or a CRp as their best response still had a 54% better OS, compared with patients who achieved no response, irrespective of the treatment received, they added.
Interestingly enough, a small number of patients who had no response to treatment also experienced prolonged survival, possibly because of successful second-line therapy, the authors speculated.
Effective salvage therapies
Commenting further in their editorial, Dr. DiNardo and Dr. Pollyea wrote that, given that there are now multiple effective salvage therapies for the treatment of AML, an OS endpoint no longer solely reflects the effectiveness of an initial therapy, as survival will also be affected by subsequent lines of AML-directed treatment.
“Accordingly, OS should no longer be considered the sole determinant of the value of a new therapy,” the editorialists emphasized.
Furthermore, as the treatment of AML is increasingly based on biologically defined and differentially targeted subsets, “the required sample sizes and timelines to run a proper randomized, phase 3 study for an OS end point of a rare AML subset become logistically untenable,” they wrote.
That said, the editorialists felt the fact that FDA employees performed this meta-analysis at all was “highly laudable.” “It is, moreover, gratifying to know that the experiences of clinical trial participants can be maximized beyond the original contributions made to the studies in which they originally volunteered,” the editorialists observed.
“In the United States, this example should inspire investigators and industry partners to prioritize similar analyses with their [own] data sets,” they added.
Dr. Norsworthy, Dr. DiNardo, and Dr. Pollyea disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has been harshly criticized for using surrogate endpoints in clinical trials in its approval of new drugs, and especially so in oncology, where critics have argued that the only truly meaningful endpoint is overall survival (OS).
But the FDA is now fighting back and is arguing that in certain cases surrogate endpoints do translate to overall survival benefits. A case in point is in clinical trials of new treatments being investigated in patients newly diagnosed with acute myeloid leukemia (AML).
The results show that these particular surrogate endpoints do have real value in predicting the efficacy of drugs for the treatment of newly diagnosed AML, they concluded.
“To our knowledge, our results represent the first direct examination of the relationship of response rate and EFS to OS using trial-level and patient-level data in patients with newly diagnosed AML treated with intensive induction chemotherapy,” the FDA investigators commented.
“The results support the FDA’s acceptance of EFS as a clinical benefit endpoint supportive of traditional approval for treatments with curative intent,” they added.
The analysis was published online on Dec. 10, 2021, in the Journal of Clinical Oncology.
“The central finding of the article, that both EFS and the CR rate are reliably associated with improved OS, is of immediate relevance and indicates that these parameters represent acceptable and appropriate surrogate endpoints for clinical trials of AML,” Courtney DiNardo, MD, University of Texas MD Anderson Cancer Center, Houston, and Daniel Pollyea, MD, University of Colorado at Denver, Aurora, wrote in an accompanying editorial.
“The establishment of CR and EFS as appropriate surrogate endpoints for patients with newly diagnosed AML receiving intensive chemotherapy will allow earlier evaluation of novel therapies and speed the delivery of safe and effective therapies to our patients,” they added.
Analysis of clinical trials submitted for approval
The FDA investigators conducted an analysis of eight trials that had been submitted to the agency for licensing approval between 2007 and 2011. Together, the trials included a total of 4,482 patients with newly diagnosed AML.
Five trials evaluated gemtuzumab ozogamicin (Mylotarg), while two trials evaluated a daunorubicin and cytarabine liposome injection, also known as CPX-351 (Vyxeos), and one trial evaluated midostaurin (RYDAPT).
“All were approved in combination with, or for use as, intensive induction chemotherapy in patients with newly diagnosed AML,” the team wrote. Both trial-level and patient-level associations between responses, EFS, and OS were evaluated.
The association between the hazard ratio for OS and the odds ratio for CR at the trial level was “moderate.” The association between the HR for OS and the OR for lesser response rates – namely, CR with incomplete hematologic recovery (CRi) and CR with incomplete platelet recovery (CRp) – was similarly moderate, as investigators note.
On the other hand, while the associations between the HR for OS and the HR for EFS were again moderate, “on the basis of the harmonized primary definition of EFS across trials, the association became stronger,” the authors reported. The harmonized definition of EFS across the trials included time from random assignment to treatment failure, relapse from CR, or death from any cause, whichever occurred earlier.
The FDA authors cautioned that a significant number of patients who relapsed did not die during the course of the clinical trial, resulting in a considerably longer OS, compared with EFS in some patients. However, to further explore the relationship between response and survival, a patient-level analysis of response – namely, CR versus CRi or CRp versus no response – was performed.”Patients who achieved a CR had a [27%] better OS, compared with patients whose best response was CRi or CRp,” the authors noted.
Patients who achieved a CRi or a CRp as their best response still had a 54% better OS, compared with patients who achieved no response, irrespective of the treatment received, they added.
