Cytogenetic Evolution in Patients with IPSS Low and Intermediate-1 Risk. Study from the Spanish Group of Myelodysplastic Syndrome

Cytogenetic abnormalities (CA) are the most important prognostic factor in MDS patients, nevertheless the incidence of CA at diagnosis is not higher than 50% and even less in lower risk patients. The acquisition of CA (ACA) has recently been reported as a frequent and poor prognostic event in patients with normal karyotype at diagnosis (Jabbour et al 2013). The aim of our study was to analyze in a large cohort of patients the incidence, characteristics, and prognosis of the ACA in patients with low and intermediate-1 IPSS risk at diagnosis.

We retrospectively reviewed 254 adult patients from the Spanish Registry of MDS with IPSS low or intermediate-1 risk diagnosed between 1995 and 2013. In total 121 patients had at least two consecutive cytogenetic analyses during the follow up. The main end points were overall survival (OS) and AML evolution (TFS). Cytogenetic analyses were conducted on unstimulated bone marrow cells after culture (24–72 hours). The ISCN 2005 criteria were used for identification of abnormal clones. ACA was defined by structural change or gain in at least 2 metaphases and loss in 3 metaphases as proposed in previous reports. Differences among variables were evaluated by non-parametric tests. OS and TFS were analyzed by Kaplan-Meier curve.

The median follow-up was 25 months (0-155). The median age at diagnosis was 71 years (26-87) and 28% of the patients were female. The IPSS risk group was low in 43% and intermediate-1 in 57% of the population. Distribution as the IPSS-R was very low 20%, low 42%, Intermediate-1 30%, poor 6%, and there were no cases with very poor risk. At diagnosis, 34.7% of patients had abnormal karyotype. ACA was detected in 16 patients (13,2%) after a median of 30 months (range, 5-165). The most common ACA identified were trisomy 8 as sole abnormality followed by chromosome 7 abnormalities in in 25% and 12.5% of patients, respectively.

Of the 42 patients with CA at diagnosis, 12% developed new ACA while among 79 patients with normal karyotype at diagnosis, 14% developed ACA (p=0,7). The presence of ACA changed the IPSS-R risk group in 14 out 16 patients. Compared with patients without ACA, the presence of ACA was significantly associated with a lower hemoglobin level (Table 1). In univariate analysis, ACA was not apparently associated with a higher incidence of AML evolution as there were 2 out of 16 patients (12,5%) with ACA that developed AML while between the 105 patients without ACA, 11 developed AML (11,5%) (P=NS). At last follow-up, 34 (28%) patients died and the median OS for the entire cohort was 67 months (IC 95% 34-99). In Kaplan-Meier curve, the presence of ACA was associated with lower overall survival (median 67 months (95% CI: 34-99) than patients without ACA (median 140 months (95% CI 36,9.243) (P =0.01).

In summary, the present analysis shows that, the ACA occurs in around 13% of cases, which is a lower frequency than previously reported in other series, and it may have impact in overall survival. Future studies should address the impact molecular alterations and somatic point mutations; molecular diagnostic may allow identified patients with higher risk to transformation.