Balanced translocations in myelodysplastic syndromes (MDS) – an unrecognised MDS patient subgroup?
Moshe Mittelman
Abstract
The role of cytogenetics in the pathogenesis, diagnosis and prognostication of haematological neoplasms in general, and myelodysplastic syndromes (MDS) in particular, has already been recognised.1-5 Recently, cytogenetics also directs the appropriate treatment. Patients with MDS with del(5q) benefit (>60% response rate) from lenalidomide,6, 7 while only 27% of patients with MDS with non-del (5q) respond to that drug.8 Schanz et al. studied 2351 patients with MDS and found chromosomal abnormalities in 51%.2 Certain common abnormalities, such as chromosome 7 abnormalities and complex karyotype (CK) were associated with inferior overall survival compared with normal karyotypes (NK). Chromosomal translocations, especially balanced translocations (BTs), in which there is no gain or loss of chromosomal material, are rare in myeloid diseases and especially in MDS.2, 9-13 A cytogenetic analysis of 5654 patients with MDS, performed by the Spanish group, detected chromosomal abnormalities in 36% of the patients.9 Translocations were found in 195 patients (10% of the patients with chromosomal abnormalities, but only 3.4% of all patients with MDS), and the distribution between the BTs and unbalanced translocations (UBTs) was 183 (86%) and 30 (14%), respectively. All chromosomes were found to be involved in translocations, with the single exception of the Y chromosome. The chromosomes most frequently involved were in decreasing frequency: 3, 1, 7, 2, 11, 5, 12, 6 and 17. Translocations were found in karyotypes as the unique chromosomal abnormality (33%), associated with another chromosomal abnormality (11%), as a part of a CK (17%), and as a part of a monosomal karyotype (38%). There were 155 translocations not previously described in MDS or chronic myelomonocytic leukaemia (CMML) and nine of them appeared to be recurrent. In search of new recurrent BTs, the Cancer and Leukemia Group B (CALGB) reviewed its cytogenetics database containing pretreatment and relapse karyotypes of 4701 adults with acute myeloid leukaemia (AML) and 565 with MDS who had been treated on CALGB trials10 Seven new recurrent BTs in AML or MDS were identified, again including various chromosomes. The authors raised the question of whether these new translocations represent a new myeloid entity, and should a different therapeutic or prognostic approach be applied. Although both these and other publications have described clinical characteristics of these patients, unfortunately, the relatively small number of such patients with MDS with BTs, as well as the little information collected to date, has not allowed answering the interesting relevant questions. Do they represent a separate MDS subgroup? What is the clinical, diagnostic, therapeutic, and prognostic significance of MDS with BTs? What are the differences between these patients and other patients with MDS with NK or CK or UBTs? These questions are relevant especially in MDS, as epigenetics has been proven to play a major role in this disease, leading to epigenetic treatments such as hypomethylating14 and histone deacetylating agents15 In this issue of the Br J Haematol, Dr Joshi and colleagues from Mayo16 have taken the challenge to shed some light on these interesting questions. Their report summarises a single institute experience, with 1269 patients with MDS. In this retrospective analysis, (only) 21 patients were found to have MDS with BTs. They compared the features of these patients with other patients with MDS with NK and UBT. Patients with BTs and CK were excluded. Obviously, the small number of patients in this subgroup (21) calls for caution in interpreting the data, and especially in drawing definitive generalised conclusions. Unfortunately, as in retrospective cohorts, missing information may compromise our understanding. The lack of genetic data and fluorescence in situ hybridisation analysis, at least in some of the patients, also compromises our understanding of the implications of this study. Nevertheless, several lessons can be learnt from this small-scale analysis. The Mayo team confirms the very small incidence of MDS with BTs, only 21 out of 1088 evaluable patients (2%), compared with 42% of the patients with NK, 21% with CK, and 35% with UBTs. Of the 21 patients with MDS and BTs, nine had MDS-known abnormal cytogenetics,17 while 12 patients were found to harbour novel cytogenetic abnormalities, which had not been described in MDS before, the clinical significance of which remains to be studied. Interestingly, the median age of these patients with MDS and BTs was relatively young, 65 years, younger than the typical patient with MDS.18 An interesting hypothesis is supported by the finding that most patients had the BTs at presentation and only two with NK developed BTs at disease progression. This probably indicates that BTs in MDS appear to be an early event and a disease driver, rather than a fortuitous event or a non-significant epiphenomenon. Although the group of patients with MDS with BTs was heterogeneous, it appears that a significant percentage of them had an aggressive disease and/or was treated with intensive treatment. Thus, 66% of the patients had a Revised International Prognostic Scoring System classification of Intermediate or more 4; 55% were categorised as excess blasts 1 (EB1) or EB2 as per the 2016 World Health Organization (WHO) classification19; 54% were treated with aggressive treatment, either 7 + 3 anti-AML chemotherapy or hypomethylating agents; and seven patients were planned to undergo allogeneic stem cell transplant, with six patients who eventually had this aggressive regimen. Surprisingly, despite these poor features, the prognosis of patients with MDS with BTs was relatively favourable. The 5-year survival was 29·8 months, compared with 30.4 months for those with UBTs. The adjusted risk of mortality for MDS with BTs was similar to NK (hazard ratio [HR] 0.99!), while patients with MDS with UBTs and CK had a higher mortality risk (HR 1.26 and 2.63, respectively). MDS and CK were also associated with disease progression. Whether the relatively favourable prognosis is related to the younger age or the more aggressive therapeutic approach (possible in younger patients) or whether it reflects a different disease entity – is still unclear. In contrast with the present study, others have suggested poor prognosis in these patients.12, 20 The reader of this commentary might conclude that the topic of MDS with BTs is still an open debate, with more questions than answers. Indeed, this is the case, due to the limitations outlined above. However, the study of Joshi et al., 16 as well as similar others, hopefully will encourage future additional, maybe international large-scale collaboration in an attempt to answer the questions raised about this MDS patient population.