Interestingly enough, a small number of patients who had no response to treatment also experienced prolonged survival, possibly because of successful second-line therapy, the authors speculated.
Effective salvage therapies
Commenting further in their editorial, Dr. DiNardo and Dr. Pollyea wrote that, given that there are now multiple effective salvage therapies for the treatment of AML, an OS endpoint no longer solely reflects the effectiveness of an initial therapy, as survival will also be affected by subsequent lines of AML-directed treatment.
“Accordingly, OS should no longer be considered the sole determinant of the value of a new therapy,” the editorialists emphasized.
Furthermore, as the treatment of AML is increasingly based on biologically defined and differentially targeted subsets, “the required sample sizes and timelines to run a proper randomized, phase 3 study for an OS end point of a rare AML subset become logistically untenable,” they wrote.
That said, the editorialists felt the fact that FDA employees performed this meta-analysis at all was “highly laudable.” “It is, moreover, gratifying to know that the experiences of clinical trial participants can be maximized beyond the original contributions made to the studies in which they originally volunteered,” the editorialists observed.
“In the United States, this example should inspire investigators and industry partners to prioritize similar analyses with their [own] data sets,” they added.
Dr. Norsworthy, Dr. DiNardo, and Dr. Pollyea disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has been harshly criticized for using surrogate endpoints in clinical trials in its approval of new drugs, and especially so in oncology, where critics have argued that the only truly meaningful endpoint is overall survival (OS).
But the FDA is now fighting back and is arguing that in certain cases surrogate endpoints do translate to overall survival benefits. A case in point is in clinical trials of new treatments being investigated in patients newly diagnosed with acute myeloid leukemia (AML).
The results show that these particular surrogate endpoints do have real value in predicting the efficacy of drugs for the treatment of newly diagnosed AML, they concluded.
“To our knowledge, our results represent the first direct examination of the relationship of response rate and EFS to OS using trial-level and patient-level data in patients with newly diagnosed AML treated with intensive induction chemotherapy,” the FDA investigators commented.
“The results support the FDA’s acceptance of EFS as a clinical benefit endpoint supportive of traditional approval for treatments with curative intent,” they added.
The analysis was published online on Dec. 10, 2021, in the Journal of Clinical Oncology.
“The central finding of the article, that both EFS and the CR rate are reliably associated with improved OS, is of immediate relevance and indicates that these parameters represent acceptable and appropriate surrogate endpoints for clinical trials of AML,” Courtney DiNardo, MD, University of Texas MD Anderson Cancer Center, Houston, and Daniel Pollyea, MD, University of Colorado at Denver, Aurora, wrote in an accompanying editorial.
“The establishment of CR and EFS as appropriate surrogate endpoints for patients with newly diagnosed AML receiving intensive chemotherapy will allow earlier evaluation of novel therapies and speed the delivery of safe and effective therapies to our patients,” they added.
Analysis of clinical trials submitted for approval
The FDA investigators conducted an analysis of eight trials that had been submitted to the agency for licensing approval between 2007 and 2011. Together, the trials included a total of 4,482 patients with newly diagnosed AML.
Five trials evaluated gemtuzumab ozogamicin (Mylotarg), while two trials evaluated a daunorubicin and cytarabine liposome injection, also known as CPX-351 (Vyxeos), and one trial evaluated midostaurin (RYDAPT).
“All were approved in combination with, or for use as, intensive induction chemotherapy in patients with newly diagnosed AML,” the team wrote. Both trial-level and patient-level associations between responses, EFS, and OS were evaluated.
The association between the hazard ratio for OS and the odds ratio for CR at the trial level was “moderate.” The association between the HR for OS and the OR for lesser response rates – namely, CR with incomplete hematologic recovery (CRi) and CR with incomplete platelet recovery (CRp) – was similarly moderate, as investigators note.
On the other hand, while the associations between the HR for OS and the HR for EFS were again moderate, “on the basis of the harmonized primary definition of EFS across trials, the association became stronger,” the authors reported. The harmonized definition of EFS across the trials included time from random assignment to treatment failure, relapse from CR, or death from any cause, whichever occurred earlier.
The FDA authors cautioned that a significant number of patients who relapsed did not die during the course of the clinical trial, resulting in a considerably longer OS, compared with EFS in some patients. However, to further explore the relationship between response and survival, a patient-level analysis of response – namely, CR versus CRi or CRp versus no response – was performed.”Patients who achieved a CR had a [27%] better OS, compared with patients whose best response was CRi or CRp,” the authors noted.
Patients who achieved a CRi or a CRp as their best response still had a 54% better OS, compared with patients who achieved no response, irrespective of the treatment received, they added.
Interestingly enough, a small number of patients who had no response to treatment also experienced prolonged survival, possibly because of successful second-line therapy, the authors speculated.
