Association of Hypomethylating Agents + Venetoclax in the Real-Life Treatment of Myeloproliferative Neoplasms in Blastic Phase
Authors: Latagliata Roberto , Cristiano Gianluca , Lame Dorela , Strazimiri Alda , Cavalca Fabrizio , Rizzo Lorenzo , De Luca Giulia , Zoletto Simone , Federico Vincenzo , Cattaneo Daniele , Biagi Annalisa , Crugnola Monica , Niscola Pasquale , Palmieri Raffaele , Piccioni Anna Lina , Mulas Olga , Esposito Vangone Beatrice , Santopietro Michelina , Carmosino Ida , Iurlo Alessandra , Di Rienzo Nicola , Binotto Gianni , Salutari Prassede , Riva Marta , Bonifacio Massimiliano , Elli Elena Maria , Curti Antonio , Poloni Antonella 
Published: December 2023

Background Association of hypomethylating agents (HMA) and venetoclax (VEN) is widely used in elderly patients (pts) with de novo Acute Myeloid Leukemia not eligible for intensive chemotherapy, with improvement of survival. However, very few data are available in pts with Myeloproliferative Neoplasms evolved in blastic phase (MPN-BP). In this setting, the survival is dismal and at present no therapy seems to have a role.

Methods Data of 54 pts with MPN-BP treated frontline with HMA+VEN in 19 hematologic Centers in Italy outside clinical trials from 11/2018 to 3/2023 were retrospectively collected and analysed. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematologic improvement (HI)], duration of response and overall survival (OS) were assessed.

Results: Baseline features at evolution and starting treatment are reported in the Table. Median interval from initial MPN diagnosis to evolution was 38.4 months [interquartile range (IQR) 15.4-124.5]. Pts were treated for a median of 3 courses (IQR 2-7): HMA were administered at standard dosage, VEN daily doses in the 1 st cycle are reported in the Table. On the whole, 40 pts (74.1%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN &lt; 0.5 x 10 9/l) was reported in 37 pts (68.5%). Thirty pts (55.5%) had at least one infective episode during the treatment: pulmonary infections were reported in 13 pts (24.0%). Response to treatment is shown in the Table: ORR was 62.7%, with a median response duration of 9.4 months (95%CI 5.8-12.9). After a median follow-up of 6.7 months (IQR 3.2-12.1), 35 pts (64.8%) died, 2 (3.7%) were lost to follow-up and 17 (31.5%) were alive. Median OS of the whole cohort was 10.6 months (95%CI 5.8-15.3), Pts with any response to HMA+VEN had a significantly longer OS compared to pts with progressive/stable disease [11.6 (95%CI 9.4-13.7) versus 5.4 (95%CI 2.1-8.6) months, respectively (p=0.002)] (Figure).

Conclusions: Our real-life data confirm that HMA+ VEN combination could have a role in MPN-BP, with ORR &gt; 50% in pts unfit for intensive approaches: however, this treatment is affected by severe hematologic and infective toxicities and the response duration is short, with a persistently poor median OS. Larger cohorts of pts and a longer follow-up are needed to assess factors predictive of CR/iCR achievement, while addition of other targeted therapies should be explored.