Monosomy Karyotype in Acute Myeloid Leukemia Predicts Adverse Treatment Outcome with Low Complete Remission Rate and Worse Event-Free and Overall Survival, and Associates with High Functional Activity of Multidrug Resistance (MDR).

It has been revealed that monosomy karyotype (MK), defined as 1) two or more distinct autosomal chromosome monosomies or 2) one single autosomal monosomy in the presence of structural abnormalities, identifies the highly unfavorable cytogenetic risk group of patients with acute myeloid leukemia (Breems, J Clin Oncol 2008), but lacking validation data. The current study aimed to validate the unfavorable impact of MK not only on overall survival (OS) but also on complete remission (CR) rate and event free survival (EFS) in AML patients.

A total of 370 consecutive AML (excluding APL) patients with available cytogenetic data who received treatment between 1995 and 2008 at the Samsung Medical Center, Seoul, Korea were included in this retrospective study, among whom 169 patients (45.7%) showed normal karyotype; 65 patients (17.6%), core binding factor (CBF) positive AML; and 136 patients (36.7%), non-CBF AML, respectively. Karyotypes were scored according to their structural abnormalities, monosomy, trisomy, deletion and marker chromosome. The CR rate, EFS and OS were compared according to the presence of each cytogenetic abnormality. In addition, multidrug resistance (MDR) functional assay (P-glycoprotein assay) was performed and MDR functional activity was calculated by verapamil-inhibited rhodamine-123 efflux activity minus uninhibited rhodamine-123 efflux activity, and positivity was determined as equal to or over 5% MDR activity.

Among treated non-CBF AML group with any kind of cytogenetic abnormalities (n=136), 95 patients (69.9%) had structural cytogenetic abnormalities, 29 pts (21.3%), autosomal monosomy, 18 pts (13.2%), sex chromosome abnormalities, 59 pts (43.4%), autosomal trisomy, 41 pts (30.1%), deletion of part of a chromosome, 18 pts (13.2%), addition and 18 pts (13.2%), marker chromosome(s). MK was noted in 23 patients (16.9%), and complex karyotype (≥3 abnormalities) were found in 40 pts (29.%), -5 in 5 pts (3.7%), -7 in 12 pts (8.8%), del(5q) in 4 pts (2.9%), del(7q) in 8 pts (5.9%), inv(3) or t(3;3) in 4 pts (2.9%), t(6;9) in 5 pts (3.7%), and t(9;22) in 2 pts (1.5%).

In univariate analyses, MK⁺ group was revealed to be associated with shorter OS and (median 10 vs 31months, p=0.044) EFS duration (median 1.3 vs 10.1 months, p=0.002), and a lower CR rate (70.8% vs 34.8%, p=0.002). In a multivariate analysis, MK was associated with lower CR rate (HR of non-CR 0.33, 95% C.I. 0.12-0.93, p=0.036).

MK has been defined as a single monosomy with structural abnormalities or multiple monosomies in a previous study. However, there were no significant difference in survival and CR rate between a single monosomy with (n=9) or without(n=6) structural abnormalities (OS, 23 vs 8 months; p =0.349; EFS, 1 vs 9months; p=0.078; CR rate 33% vs 56%; p=0.608). The group with single autosomal monosomy showed a trend of better survival (n=15, median OS 23 months, EFS 1month) than multiple autosomal monosomy group (n=14, OS 6months, EFS 1month), but it was not significantly different (p = 0.322, p=0.221).

The functional MDR activity was measured in 40 patients, and positive MDR activity was found to be significantly associated with the presence of MK (87.5% vs 33.3%, p=.013). In addition, the functional MDR activity was significantly higher in MK⁺ group (n=8, 45.9±17.8%, mean±S.E.) than in MK^- group (n=32, 4.3 ±2.7%, p=0.005 by Mann-Whitney U-test).

The current study demonstrated that the AML patients harboring MK showed a poor outcome in terms of lower CR rate and worse EFS/OS in an independent cohort of Korean AML patients, and that MK karyotype was associated with high MDR functional activity of leukemic blasts.

No relevant conflicts of interest to declare.