P199 | REAL-WORLD INSIGHTS INTO MOLECULAR PREDICTORS OF RESPONSE AND RESISTANCE TO JAK INHIBITORS IN MYELOFIBROSIS

BACKGROUND JAK inhibitors (JAKi) improve splenomegaly and symptoms in patients (pts) with primary and secondary myelofibrosis. A substantial subset of pts discontinues treatment due to loss of response (LoR) after 2–3 years (yrs), a phenomenon associated with clonal evolution and decreased overall survival (OS). The molecular mechanisms behind LoR are not fully understood. AIM To identify clinical and molecular predictors of response/resistance to JAKi therapy. METHODS We analyzed 228 pts with PMF or sMF (ICC2022 criteria) from three centers (Careggi, Policlinico Tor Vergata and Umberto I) treated with JAKi. NGS was performed using a panel targeting 40 genes including spliceosome (SF3B1, U2AF1, SRSF2, ZRSR2), DNA methylation (TET2, DNMT3A, IDH1, IDH2), histone modification (ASXL1, EZH2), RAS pathway (NRAS, KRAS, CBL, NF1) and transcription factor (RUNX1, TP53) genes. Spleen response (SR) and LoR defined per IWG-MRT criteria. RESULTS 127 pts (55.7%) were male; diagnosis was PMF for 128 pts (56.2%). 22 pts (9.6%) progressed to blast phase; 87 pts (38.2%) died. Median OS from JAKi start was 2.7 yrs (range 0.3-13.7), with median follow-up of 12.4 mo. 212 pts (93%) received RUX, 16 pts (7%) FEDR. At last FU, 128 pts (56.1%) discontinued treatment. Aside from drivers, 90 (31.9%) had 1 and 96 (34%) pts had ≥2 mutated genes. SR was achieved in 116 pts (50.9%) after a median of 2.8 months (range 0.2-105.1). At baseline, factors influencing SR were age <65 yrs (p=0.009), smaller spleen (p=0.032), and higher Hb levels (p=0.005); age and spleen size confirmed by multivariate analysis. ASXL1 mutation was a strong predictor of NR (23.5% vs 42.2%, p=0.001; HR 0.4 95%CI 0.2–0.7;Figure A), as were RAS pathway mutations (12.9% vs 4.6%, p=0.011; HR 0.3 95%CI 0.1–0.8, p=0.011;Figure B), confirmed by multivariate analysis. SR was lost in 33 pts (28.7%) after a median of 17.9 months (range 0.9–137.5 mo). Spliceosome mutations shorten SR duration (4 vs 8.8 yrs, p=0.008;Figure C); ZRSR2 conferred increased LoR risk (HR 5.3, 95%CI 1.1-24.6, p=0.033). ASXL1 was also associated with a shorter SR (4.7 vs 8.8 yrs, HR 2.2 95%CI 1-4.9, p=0.045). OS was shorter in pts with 1 additional non-driver mutation (12.7 yrs range 11.4-14.3) or ≥2 mutations (7.5 yrs range 4.9-10) compared to wild type (14.4 yrs range 8.8-20.1, p<0.001). CONCLUSIONS Molecular mechanisms impact response or resistance to JAKi; further studies are needed to define these pathways and the role of specific mutations.