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Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.
Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.
Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.
In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.
Decitabine was administered at a dose of 20 mg/m2 of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.
Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).
Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).
“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.
The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.
The current study raises the important question of the definition of a response. Complete remission conventionally entails bone marrow with less than 5% blasts and normalization of blood counts; absent these, remission is considered incomplete. After various confounding factors are taken into account, a complete response with cytotoxic therapy is associated with longer remissions and longer survival than is complete remission with incomplete count recovery.
The authors of this paper considered a response to be blast clearance to less than 5%, but complete remission was seen in only 4 of the 21 patients with TP53 mutations who fulfilled this criterion. The mutant allele burden was also similar in patients who had a response, regardless of blood count recovery.
In contrast, measurable residual disease is considerably more frequent in patients with complete remission with incomplete count recovery than in patients with complete remission who have received cytotoxic therapy, indicating that more data are needed on subsequent clinical outcomes according to whether clearance of blasts is accompanied by count recovery in patients with AML and TP53 mutations who have received decitabine.
AML “targeted-therapy” trials typically involve one drug, and this policy is called into question by the diverse molecular architecture (and brief remissions) observed in this trial. The trial by Welch et al. points to inevitable, rational replacement of large trials in which homogeneous therapy is administered for a heterogeneous disease by smaller, subgroup-specific trials.
The article also suggests questions that are likely to complicate this future.
Dr. Elihu Estey is with the division of hematology, University of Washington Medical Center, and the clinical research division, Fred Hutchinson Cancer Research Center, Seattle. He had no disclosures. These remarks were taken from an editorial accompanying Dr. Welch’s paper (N Engl J Med. 2016;375:2023-36).
The current study raises the important question of the definition of a response. Complete remission conventionally entails bone marrow with less than 5% blasts and normalization of blood counts; absent these, remission is considered incomplete. After various confounding factors are taken into account, a complete response with cytotoxic therapy is associated with longer remissions and longer survival than is complete remission with incomplete count recovery.
The authors of this paper considered a response to be blast clearance to less than 5%, but complete remission was seen in only 4 of the 21 patients with TP53 mutations who fulfilled this criterion. The mutant allele burden was also similar in patients who had a response, regardless of blood count recovery.
In contrast, measurable residual disease is considerably more frequent in patients with complete remission with incomplete count recovery than in patients with complete remission who have received cytotoxic therapy, indicating that more data are needed on subsequent clinical outcomes according to whether clearance of blasts is accompanied by count recovery in patients with AML and TP53 mutations who have received decitabine.
AML “targeted-therapy” trials typically involve one drug, and this policy is called into question by the diverse molecular architecture (and brief remissions) observed in this trial. The trial by Welch et al. points to inevitable, rational replacement of large trials in which homogeneous therapy is administered for a heterogeneous disease by smaller, subgroup-specific trials.
The article also suggests questions that are likely to complicate this future.
Dr. Elihu Estey is with the division of hematology, University of Washington Medical Center, and the clinical research division, Fred Hutchinson Cancer Research Center, Seattle. He had no disclosures. These remarks were taken from an editorial accompanying Dr. Welch’s paper (N Engl J Med. 2016;375:2023-36).
The current study raises the important question of the definition of a response. Complete remission conventionally entails bone marrow with less than 5% blasts and normalization of blood counts; absent these, remission is considered incomplete. After various confounding factors are taken into account, a complete response with cytotoxic therapy is associated with longer remissions and longer survival than is complete remission with incomplete count recovery.
The authors of this paper considered a response to be blast clearance to less than 5%, but complete remission was seen in only 4 of the 21 patients with TP53 mutations who fulfilled this criterion. The mutant allele burden was also similar in patients who had a response, regardless of blood count recovery.
In contrast, measurable residual disease is considerably more frequent in patients with complete remission with incomplete count recovery than in patients with complete remission who have received cytotoxic therapy, indicating that more data are needed on subsequent clinical outcomes according to whether clearance of blasts is accompanied by count recovery in patients with AML and TP53 mutations who have received decitabine.
AML “targeted-therapy” trials typically involve one drug, and this policy is called into question by the diverse molecular architecture (and brief remissions) observed in this trial. The trial by Welch et al. points to inevitable, rational replacement of large trials in which homogeneous therapy is administered for a heterogeneous disease by smaller, subgroup-specific trials.
The article also suggests questions that are likely to complicate this future.
Dr. Elihu Estey is with the division of hematology, University of Washington Medical Center, and the clinical research division, Fred Hutchinson Cancer Research Center, Seattle. He had no disclosures. These remarks were taken from an editorial accompanying Dr. Welch’s paper (N Engl J Med. 2016;375:2023-36).
Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.
Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.
Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.
In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.
Decitabine was administered at a dose of 20 mg/m2 of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.
Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).
Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).
“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.
The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.
Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.
Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.
Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.
In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.
Decitabine was administered at a dose of 20 mg/m2 of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.
Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).
Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).
“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.
The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Of 116 patients, 53 (46%) experienced bone marrow blast clearance (less than 5% blasts), and response rates were higher among those with an unfavorable cytogenetic risk profile.
Data source: A prospective single-center clinical trial that evaluated single-agent decitabine in 84 adult patients with AML or MDS, with an extension cohort.
Disclosures: The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.