Effective salvage therapies
Commenting further in their editorial, Dr. DiNardo and Dr. Pollyea wrote that, given that there are now multiple effective salvage therapies for the treatment of AML, an OS endpoint no longer solely reflects the effectiveness of an initial therapy, as survival will also be affected by subsequent lines of AML-directed treatment.
“Accordingly, OS should no longer be considered the sole determinant of the value of a new therapy,” the editorialists emphasized.
Furthermore, as the treatment of AML is increasingly based on biologically defined and differentially targeted subsets, “the required sample sizes and timelines to run a proper randomized, phase 3 study for an OS end point of a rare AML subset become logistically untenable,” they wrote.
That said, the editorialists felt the fact that FDA employees performed this meta-analysis at all was “highly laudable.” “It is, moreover, gratifying to know that the experiences of clinical trial participants can be maximized beyond the original contributions made to the studies in which they originally volunteered,” the editorialists observed.
“In the United States, this example should inspire investigators and industry partners to prioritize similar analyses with their [own] data sets,” they added.
Dr. Norsworthy, Dr. DiNardo, and Dr. Pollyea disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
DKMS: Small nonprofit to world’s largest stem cell donor registry
When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.
“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.
In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.
“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.
Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).
In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”
From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.
Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
World’s largest registry
“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.
“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,
Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.
Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
Global partners
DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.
“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.
The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
Pandemic affects donations
But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.
Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.
“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.
However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.
“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
Workforce and clinical problems
Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.
“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.
“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.
Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.
“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.
In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.
“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.
To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.
The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
‘Every patient saved’
The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.
DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.
In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.
The last word goes to Mechtild Harf’s daughter Katharina.
“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”
“I have to believe that this dream will come true because otherwise, why dream, right?” she said.
Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.
When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.
“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.
In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.
“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.
Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).
In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”
From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.
Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
World’s largest registry
“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.
“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,
Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.
Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
Global partners
DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.
“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.
The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
Pandemic affects donations
But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.
Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.
“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.
However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.
“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
Workforce and clinical problems
Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.
“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.
“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.
Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.
“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.
In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.
“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.
To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.
The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
‘Every patient saved’
The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.
DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.
In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.
The last word goes to Mechtild Harf’s daughter Katharina.
“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”
“I have to believe that this dream will come true because otherwise, why dream, right?” she said.
Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.
When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.
“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.
In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.
“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.
Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).
In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”
From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.
Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
World’s largest registry
“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.
“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,
Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.
Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
Global partners
DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.
“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.
The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
Pandemic affects donations
But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.
Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.
“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.
However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.
“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
Workforce and clinical problems
Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.
“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.
“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.
Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.
“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.
In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.
“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.
To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.
The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
‘Every patient saved’
The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.
DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.
In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.
The last word goes to Mechtild Harf’s daughter Katharina.
“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”
“I have to believe that this dream will come true because otherwise, why dream, right?” she said.
Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.
AGILE: ‘Exciting’ survival results for IDH1-mutated AML
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
ATLANTA – Patients with acute myeloid leukemia (AML) bearing mutations in IDH1 who could not withstand the rigors of intensive therapy had improved event-free and overall survival when they were treated with the combination of ivosidenib (Tibsovo) and azacitidine (Onureg, Vidaza), compared with azacitidine alone.
The results come from the phase 3 AGILE trial., reported Hartmut Döhner, MD, from Ulm (Germany) University Hospital.
Median overall survival was 24 months with the combination, compared with 7.9 months for azacitidine-placebo, translating into a hazard ratio for death with the IVO-AZA of 0.44 (P = .0005).
“The IVO-AZA combination was safe and tolerable, with fewer infections reported relative to placebo plus AZA. Additionally, the clinical benefit of the combination was supported by favorable health-related quality of life,” he said.
Dr. Döhner spoke at a press briefing prior to the presentation of the trial results at the annual meeting of the American Society of Hematology.
“I’m really excited by the results from the AGILE trial,” commented Mikkael A. Sekeres, MD, chief of the division of hematology at the University of Miami’s Sylvester Comprehensive Cancer Center, who moderated the briefing.
The results show “survival that’s three times longer for a combination of ivosidenib plus azacitidine versus azacitidine alone in a very distinct population of patients who have an IDH1 mutation,” he said.
“The question that will arise is, if the standard of care is now to give azacitidine and venetoclax [Venclexta] to patients who don’t receive intensive chemotherapy in the inpatient setting, where does this trial end? And I would answer [by saying] that the combination of azacitidine is not truly nonintensive therapy, and it’s probably on a spectrum between nonintensive and intensive therapy, and probably closer to seven plus three than a lot of people recognize,” Dr. Sekeres said.
The combination of ivosidenib and azacitidine may therefore be a better choice for treatment of older patients with IDH1-mutated AML – particularly those with comorbidities – who may not be able to tolerate venetoclax plus azacitidine, he added.
