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Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.
About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.
“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).
Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.
Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.
The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).
Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).
The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.
As well as providing critical insights into the role of molecular monitoring in AML and the dynamics of genetic mutations during AML treatment, the findings of this study suggest that the clearance of all leukemia-associated mutations was associated with favorable overall survival. Thus, clearance of all leukemia cells and of preleukemic cells with founder mutations is necessary to achieve a cure in this disease.
But to cure patients with AML, it may be important to direct therapy after remission toward the eradication of disease-initiating mutations, including epigenetic modifiers, given these mutations are often present at clinical remission and can initiate relapse through the acquisition of additional mutations.
Since this was a small, single-institution cohort, high-quality studies in larger AML cohorts are needed, to ascertain if whole-genome or whole-exome sequencing or other state-of-the-art genomic approaches used at the time of diagnosis can better predict prognosis than currently used methodologies.
Although subsequent studies will be needed to validate these findings and to credential clinical-grade assays for dynamic molecular studies, these data illustrate that the depth of remission after initial therapy represents an important parameter that is not sufficiently interrogated in the clinical context.
Dr. Friederike Pastore, of the human oncology and pathogenesis program, Memorial Sloan Kettering Cancer Center, New York, is receiving a grant from the German Research Foundation. Dr. Ross L Levine, of the leukemia service, department of medicine, Memorial Sloan Kettering Cancer Center, New York, has no disclosures. These remarks were taken from their editorial accompanying Dr. KLco’s report (JAMA. 2015;314[8]:778-80.).
As well as providing critical insights into the role of molecular monitoring in AML and the dynamics of genetic mutations during AML treatment, the findings of this study suggest that the clearance of all leukemia-associated mutations was associated with favorable overall survival. Thus, clearance of all leukemia cells and of preleukemic cells with founder mutations is necessary to achieve a cure in this disease.
But to cure patients with AML, it may be important to direct therapy after remission toward the eradication of disease-initiating mutations, including epigenetic modifiers, given these mutations are often present at clinical remission and can initiate relapse through the acquisition of additional mutations.
Since this was a small, single-institution cohort, high-quality studies in larger AML cohorts are needed, to ascertain if whole-genome or whole-exome sequencing or other state-of-the-art genomic approaches used at the time of diagnosis can better predict prognosis than currently used methodologies.
Although subsequent studies will be needed to validate these findings and to credential clinical-grade assays for dynamic molecular studies, these data illustrate that the depth of remission after initial therapy represents an important parameter that is not sufficiently interrogated in the clinical context.
Dr. Friederike Pastore, of the human oncology and pathogenesis program, Memorial Sloan Kettering Cancer Center, New York, is receiving a grant from the German Research Foundation. Dr. Ross L Levine, of the leukemia service, department of medicine, Memorial Sloan Kettering Cancer Center, New York, has no disclosures. These remarks were taken from their editorial accompanying Dr. KLco’s report (JAMA. 2015;314[8]:778-80.).
As well as providing critical insights into the role of molecular monitoring in AML and the dynamics of genetic mutations during AML treatment, the findings of this study suggest that the clearance of all leukemia-associated mutations was associated with favorable overall survival. Thus, clearance of all leukemia cells and of preleukemic cells with founder mutations is necessary to achieve a cure in this disease.
But to cure patients with AML, it may be important to direct therapy after remission toward the eradication of disease-initiating mutations, including epigenetic modifiers, given these mutations are often present at clinical remission and can initiate relapse through the acquisition of additional mutations.
Since this was a small, single-institution cohort, high-quality studies in larger AML cohorts are needed, to ascertain if whole-genome or whole-exome sequencing or other state-of-the-art genomic approaches used at the time of diagnosis can better predict prognosis than currently used methodologies.
Although subsequent studies will be needed to validate these findings and to credential clinical-grade assays for dynamic molecular studies, these data illustrate that the depth of remission after initial therapy represents an important parameter that is not sufficiently interrogated in the clinical context.
Dr. Friederike Pastore, of the human oncology and pathogenesis program, Memorial Sloan Kettering Cancer Center, New York, is receiving a grant from the German Research Foundation. Dr. Ross L Levine, of the leukemia service, department of medicine, Memorial Sloan Kettering Cancer Center, New York, has no disclosures. These remarks were taken from their editorial accompanying Dr. KLco’s report (JAMA. 2015;314[8]:778-80.).
Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.
About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.
“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).
Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.
Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.
The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).
Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).
The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.
Persistent leukemia-associated mutations that can be detected in at least 5% of bone marrow cells at 30 days after remission were associated with a significantly increased risk of relapse and reduced overall survival in patients with acute myeloid leukemia (AML), in a study published Aug. 25 in JAMA.
About 20% of adult patients with AML fail to achieve remission following standard initial induction chemotherapy, and approximately half of them will subsequently experience a relapse after achieving complete remission. Currently, tests that predict outcomes for these patients are imprecise, especially for those with intermediate-risk disease.
“The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations after chemotherapy than the identification of specific mutations at the time of presentation,” wrote Dr. Jeffery M. Klco, Washington University, St Louis, and his colleagues. (JAMA. 2015;314[8]:811-22).
Whole-genome or exome sequencing was performed on samples that were obtained at disease presentation from 71 patients with AML who were treated with standard induction chemotherapy in March 2002, with follow-up through January 2015. A subsequent re-analysis was conducted in a cohort of 50 patients, who had available samples from both presentation and documented remission.
Of this group, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission, while 26 patients had cleared all mutations.
The investigators noted that patients with at least one persistent mutation on day 30 had significantly reduced event-free survival compared with those who had cleared all mutations (median, 6.0 months [95% CI, 3.7-9.6] vs 17.9 months [95% CI, 11.3-40.4], hazard ratio [HR], 3.67 [95%CI, 1.93-7.11], P less than .001).
Findings were similar for overall survival. Median survival was 10.5 months [95% CI, 7.5-22.2] for those with persistent mutations vs 42.2 months [95% CI, 20.6-not estimable] for those without them (HR, 2.86 [95% CI, 1.39-5.88], P = .004).
The results were similar for the 32 patients with intermediate-risk AML, in that persistent mutations were associated with reduced event-free survival as well as overall survival.
FROM JAMA
Key clinical point: Leukemia-associated mutations that persisted 30 days after chemotherapy initiation were associated with a significantly increased risk of relapse and reduced overall survival in patients with AML.
Major finding: Patients with one persistent mutation at day 30 had an overall median survival of 10.5 months compared to 42.2 months for those who cleared all mutations (P = .003; HR, 2.86 [95% CI, 1.39-5.88]).
Data source: Whole-genome or exome sequencing was performed on specimens from 71 AML patients treated at a single center with standard induction chemotherapy.
Disclosures: The study was supported by grants from the National Institutes of Health and from the Barnes–Jewish Hospital Foundation. Dr. Spencer reports receiving personal fees from Cofactor Genomics, Dr Duncavage reports receiving personal fees from Cofactor Genomics and nonfinancial support from Agilent Technologies, and Dr Ozenberger reports receiving grant funding from the National Cancer Institute. There were no other disclosures.
