AML in the Elderly: a Biologically Distinct Disease in which MDR1 Expression and Unfavorable Cytogenetics Contribute to Poor Clinical Response. Studies of the Southwest Oncology Group

Elderly patients with acute myeloid leukemia (AML) respond poorly to chemotherapy compared to younger cohorts. To determine the contribution of biologic factors to this poor response, we studied 211 patients (161 de novo, 50 secondary AML) over 55 years of age (median: 68 years) registered to a single clinical trial for previously untreated AML (SWOG 9031: Phase III randomized trial of standard dose cytosine arabinoside and daunomycin +/− rhG-CSF). Pretreatment blasts were karyotyped, and were analyzed for MDR1 expression and functional efflux by multiparameter flow cytometry. In addition, pre-treatment marrows were analyzed for trilineage dyspoiesis. MDR1 expression was very high (71%) in these cases, distinctly different from a frequency of about 35% detected in a group of younger patients by similar methods. Functional efflux (58% of cases were efflux +) and unfavorable karyotype (e.g. −5/5q−, −7/7q−, complex abn; present in 32% of cases) were also frequent in both de novo and secondary AML cases. Over 80% of evaluable cases showed erythroid or megakaryocyte dyspoiesis while 68% showed myeloid dyspoiesis. Secondary AML, CD34 and MDR1 expression, functional efflux, and unfavorable cytogenetics were all associated with lower complete remission (CR) rates in univariate analysis. Dyspoiesis, while associated with MDR1 expression and unfavorable cytogenetics, was not clearly predictive of CR. In multivariate analysis, three independent predictors of CR were found: secondaryAML (p= 0.0035),MDR1 expression (p = 0.0041) and unfavorable cytogenetics (p = 0.0031). Resistant disease was associated with MDR1 expression (p = 0.0007) and unfavorable cytogenetics (p = 0.017). AML in the elderly is associated with a high frequency of dyspoiesis, unfavorable cytogenetics and MDR1 expression, and thus more closely resembles myelodysplasia related AML than the de novo AML of younger patients. Analysis of biologic disease parameters at AML diagnosis may help identify patients with a high likelihood of achieving CR with current therapies. Biologic studies can identify MDR1+ cases where patients may benefit from therapies which include MDR1 modulators, or non-MDR1 transported drugs. Other biologic factors are also likely important in AML in the elderly, and await further investigation.