AGILE results
For the analysis presented at the meeting, there was a data cutoff in March 2021, at which point 146 patients out of a planned 200 had been enrolled and randomly assigned. They received treatment with either oral ivosidenib 500 mg daily plus azacitidine 75 mg/m2, delivered subcutaneously or intravenously, or azacitidine plus placebo.
In May 2021, after an interim analysis, the independent data-monitoring committee recommended a halt to the trial because of significant improvements in outcomes among patients assigned to the combination, and those data are reported at the meeting.
The median patient age was about 76 years in each group. Approximately 75% of patients in each arm had de novo AML, and about 25% had AML secondary to treatment, myelodysplastic syndrome, or myeloproliferative neoplasms. The majority of patients in each group had intermediate cytogenetic risk disease.
The analysis was by intention to treat, with patients who did not have complete remission (CR) by week 24 considered to have had an event on day 1 of randomization.
At the time of the interim analysis, with the longest follow-up out to 29 months (the investigators did not report median follow-up time for the study), there were significantly fewer study events – defined as treatment failure by week 24, relapse from remission, or death from any cause – in the ivosidenib/azacitidine combination, with a hazard ratio of 0.33 (P = .0011).
The EFS benefit and the overall survival benefit were consistent across subgroups, the researchers noted, including in patients with de novo disease, demographics, baseline cytogenetic risk status, World Health Organization AML classification, baseline white blood cell count, and baseline percentage of bone marrow blasts.
Clinical and hematologic responses also favored the combination, with a complete response (CR) rate of 34%, compared with 11% for azacitidine alone (odds ratio, 4.8; P < .0001), and respective overall response rates of 45% versus 14% (odds ratio, 7.2; P < .0001).
Health-related quality of life measures also trended better with the combination across all subscales, and were significantly better at day 1 of cycle 5 in the diarrhea and appetite loss domains.
Treatment-emergent adverse events included grade 2 or higher differentiation syndrome, which occurred in 14.1% of patients treated with IVO-AZA versus 8.2% treated with AZA alone. Grade 3 or higher QT interval prolongation was also more frequent with the combination, at 9.9% versus 4.1%.
Any-grade infections were less common with IVO-AZA, however, at 28.2% versus 49.3% with AZA alone. At the briefing, this news organization asked coinvestigator Stephane de Botton, MD, Gustave Roussy Cancer Center, Villejuif, France, whether he could explain this seemingly paradoxical result.
He replied that the combination results in greater production of neutrophils and therefore better protection against infections, compared with azacitidine alone.
The study was funded by Agios Pharmaceuticals, now a part of Servier Pharmaceuticals. Dr. Döhner disclosed consultancy and other relationships with various companies. Dr. Sekeres disclosed consulting/advising for Novartis, Takea/Millennium, and Bristol-Myers Squibb.
A version of this article first appeared on Medscape.com.
AT ASH 2021
Talk early to patients with high-risk AML about end-of-life decisions
The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.
Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.
Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.
Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.
When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.
He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.
Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.
“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”
Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.
As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”
“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.
Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.
Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.
The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.
There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.
[email protected]
The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.
Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.
Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.
Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.
When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.
He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.
Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.
“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”
Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.
As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”
“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.
Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.
Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.
The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.
There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.
[email protected]
The prognosis isn’t good for high-risk AML, defined in the study as either relapsing/recurrent disease or a diagnosis made past the age of 59 years. Almost 60% of the patients (114) died during the 7 years of the study, which started in 2014.
Therefore, it’s important to bring up end-of-life decisions when patients are still able to discuss them, so families aren’t left struggling to guess how aggressive their loved ones might have wanted their final care to be, said lead investigator Hannah Abrams, MD, an internal medicine resident at Massachusetts General. She presented these findings at the annual meeting of the American Society of Hematology.
Much of the time, however, end-of-life discussions come too late. The study team found that nearly 40% (45/114) of the patients who died during the study were not involved in their final code decisions, which most often were to administer comfort care only. Many patients were too ill to participate; the median time between the last code change and death was just 2 days.
Dr. Abrams said she’s seen how families agonize when patients haven’t addressed the issue beforehand. “Witnessing that made me think this is really important to look at. Having these conversations upfront is really important,” she said in an interview.
When asked for comment, hematologist-oncologist Toby Campbell, MD, chief of palliative care at the University of Wisconsin, Madison, agreed.
He called this issue a “missed opportunity for patient autonomy and self-determination. Patients with high-risk AML commonly experience rapid changes in their clinical condition, which catch everyone by surprise. Healthcare providers should do more to prepare patients and families, rather than allow them to be surprised,” Dr. Campbell said.
Part of the problem, Dr. Abrams said, is that end-of-life discussions can fall through the cracks amid urgent discussions about chemotherapy options and other matters.
