Clinical Impact of Complex Karyotype, Monosomal Karyotype and Acquisition of Chromosomal Abnormalities in Patients with Myelodysplastic Syndromes
Authors: Takeda June , Kawabata Hiroshi , Aoki Kazunari , Shiga Shuichi , Kawahara Masahiro , Kitawaki Toshio , Hishizawa Masakatsu , Kondo Tadakazu , Kitano Toshiyuki , Yonetani Noboru , Tabata Sumie , Hiramoto Nobuhiro , Matsushita Akiko , Hashimoto Hisako , Ishikawa Takayuki , Kadowaki Norimitsu , Takaori Akifumi 
Published: October 2019

Abstract
Objectives
Despite azacitidine prolonging the survival of patients (pts) with myelodysplastic syndromes (MDS), the overall survival (OS) of those with complex karyotype (CK) or monosomal karyotype (MK) remains dismal, and optimal treatments for these pts have not been established. Furthermore, the prognostic impact of acquisition of additional cytogenetic abnormalities (ACA) during the follow-up periods is poorly understood. In this retrospective study, we aimed to evaluate the prognostic impact of CK, MK, and ACA in MDS pts, and determine optimal treatments.
Methods
We collected clinical data on consecutive adult MDS pts who first visited Kobe City Medical Center General Hospital or Kyoto University Hospital between January 2004 and April 2014. Patients were divided into groups based on the number of chromosomal abnormalities (abns) and presence or absence of MK. ACA was defined as any gain in the number of chromosomal abns before treatments. Survival analysis was adjusted using the following variables; sex, age, IPSS-R parameters and MK. A Cox regression model was applied to the results. ACA was fit into the model as a time-dependent covariate.
Results
A total of 299 pts with MDS were identified, five of which were excluded from the study due to a lack of chromosomal information. Median follow-up time was 24.5 months (M). Pts' characteristics, treatments and incidence of ACA are summarized in Table 1. Among 47 CK pts, 34 (72%) carried MK. Survival analysis revealed that presence of 4 or more chromosomal abns was significantly associated with increased mortality. Among pts with 2–3 chromosomal abns, the presence of MK was a poor prognostic factor, although it had no significant impact on survival in pts with 4 or more abns (Figure 1). Median survival times of pts with 2–3-abns without MK, with 2–3-abns together with MK, and 4 or more abns were 39 M, 12 M (HR 6.6, 95% confident interval, [2.6-17], p < 0.001), and 9 M(HR 5.4, [3.1–9.3], p < 0.001) respectively. Regarding ACA, changes from normal karyotype (NK) to 1 abn (N=15) had no effect on mortality, but changes from NK to 2 or more abns (N=10) led to a significant increase in mortality (HR 9.2 [3.7–24], p < 0.001). Further, changes from 0–3 chromosomal abns without MK to either MK or 4 or more abns were associated with higher mortality (HR 2.7 [1.0–7.1], p = 0.045). Among pts with 2–3-chromosomal abns with MK or those with 4 or more abns at diagnosis (N=45) or during follow-up (N=10), 20 (36%) underwent allogeneic stem cell transplantation (allo-SCT) and only six survived beyond 24 M. Five of these received allo-SCT and were alive at the last follow-up. The other was treated with azacitidine and lived for 33 M.
Conclusion
This study revealed that MK or 4 or more chromosomal abns is significantly associated with high mortality. Among NK pts, acquisition of 2 or more abns was associated with a poor outcome. Allo-SCT is the only strategy to increase the chance of long-term survival for pts with MK or 4 or more chromosomal abns, although only a few survivors were identified even after allo-SCT. More data are needed to identify the optimal therapeutic options for this subgroup.
Table 1 Clinical parameters and treatments received by patients Number of abnormalities <3 (N=247) (%) 3 (N=10) (%) 4<= (N=37) (%) p-value Sex (male/female) (N=195/99) 170(69)/77(31) 4(40)/6(60) 21(57)/16(43) 0.04 Age =<65 (N=158) >65 (N=136) 130(53) 117(47) 7(70) 3(30) 21(57) 16(43) 0.89 Bone marrow blast% <=2 (N=123) >2-<5 (N=45) >=5-<=10 (N=50) >10 (N=74) Missing (N=2) 112(45) 35(14) 39(16) 59(24) 2(0.81) 4(40) 3(30) 2(20) 1(10) 0 7(19) 7(19) 9(24) 14(38) 0 0.06 Hemoglobin (g/dL) >=10 (N=91) >=8-<10 (N=93) <8 (N=106) Missing (N=4) 83(34) 72(29) 88(36) 4(1.6) 3(30) 5(50) 2(20) 0 5(14) 16(43) 16(43) 0 0.076 Platelets (103/ƒÊL) >=100 (N=118) >50-<100 (N=82) <50 (N=90) Missing (N=4) 100(40) 68(28) 75(30) 4(1.6) 6(60) 1(10) 3(30) 0(0) 12(32) 13(35) 12(32) 0 0.50 Neutrophils (/ƒÊL) >=800 (N=183) <800 (N=106) Missing (N=5) 160(65) 82(33) 5(2.0) 5(50) 5(50) 0 18(49) 19(51) 0 0.078 Monosomal karyotype (N=39) 5(2) 3(30) 31(79) <0.001 ACA (N=37) 30(12) 1(10) 6(16) 0.7 Initial treatments CC (N=92) azacitidine (±CC) (N=63) Chemo-naïve allo-SCT (N=37) Palliative CT/BSC (N=102) 78(32) 43(17) 31(13) 95(38) 1(10) 3(30) 3(30) 3(30) 13(35) 17(46) 3(8) 4(11) <0.001 Allo-SCT (total) 79(32) 7(70) 13(35) 0.77
Figure 1 Kaplan-Meier curves in groups divided by chromosomal abnormalities Figure 1. Kaplan-Meier curves in groups divided by chromosomal abnormalities

Disclosures
No relevant conflicts of interest to declare.