Genomic Landscape and Molecular Risk in Patients with Advanced Myelofibrosis Treated within the Multicenter Phase Ib/II MPNSG0212 (POMINC) Trial

▪ Introduction: Mutations (muts) in JAK2, MPL, and CALR are genetic hallmarks in myeloproliferative neoplasms such as myelofibrosis (MF). Prognostication in MF is predominantly based on clinical parameters according to the Dynamic International Prognostic Scoring System (DIPSS). However, gene mutations become increasingly important allowing for a more precised assessment of prognosis. For instance, CALR mutated MF is associated with favorable prognosis, while mutations in distinct high molecular-risk (HMR) genes are considered adverse. Our multicenter phase-Ib/II MPNSG-0212 trial (NCT01644110) investigating ruxolitinib plus pomalidomide in a total cohort of 92 patients with advanced MF and anemia provides an ideal basis for investigating the genomic landscape and molecular risk in a well-defined study population. Aims & Methods: To assess the genomic landscape in MF patients treated within the MPNSG-0212 trial and to correlate the results with clinical parameters and overall survival (OS). So far, targeted next generation sequencing (NGS) of 269 candidate genes was performed in peripheral blood or bone marrow from 81/92 patients using libraries prepared with SureSelectXT HS (Agilent, Santa Clara, USA). NGS was carried out on a NextSeq550 (Illumina, San Diego, USA). Results: At study entry, median age of the 81 patients was 71 years (range 52-86), median Hb 8.6 g/dL (range 5.4-11.7 g/dl); 30% of patients were RBC transfusion-dependent; 67% had primary MF (PMF) and 33% secondary MF (SMF), respectively. According to DIPSS, the vast majority of the patients were categorized as intermediate-2 (63%) or high-risk (26%) MF; 11% were low- and intermediate-1 risk patients. Overall, 315 muts were identified in 80/81 (99%) patients with a median of 3 muts/patient (range 0-9). Recurrent muts (≥5%) were identified in JAK2 (60%), ASXL1 (30%), SRSF2 (21%), CALR (20%; type-1: 75% [n=12], type-2 and non-type-1/2: 12.5% [n=2] each), MPL (19%), SF3B1 (19%), TET2 (16%), U2AF1 (15%), CBL and EZH2 (10% each), IDH2 and DNMT3A (7% each), PHF6, ZRSR2, and CUX1 (5% each). The majority of the patients (95%) was characterized by the presence of a driver mut in JAK2, CALR, or MPL; 4/81 patients (5%) were triple negative (Figure 1). JAK2mut was associated with TET2mut (p=.047), whereas muts in CALR and TET2 were mutually exclusive (p=.05). CALRmut patients had less co-muts than patients with JAK2/MPL muts (mean 2.5 vs. 4.1, p=.007) and were mutually exclusive with muts in the spliceosom