“One of the biggest things to make this more feasible is to schedule and reimburse time in clinic for this to happen,” she said, noting a need to carve out and protect “15 minutes for patients and clinicians to talk about this.”
Another aspect is that patients are often overly optimistic about their prognoses, so end-of-life discussions don’t seem as pressing. Educational materials about the meaning of various code options and when they are appropriate could help, Dr. Abrams said.
As for the psychological impact of bringing up end-of-life decisions early on, Mikkael Sekeres, MD, chief of the division of hematology at the University of Miami, stressed the importance of telling patients, “We are having this conversation because you are doing well, not because you are doing poorly, and this is the time to have it.”
“Sometimes it does take a sentinel event like an ICU stay before some people want to engage in that conversation, and unfortunately, that is often too late,” said Dr. Sekeres, who moderated Dr. Abrams’ presentation at the meeting.
Among other findings, Dr. Abrams and her team reported that at diagnosis, 86.0% of patients were full-code, and 8.5% had restrictions on life-sustaining therapies. Overall, 57% (114/200) of patients experienced a code status transition, with a median of two transitions during their illness.
Among patients who died, older age and receipt of non-intensive chemotherapy were associated with earlier discussions about code status.
The next step in the project is to determine if palliative care consults yield earlier discussions and greater patient involvement.
There was no commercial funding for the study, and Dr. Abrams and Dr. Campbell didn’t have any relevant disclosures. Dr. Sekeres is an advisor to Novartis, Takeda, and BMS.
[email protected]
FROM ASH 2021
Precision medicine: A new approach to AML, other blood cancers
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.
Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.1 With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.2
In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.
AML: Historical perspective
AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.2 These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.
Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.1 In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.
However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.2 These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.
Novel therapeutics in AML
Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.2 Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.
Acute promyelocytic leukemia
APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.2 Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.
Core binding factor AML
CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.
Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).
Intensive chemotherapy in younger/fit AML
Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.
Older/unfit patients with AML: Low-intensity therapy
Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.
Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.
Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.
Other FDA-approved therapies in AML
CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.
Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.
Expert perspectives: Future of AML therapy
Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.1
“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”
Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.
“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.
“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.
They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.
Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.
References
1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.
2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.
Myeloid patients respond robustly to Moderna COVID vaccine
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
[email protected]
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
[email protected]
Factors including age, gender, race, disease status, lower-intensity active treatment, baseline neutrophil and lymphocyte counts, and past history of stem cell transplant had no effects on seroconversion in the study, which, despite its small numbers, is one of the largest series to date among patients with myeloid cancers. The findings were reported at the annual meeting of the American Society of Hematology.
COVID vaccination “appears to induce a strong antibody response” in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), unlike with B-cell malignancies. “It indicates we should be aggressive about vaccinating such patients,” said senior investigator Jeffrey Lancet, MD, a blood cancer specialist at Moffitt, when he presented the findings at the meeting.
Presentation moderator Laura Michaelis, MD, a hematologist-oncologist at the Medical College of Wisconsin, Milwaukee, agreed.
The “strong antibody response in this group,” coupled with its high risk for severe COVID, “confirm the importance of these patients getting vaccinated,” she said.
Thirty patients with AML and 16 with MDS were included in the review. Most patients were in remission at the time of vaccination, but a third were in active treatment, including six on hypomethylating agents, six on targeted therapies, two on luspatercept, and one on lenalidomide. Thirty-two patients (69.6%) were a median of 17 months past allogeneic stem cell transplant.
Overall, 69.6% of patients developed IgG against spike proteins after the first shot and 95.7% of patients after the second dose, with a large increase in titer levels from the first to the second dose, from a mean of 315 AU/mL to 3,806.5 AU/mL following the second dose.
“Lab and clinical variables did not affect the antibody positivity rate after the second dose,” but patients on steroids and other immunosuppressants seemed less likely to respond to the first shot, Dr. Lancet said.
The study, conducted in early 2021, did not include acutely ill patients or those undergoing cheomotherapy induction and other aggressive treatments, because such patients were not being vaccinated at Moffitt during the study period.
The investigators measured anti-spike IgG by ELISA at baseline, then again about a month after the first shot and a month after the second shot.
Side effects were common and typically mild, including injection site pain, fatigue, headache, and arm swelling. Two patients with AML relapsed after vaccination.
Patients were a median of 68 years old when they were vaccinated; 58.7% were men; and almost all of the subjects were White. The median time from diagnosis to the first shot was 2 years.
The next step in the project is to study the timing of vaccination and response to it among patients on aggressive treatment and to perform neutralizing antibody assays to correlate IgG response with protection from COVID.
No funding was reported for the study. Investigators had numerous industry ties, including Dr. Lancet, a consultant for Celgene/BMS, Millenium Pharma/Takeda, AbbVie, and other firms. Dr. Michaelis didn’t have any disclosures.
