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Prediction of adverse events during intensive induction chemotherapy for acute myeloid leukemia or high-grade myelodysplastic syndromes.

ABSTRACT: Intensive chemotherapy for newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with significant treatment-related morbidity and mortality. Herein, we investigate how pretreatment characteristics relate to early adverse outcomes in such patients, studying 205 consecutive individuals receiving curative-intent induction chemotherapy with cytarabine and an anthracycline ("7 + 3"; n?= 175) or a "7 + 3"-like regimen (n?=?30). Among the entire cohort, baseline grade 4 neutropenia (i.e., absolute neutrophil count <500 cells/µL) was associated with development of fever (P?=?0.04), documented infection (P < 0.0001), and bacteremia (P = 0.002) but not requirement for intensive care unit-level care; after exclusion of the 30 patients who received "7?+?3"-like induction, baseline grade 4 neutropenia remained associated with documented infection (P < 0.0001) and bacteremia (P = 0.0005). Among patients achieving a complete remission with the initial treatment cycle, grade 4 neutropenia was associated with delayed neutrophil count recovery (P < 0.0001). Low monocyte and lymphocyte counts at baseline were similarly associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, cytogenetic/molecular risk, and performance status, the risk of fever, documented infection, or bacteremia was 1.87 (95% confidence interval: 1.04-3.34; P=0.04)-fold, 4.95 (2.20-11.16; P<0.001)-fold, and 3.14 (0.99-9.98; P=0.05)-fold higher in patients with initial grade 4 neutropenia. Together, our studies identify severe baseline neutropenia as a risk factor for infection-associated adverse events after induction chemotherapy and may provide the rationale for the risk-adapted testing of myeloid growth factor support in this high-risk AML/MDS patient subset.

SUBMITTER: Buckley SA

PROVIDER: S-EPMC4391649 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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Project description:BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.MethodsWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.ResultsOf the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.ConclusionsPatients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

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Prediction of adverse events during intensive induction chemotherapy for acute myeloid leukemia or high-grade myelodysplastic syndromes.

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