Acute Myeloid Leukemia in the Elderly: Assessment of Multidrug Resistance (MDR1) and Cytogenetics Distinguishes Biologic Subgroups With Remarkably Distinct Responses to Standard Chemotherapy. A Southwest Oncology Group Study

Abstract

Compared with younger patients, elderly patients with acute myeloid leukemia (AML) respond poorly to conventional chemotherapy. To determine if this poor response is due to differences in the biologic characteristics of AML in the elderly, 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 leukemic blasts were karyotyped and were also analyzed for intrinsic drug resistance by quantitating expression of the multidrug resistance glycoprotein MDR1 and functional drug efflux using sensitive flow cytometric techniques. Results were correlated with clinical variables and outcome. These elderly AML patients had a high frequency of unfavorable cytogenetics (32%), MDR1 protein expression (71%), and functional drug efflux (58%); each of these factors occurred at high frequencies in both de novo and secondary AML patients and was associated with a significantly poorer complete remission (CR) rate. In multivariate analysis, secondary AML (P = .0035), unfavorable cytogenetics (P = .0031), and MDR1 (P = .0041) were each significantly and independently associated with lower CR rates. Resistant disease was associated with unfavorable cytogenetics (P = .017) and MDR1 expression (P = .0007). Strikingly, elderly MDR1(−) de novo AML patients with favorable/intermediate cytogenetics had a CR rate of 81%; with increasing MDR1 expression, CR rate decreased in this cytogenetic group. MDR1(+) secondary AML patients with unfavorable cytogenetics had a CR rate of only 12%. Thus, AML in the elderly is associated with an increased frequency of unfavorable cytogenetics and MDR1 expression, both of which independently contribute to poor outcomes. The high frequencies of these features in both de novo and secondary elderly AML patients suggest a common biologic mechanism for these leukemias distinct from that in younger patients. Investigation of biologic parameters at diagnosis in AML in the elderly may help identify patients with a high likelihood of achieving CR with conventional regimens, as well as those who may require alternate regimens designed to overcome therapy resistance.

Elevated levels of cyclin A1 and A (A2) mRNA in acute myeloid leukaemia are associated with increased survival

“…The poor response to therapy in the elderly individual with AML has been associated with an unfavourable cytogenetic change, as well as the expression of MDR1 and CD34 in the blast cells (Leith et al, 1997). In addition, in the elderly patient, AML cells have been associated with a resistance to apoptosis (Garrido et al, 2001).…”

Intensive consolidation with G‐CSF support: Tolerability, safety, reduced hospitalization, and efficacy in acute myeloid leukemia patients ≥60 years

“…The prognostic importance of karyotyping has been demonstrated in various studies. [37][38][39]51 Similarly, in our study cohort, patients with a monosomal karyotype had the worst outcome.…”

“…At diagnosis the karyotype (HOVON, SWOG, and ELN criteria) and molecular markers were recorded. [36][37][38] Karyotyping was performed by conventional chromosome banding-studies and fluorescence in situ hybridization (FISH) techniques. Karyotyping results were described according to published guidelines.…”

Granulocyte‐macrophage colony‐stimulating factor to increase efficacy of mitoxantrone, etoposide and cytarabine in previously untreated elderly patients with acute myeloid leukaemia: a Swedish multicentre randomized trial

“…We found a small but significant reduction of the time to neutrophil recovery for the GM-CSF-treated patients, which is in accordance with previous studies with GM-CSF (Rowe et al, 1995), as well as granulocyte colony-stimulating factor (G-CSF) (Heil et al, 1997;Bennet et al, 2001) but, even for our growth factor-treated patients, this period was comparably long (median 17 d), despite initiating GM-CSF treatment 1 d before the start of induction treatment. This probably mirrors a weaker proliferative capacity of the normal haematopoietic stem cells in these older patients (Stone et al, 1995;Leith et al, 1997).…”