[email protected]
FROM ASH 2021
For leukemias, COVID-19 death risks tied to poor prognoses, ICU deferrals
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
, results of an American Society of Hematology (ASH) COVID-19 registry study suggest.
Rates of severe COVID-19 were significantly higher among patients who had active disease or neutropenia at the time of their COVID-19 diagnosis. Mortality related to COVID-19 was linked to neutropenia, primary disease prognosis of less than 6 months, and deferral of recommended ICU care, study results show.
By contrast, mortality was not associated with active primary disease or its treatment, according to researcher Pinkal Desai, MD, MPH.
Taken together, these findings provide preliminary evidence to support the use of aggressive supportive treatment of COVID-19 in patients with acute leukemias and myelodysplastic syndromes, said Dr. Desai, a hematologist-oncologist with Weill Cornell Medicine and NewYork-Presbyterian in New York.
“If desired by patients, aggressive support for hospitalized patients with COVID-19 is appropriate, regardless of remission status, given the results of our study,” Dr. Desai said in a press conference during the annual meeting of the American Society of Hematology.
In non-cancer patient populations, advanced age and cytopenias have been associated with mortality related to COVID-19, Dr. Desai said. Likewise, patients with acute leukemias and myelodysplastic syndrome are generally older and have disease- or treatment-related cytopenias, which might affect the severity of and mortality from COVID-19, she added.
With that concern in mind, Dr. Desai and co-investigators looked at predictors of severe COVID-19 disease and death among patients in the ASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology.
This registry was started in the early days of the pandemic to provide real-time observational COVID-19 data to clinicians, according to an ASH news release.
The analysis by Dr. Desai and co-authors included 257 patients with COVID-19 as determined by their physician, including 135 with a primary diagnosis of acute myeloid leukemia, 82 with acute lymphocytic leukemia, and 40 with myelodysplastic syndromes. Sixty percent of the patients were hospitalized due to COVID-19.
At the time of COVID-19 diagnosis, 46% of patients were in remission, and 44% had active disease, according to the report.
Both neutropenia and active disease status at COVID-19 diagnosis were linked to severe COVID-19, defined as ICU admission due to a COVID-19-related reason, according to results of multivariable analysis. Among patients with severe COVID-19, 67% had active disease, meaning just 33% were in remission, Dr. Desai noted.
In multivariable analysis, two factors were significantly associated with mortality, she added: having an estimated pre-COVID-19 prognosis from the primary disease of less than 6 months, and deferral of ICU care when it was recommended to the patient.
Mortality was 21% overall, higher than would be expected in a non-cancer population, Dr. Desai said. For patients with COVID-19 requiring hospitalization, the mortality rate was 34% and for those patients who did go to the ICU, the mortality rate was 68%.
By contrast, there was no significant association between mortality and active disease as compared to disease in remission, Dr. Desai noted in her presentation. Likewise, mortality was not associated with active treatment at the time of COVID-19 diagnosis as compared to no treatment.
Gwen Nichols, MD, executive vice president and chief medical officer of the Leukemia & Lymphoma Society, New York, said those are reassuring data for patients with acute leukemias and myelodysplastic syndromes and their healthcare providers.
“From our point of view, it helps us say, ‘do not stop your treatment because of worries about COVID-19—it’s more important that you treat your cancer,” Dr. Nichols said in an interview. “We now know we can help people through COVID-19, and I think this is just really important data to back that up,” she added.
Dr. Desai provided disclosures related to Agios, Kura Oncology, and Bristol Myers Squibb (consultancy), and to Janssen R&D and Astex (research funding).
FROM ASH 2021
Clinical Edge Journal Scan Commentary: AML December 2021
This month, the phase II randomized study of azacitidine vs. azacitidine + enasidenib was reported by Dinardo et al.1 The primary endpoint was overall response rate. The study included 101 adult patients with newly diagnosed mutant-IDH2 acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. They were randomly assigned to enasidenib and azacitidine (Ena-AZA, n = 68) or azacitidine alone (AZA, n = 33). The overall response rate was significantly higher in patients receiving Ena-AZA vs. AZA (74% vs. 36%; odds ratio 4.9; P = .0003). More importantly, the rates of complete remission/complete remission with partial hematologic recovery was higher with Ena-AZA vs. AZA (57% vs. 18% P = .0001). The duration of response was 24.1 months vs 9.9 months for the Ena-AZA vs AZA group. Despite the higher and more durable responses with Ena+AZA, there was no difference in overall survival. The authors attributed that to patients receiving other effective therapies after disease progression. Overall patients tolerated the combination therapy well. The most frequent grade 3 or 4 events in the Ena-AZA vs. AZA groups were thrombocytopenia (37% vs. 19%) and neutropenia (37% vs. 25%).
