MPN-400: Exploring the Molecular Grey Zone of Myeloid Neoplasms: Concurrent SRSF2 and Classic MPN Driver Mutations

Abstract

Context: Myeloproliferative neoplasms (MPNs) are clonal myeloid neoplasms frequently associated with classic driver mutations in JAK2, MPL, or CALR. SRSF2 is among the most frequently mutated splicing genes in myeloid neoplasms and is known to confer a poor prognosis in patients with MPNs. Objective: We sought to explore the phenotypic features of myeloid neoplasms harboring concurrent SRSF2 and classic MPN driver mutations. Design: We identified myeloid neoplasms harboring concurrent SRSF2 and MPN-associated driver mutations. Mutation analysis was performed using next-generation sequencing (Illumina, San Diego, California). Results: Patients included 24 men and 5 women with a median age of 71 years (range, 51–84). BM fibrosis was present in all cases assessed [n=22]. Organomegaly was present in 15 patients. Relative and absolute monocytosis was present 38% of cases. Morphologic dysplasia (53.6%) and megakaryocytic hyperplasia and/or clustering (42%) were common. Twelve cases had an abnormal karyotype. Cases were classified as primary myelofibrosis (13), acute myeloid leukemia (5), chronic myelomonocytic leukemia (3), polycythemia vera (PV; 3), post-ET/PV myelofibrosis (2), MPN-unclassifiable, MDS-unclassifiable, and MDS/MPN-unclassifiable (WHO 2016). SRSF2 variants included P95H (67%), P95R (20%), P95L (6.5%), and p.P95_R102del (6.5%) with median variant allelic frequency (VAF) of 44% (range, 2–65). MPN driver mutations included JAK2 [n=20; median VAF 36% (range, 2–73)]; MPL [n=8; W515L (4), S493A (1), L629Q (1), Y591N (1), V501M (1)]; median VAF 24% (range, 5.54–88.31)]; and CALR [n=2; E396del (1), K385fs (1)]; VAF 51.34 and 57.5, respectively]. Other recurrent co-mutations included ASXL1 (n=20), TET2 (n=11), and NRAS/KRAS (n=8). Nine patients progressed to AML; the median time to transformation was 27.6 months (range 0–297.67). The median overall survival was 42.6 months, range (9.7–313.4). Five patients underwent stem cell transplant and were alive at last follow-up. Six patients had died at the time we conducted this study. Conclusions: Most neoplasms with concurrent SRSF2 and MPN-associated mutations have classic MPN-like phenotypes, but a subset of cases present as AML and MDS/MPN. BM fibrosis, morphologic dysplasia, monocytosis, organomegaly, and AML transformation are common, and overall prognosis is poor. Allogeneic HSCT may be of value in the treatment of these neoplasms.