Cytogenetic abnormalities in primary Myelofibrosis: Clinical association and outcome in an Italian multicenter series

Cytogenetic abnormalities have been reported in 30-70% of primary myelofibrosis (PMF) patients (pts) and specific alterations have been associated with worse outcome. We analyzed cytogenetic data at diagnosis in 395 out of 480 PMF pts to evaluate any possible association between karyotype and clinical phenotype and its impact on prognosis. All the cases were diagnosed at five Italian Hematological Centers between November 1983 and December 2016. G-banding technique were used and at least 20 metaphases analyzed. Bone marrow (BM) biopsies were reviewed to adhere to WHO 2016 criteria. An abnormal karyotype (AK) was found in 69 (17.5%) pts: 56 (81.2%) were sole abnormality, 10 (14.5%) double abnormalities, and three (4.3%) complex karyotype (of which one was monosomal karyotype). Table 1 reports clinical and laboratory features of PMF pts according to AK and normal karyotype (NK) status. AK clustered differently according to BM fibrosis grade as it was found in 31 (27.0%) cases with overt fibrotic and 38 (13.6%) with pre-fibrotic PMF (p=0.001). Male sex, older (>65 years) age, anemia (Hb <10 g/dl), thrombocytopenia (PLTs <100x109/L), circulating blasts >1%, splenomegaly and higher LDH were significantly associated with AK. A significant association was also found between higher IPSS and AK (p<0.001). Concerning driver mutations, chromosomal abnormalities were described in eight (16.0%) out of 50 type 1 CALR-mutated, in 55 (17.6%) out of 312 non-type 1 CALR / JAK2 or MPL-mutated, and in six (18.2%) out of 33 triple-negative pts. After a follow-up of >6 years, 101 deaths (25.6%) were recorded. Survival was different between AK and NK patients with an estimated median OS of 8.9 and 25.7 years, respectively (p=0.015). Blast phase (BP) transformation occurred in 20 (5.1%) pts and 82 (20.8%) suffered from thrombosis. Any relationship between karyotype and BP, nor between karyotype and thrombotic events was observed. In conclusion, around 20% of pts showed an AK, with the latter clustering more frequently in pts with an advanced BM fibrosis grade and clinical-laboratory features indicative of a more aggressive disease. As in secondary myelofibrosis (MYSEC project), any significant difference in AK distribution according to driver mutations was found. This present study showed that an AK confers a more severe clinical phenotype and significantly influenced OS, thus representing an additional tool to be considered in the evaluation of PMF prognosis.