Another study from the NCRI AML 16 trial demonstrated that reduced intensity conditioning (RIC) transplant in first remission vs. chemotherapy alone improved survival in older patients with AML who lacked favorable risk cytogenetics and were considered fit for intensive treatment. During a median follow-up of 60 months from remission, patients receiving RIC transplant vs. no transplant had superior survival (37% vs. 20%; hazard ratio [HR] 0.67; P < .001). Survival benefit with transplant in first remission vs. chemotherapy alone was observed across all Wheatley risk groups (adjusted HR 0.68; P < .001). The trial including 932 patients (age 60-70 years) with AML who entered remission and lacked favorable risk. Of these, 144 underwent RIC transplants from either matched sibling donors (n = 52) or matched unrelated donors (n = 92).
The outcome of patients with AML and central nervous system (CNS) involvement at presentation was reported by Ganzel et al. In that study, the investigators evaluated the incidence of CNS involvement in 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials. The incidence of CNS incolvement was 1.111 % (36 of 3240 patients). CNS involvement had no effect on remission rates or survival.
References
- Dinardo CD et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021;22(11):P1597-1608 (Nov 1).
- Russell NH et al. Outcomes of older patients aged 60 to 70 years undergoing reduced intensity transplant for acute myeloblastic leukemia: results of the NCRI acute myeloid leukemia 16 trial. Haematologica. 2021(Oct 14).
- Ganzel C et al. CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials. Blood Adv. 2021(Nov 12);5(22):4560-4568. doi: 10.1182/bloodadvances.2021004999.
This month, the phase II randomized study of azacitidine vs. azacitidine + enasidenib was reported by Dinardo et al.1 The primary endpoint was overall response rate. The study included 101 adult patients with newly diagnosed mutant-IDH2 acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. They were randomly assigned to enasidenib and azacitidine (Ena-AZA, n = 68) or azacitidine alone (AZA, n = 33). The overall response rate was significantly higher in patients receiving Ena-AZA vs. AZA (74% vs. 36%; odds ratio 4.9; P = .0003). More importantly, the rates of complete remission/complete remission with partial hematologic recovery was higher with Ena-AZA vs. AZA (57% vs. 18% P = .0001). The duration of response was 24.1 months vs 9.9 months for the Ena-AZA vs AZA group. Despite the higher and more durable responses with Ena+AZA, there was no difference in overall survival. The authors attributed that to patients receiving other effective therapies after disease progression. Overall patients tolerated the combination therapy well. The most frequent grade 3 or 4 events in the Ena-AZA vs. AZA groups were thrombocytopenia (37% vs. 19%) and neutropenia (37% vs. 25%).
Another study from the NCRI AML 16 trial demonstrated that reduced intensity conditioning (RIC) transplant in first remission vs. chemotherapy alone improved survival in older patients with AML who lacked favorable risk cytogenetics and were considered fit for intensive treatment. During a median follow-up of 60 months from remission, patients receiving RIC transplant vs. no transplant had superior survival (37% vs. 20%; hazard ratio [HR] 0.67; P < .001). Survival benefit with transplant in first remission vs. chemotherapy alone was observed across all Wheatley risk groups (adjusted HR 0.68; P < .001). The trial including 932 patients (age 60-70 years) with AML who entered remission and lacked favorable risk. Of these, 144 underwent RIC transplants from either matched sibling donors (n = 52) or matched unrelated donors (n = 92).
The outcome of patients with AML and central nervous system (CNS) involvement at presentation was reported by Ganzel et al. In that study, the investigators evaluated the incidence of CNS involvement in 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials. The incidence of CNS incolvement was 1.111 % (36 of 3240 patients). CNS involvement had no effect on remission rates or survival.
References
- Dinardo CD et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021;22(11):P1597-1608 (Nov 1).
- Russell NH et al. Outcomes of older patients aged 60 to 70 years undergoing reduced intensity transplant for acute myeloblastic leukemia: results of the NCRI acute myeloid leukemia 16 trial. Haematologica. 2021(Oct 14).
- Ganzel C et al. CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials. Blood Adv. 2021(Nov 12);5(22):4560-4568. doi: 10.1182/bloodadvances.2021004999.
This month, the phase II randomized study of azacitidine vs. azacitidine + enasidenib was reported by Dinardo et al.1 The primary endpoint was overall response rate. The study included 101 adult patients with newly diagnosed mutant-IDH2 acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. They were randomly assigned to enasidenib and azacitidine (Ena-AZA, n = 68) or azacitidine alone (AZA, n = 33). The overall response rate was significantly higher in patients receiving Ena-AZA vs. AZA (74% vs. 36%; odds ratio 4.9; P = .0003). More importantly, the rates of complete remission/complete remission with partial hematologic recovery was higher with Ena-AZA vs. AZA (57% vs. 18% P = .0001). The duration of response was 24.1 months vs 9.9 months for the Ena-AZA vs AZA group. Despite the higher and more durable responses with Ena+AZA, there was no difference in overall survival. The authors attributed that to patients receiving other effective therapies after disease progression. Overall patients tolerated the combination therapy well. The most frequent grade 3 or 4 events in the Ena-AZA vs. AZA groups were thrombocytopenia (37% vs. 19%) and neutropenia (37% vs. 25%).
