Prognostic Impact of Chromosomal Translocations in 751 Korean Patients with Primary Myelodysplastic Syndrome

Introduction Chromosomal translocations are rare in myelodysplastic syndrome (MDS) and their impact on overall survival (OS) and response to hypomethylating agents (HMA) is unknown.

Methods The prognostic impact of the revised International Prognostic Scoring System (IPSS-R) and for chromosomal translocations was assessed in 751 patients from the Korea MDS Registry. Patients with secondary MDS, chronic myelomonocytic leukaemia, and patients with AML and a BM blast count of 20-30% who were classified as having refractory anaemia with excess blast (RAEB)-t according to the French-American-British classification were excluded. Cytogenetic aberrations were counted following the International Working Group on MDS Cytogenetics (IWGMC) consensus guidelines. Complex karyotype (CK) was defined as having 3 or more chromosomal abnormalities. Monosomal karyotype (MK) was defined as the presence of 2 or more autosomal monosomies or 1 single autosomal monosomy in combination with structural abnormalities.

Results The median age of the patients was 65 years, and 457 (61.9%) were male. The median follow-up time was 71.7 months for survivors (range, 0.1 - 230.5). The most common WHO subtype was refractory cytopaenia with multilineage dysplasia (29.7%), followed by RAEB-1 (19.8%), RAEB-2 (18.4%), refractory cytopaenia with unilineage dysplasia (15.4%), and MDS-unclassifiable (11.9%). More than half of patients received disease-modifying treatment; 381 (50.7%) received hypomethylating agents (HMAs), and 83 (11.1%) received haematopoietic stem cell transplantation (HSCT). IPSS-R effectively discriminated patients according to leukaemia evolution risk and OS.

We identified 40 patients (5.3%) carrying translocations. Among these, 46 translocations involving 72 breakpoints were identified including balanced translocations in 13 (28.3%) and unbalanced translocation in 33 (71.7%). Translocations were found as a part of CK in 30/46 cases (65.2%) and as a part of MK in 21/46 (45.7%). Frequently involved chromosomes were chromosome 7 (n = 13); ch1 (n = 12); ch5 (n = 9); ch12 (n = 6); ch6, ch11, and ch14 (n = 5); ch10 and ch20 (n = 4); and ch16, ch17, and X (n = 3) in decreasing order. To the best of our knowledge, 43 (93.5%) of the 46 translocations have not been previously described in MDS, nor in AML or CMML. Patients with translocation also had a higher percentage of BM blasts and included a significantly larger proportion of RAEB-1 and RAEB-2. Translocation presence was associated with a shorter OS (median, 12.0 versus 79.7 months, P < 0.01), and multivariate analysis demonstrated that translocations (hazard ratio [HR] 1.64 [1.06-2.63]; P = 0.03) as well as age, sex, IPSS-R, and CK were independent predictors of OS. In the IPSS-R high and very high risk subgroup (n = 260), translocations remained independently associated with OS (HR 1.68 [1.06-2.69], P = 0.03) whereas HMA treatment was not associated with improved survival (median OS, 20.9 versus 21.2 months, P = 0.43). However, translocation carriers exhibited enhanced survival following HMA treatment (median 2.1 versus 12.4 months, P = 0.03).

Conclusion Our data suggest that chromosomal translocation is an independent predictor of adverse outcome and has an additional prognostic value in discriminating patients with MDS having higher risk IPSS-R who could benefit from HMA treatment. Further studies in other populations are needed to validate the clinical relevance of translocation in patients with MDS.