Background. MPN-BP occurs in 5-20% of patients (pts) with prior chronic phase (ChP) MPN, and is associated with treatment refractoriness and rapidly fatal course, representing a major unmet treatment need. Long-term responses can be secured only with stem cell transplantation (SCT) in a minority of younger, fit pts. The BCL-2 inhibitor venetoclax (VEN), in association with hypomethylating agents (HMA), including azacytidine and decitabine (DEC), is standard treatment for unfit and refractory pts with de-novo AML. There are small uncontrolled series with conflicting results using VEN/HMA in MPN-BP. We report here results of ENABLE, an academic, multicenter phase 2 trial of VEN/DEC in MPN-BP pts (NCT04763928).

Patients and Methods. MPN-BP pts, diagnosed (dx) according to IWG-MRT criteria (Mesa R, 2007), unfit for intensive chemo, were enrolled from 28 GIMEMA centers (Dec 2021-Sept 2024). Responses were categorized based on post-MPN AML Consortium criteria (Mascarenhas J, 2012). Treatment scheme was DEC, 20mg/sqm iv, d1-5 every 28d, and VEN 400 mg QD, 1-28d, with ramp-up at cycle1 (Cy1). The study primary endpoint was an improvement of event free survival (EFS) rate at 1y from 15% in historical controls (Tefferi A, 2023) to 25% with VEN-DEC. EFS was the time between treatment start and primary refractoriness after >Cy2, or first relapse after achieving complete response (CR), or death. Target enrollment was set at 101 pts, with power 80% and Type 1 error 5%. VEN was provided free of charge from AbbVie, that had no role in trial design, conduction and interpretation.

Results. ENABLE fully enrolled 101 evaluable patients; 1 pt rapidly progressed after screening and was not treated. Median age 71y (54-87), male 69%, all caucasian. Dx at ChP was ET in 36%, PV 24%, PMF 38%, MPN-u 2%. Time from ChP dx to MPN-BP was 8y (0-33). Driver mutation profile at ChP (n=80): JAK2V617F 80%, CALR 12.5%, MPL 2.5%, triple-negative (TN) 5.0%. In 4 pts (5.2%), loss of driver mutation occurred at BP transformation. Non-driver myeloid mutations were detected in 74/80 pts (92.5%), median 4 mut/pt; most common were ASXL1 (40%), TET2 (25%), SRSF2 (25%), RUNX1 (20%), EZH2 (16%); TP53 23.5%, multihit 17.5%. Karyotype was abnormal in 39% at ChP and 59% at BP; most common abnormality at BP was +8 (17%) and complex karyotype (13%). Median time on study: 200d (14-1,061), median FU, 12.2mo (0.5-34.9). Seventeen pts were still on therapy after Cy6. Eleven pts were bridged to ASCT, all before Cy5.

The study primary endpoint was met, with EFS rate at 12mo of 32.8% (95%CI, 23.9-45.1%). Age did not affect EFS rate: 38.0% (24.5-59.0%) vs 31.2% (20.7-47.0%) in pts < vs >70y (p=0.54). A CR and CR+PR (partial response) was obtained in 38% and 60% respectively at Cy1, and 46% and 65% at Cy2. Achievement of CR+PR was predicted by IDH2mut (19.4% vs 4.0% for wild-type pts; p=0.036) and DNMT3Amut (25.0% vs 2.3%, p=0.002), while it was negatively impacted by PTPN11mut (0 vs 13.6%; p=0.02) and EZH2mut (5.6% vs 25.0%; p=0.02). High molecular risk (HMR) status did not impact on CR+PR achievement. EFS outcome at 12mo was predicted by achievement of CR/PR at Cy1: 63.6% (n=33) and 57.3% (n=13) for CR and PR, respectively, vs 9.1% (n=55) for non-responders (NR) (p<0.0001). EFS at 12mo was better for pts with ChP dx of PV (56.3%) compared to ET (33.8%) and PMF (18.5%); JAK2 mut status was irrelevant. Overall survival (OS) at 12mo was 45.7% (35.1-58.2%). Pts achieving CR/PR at Cy1 had better OS at 12mo (56.7%) compared to NR (28.5%; p<0.0001). The type of ChP disease was not informative. DFS at 12mo was 57% (38.4-84.7%).

A total of 120 G>3 treatment-related AEs were noted, most common were neutropenia (39.2%), thrombocytopenia (14.2%) infections (10.8%) and anemia (9.2%). G>3 treatment-not-related AEs were 75: infection 26.7%, cytopenia 24%. Median exposure to VEN was 24d (17–27) in Cy1, median time to initiation of Cy2 was 37d (32–47). From Cy2 to Cy6, median exposure to VEN was 14d (3–27), while median time to the next cycle was 41d (34–43)

Conclusions: Results of ENABLE, an academic multicenter, controlled trial in pts with MPN-BP, support safety and efficacy of a VEN/DEC combination for unfit pts, some of whom could be successfully bridged to SCT. Longer EFS and OS after VEN/DEC is predicted by achievement of CR/PR at cycle 1, by IDH2 and DNMT3A mutated status, and is better for pts with dx at ChP of PV and ET compared to PMF.

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2025
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