Another study from the NCRI AML 16 trial demonstrated that reduced intensity conditioning (RIC) transplant in first remission vs. chemotherapy alone improved survival in older patients with AML who lacked favorable risk cytogenetics and were considered fit for intensive treatment. During a median follow-up of 60 months from remission, patients receiving RIC transplant vs. no transplant had superior survival (37% vs. 20%; hazard ratio [HR] 0.67; P < .001). Survival benefit with transplant in first remission vs. chemotherapy alone was observed across all Wheatley risk groups (adjusted HR 0.68; P < .001). The trial including 932 patients (age 60-70 years) with AML who entered remission and lacked favorable risk. Of these, 144 underwent RIC transplants from either matched sibling donors (n = 52) or matched unrelated donors (n = 92).
The outcome of patients with AML and central nervous system (CNS) involvement at presentation was reported by Ganzel et al. In that study, the investigators evaluated the incidence of CNS involvement in 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials. The incidence of CNS incolvement was 1.111 % (36 of 3240 patients). CNS involvement had no effect on remission rates or survival.
References
- Dinardo CD et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021;22(11):P1597-1608 (Nov 1).
- Russell NH et al. Outcomes of older patients aged 60 to 70 years undergoing reduced intensity transplant for acute myeloblastic leukemia: results of the NCRI acute myeloid leukemia 16 trial. Haematologica. 2021(Oct 14).
- Ganzel C et al. CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials. Blood Adv. 2021(Nov 12);5(22):4560-4568. doi: 10.1182/bloodadvances.2021004999.
Phase 3 fails to demonstrate survival benefit with tipifarnib maintenance in AML in remission
Key clinical point: Maintenance therapy with tipifarnib did not prolong survival in patients with acute myeloid leukemia (AML) in remission.
Major finding: The median disease-free survival for tipifarnib vs. observation arms was 8.9 vs. 5.3 months (hazard ratio [HR] 0.70; P = .026), which did not meet the prespecified limit to call a positive effect. The median overall survival was not significantly different between tipifarnib vs. observation arms (16.4 vs. 9.3 months; HR 0.74; P = .056).
Study details: Findings are from the phase 3 E2902 trial including 144 adult patients with non-M3 AML in remission and who were randomly assigned to tipifarnib or observation arms.
Disclosures: This study was supported by the US National Cancer Institute of the National Institutes of Health. No disclosures were reported.
Source: Luger SM et al. Leuk Res. 2021;111:106736 (Oct 28). Doi: 10.1016/j.leukres.2021.106736.
Key clinical point: Maintenance therapy with tipifarnib did not prolong survival in patients with acute myeloid leukemia (AML) in remission.
Major finding: The median disease-free survival for tipifarnib vs. observation arms was 8.9 vs. 5.3 months (hazard ratio [HR] 0.70; P = .026), which did not meet the prespecified limit to call a positive effect. The median overall survival was not significantly different between tipifarnib vs. observation arms (16.4 vs. 9.3 months; HR 0.74; P = .056).
Study details: Findings are from the phase 3 E2902 trial including 144 adult patients with non-M3 AML in remission and who were randomly assigned to tipifarnib or observation arms.
Disclosures: This study was supported by the US National Cancer Institute of the National Institutes of Health. No disclosures were reported.
Source: Luger SM et al. Leuk Res. 2021;111:106736 (Oct 28). Doi: 10.1016/j.leukres.2021.106736.
Key clinical point: Maintenance therapy with tipifarnib did not prolong survival in patients with acute myeloid leukemia (AML) in remission.
Major finding: The median disease-free survival for tipifarnib vs. observation arms was 8.9 vs. 5.3 months (hazard ratio [HR] 0.70; P = .026), which did not meet the prespecified limit to call a positive effect. The median overall survival was not significantly different between tipifarnib vs. observation arms (16.4 vs. 9.3 months; HR 0.74; P = .056).
Study details: Findings are from the phase 3 E2902 trial including 144 adult patients with non-M3 AML in remission and who were randomly assigned to tipifarnib or observation arms.
Disclosures: This study was supported by the US National Cancer Institute of the National Institutes of Health. No disclosures were reported.
Source: Luger SM et al. Leuk Res. 2021;111:106736 (Oct 28). Doi: 10.1016/j.leukres.2021.106736.