Association of Hypometilating Agents (HMA) + Venetoclax (VEN) in the Treatment of Myeloproliferative Neoplasms in Blastic Phase (MPN-BP) and Acute Leukemias Evolved from Myelodysplastic Syndromes (AML-MDS) Already Treated with Azacytidine

Background Association of hypometilating agents (HMA) and venetoclax (VEN) is widely used in the treatment of elderly patients with de novo Acute Myeloid Leukemia (AML) not eligible for intensive chemotherapy, with improvement of survival. However, very few data are available about the use of this combined regimen in patients with Myeloproliferative Neoplasms evolved in blastic phase (MPN-BP) and in patients with AML secondary to Myelodysplastic Syndrome (AML-MDS) previously treated with HMA during the dysplastic phase. In both these settings the survival is dismal and at present no therapy seems to have a role.

Methods Data of patients with MPN-BP and AML-MDS treated frontline with HMA+VEN in 20 hematological Italian Centers outside clinical trials were retrospectively collected and analysed. Patients treated with HMA + VEN as salvage therapy after induction failure/relapse were excluded. Composite overall response rate [ORR; complete remission (CR) + CR with incomplete hematologic recovery (iCR) + partial remission (PR) + hematological improvement (HI)], duration of response and overall survival (OS) were assessed.

Results: A total of 64 patients (41 MPN-BP and 23 AML-MDS) treated between 11/2018 and 5/2022 were included. Baseline characteristics at evolution and starting treatment for the whole cohort and according to previous disease are reported in the Table 1. Median interval from initial MPN/MDS diagnosis to evolution was 31.5 months [interquartile range (IQR) 16.0 – 108.1] in the entire cohort [42.0 months (IQR 22.0 – 124.9) in MPN-BP and 18.8 months (IQR 10.9 – 39.8) in AML-MDS]. Patients were treated for a median of 2 courses (IQR 2-6): HMA were administered at standard dosage, VEN daily dose in the 1^st cycle was 50 mg in 6 patients (9.4%), 100 mg in 27 patients (42.2%), 200 mg in 8 patients (12.5%) and 400 mg in 23 patients (35.9%), respectively. On the whole, 50/64 patients (78.1%) had at least one hematological toxicity of grade 3-4: in particular, severe neutropenia (PMN < 0.5 x 10⁹/l) was reported in 46 patients (71.8%). Twenty-nine patients (45.3%) had at least one infective episode during the treatment: pulmonary infections were reported in 18 patients (28.1%). Response to treatment is shown in the Table 1: ORR was 60.0% (60.5% in MPN-BP and 59.1% in AML-MDS, respectively). Median response duration of the whole cohort was 5.3 months (95%CI 2.2-8.4), without significant differences in MPN-BP and AML-MDS patients [4.8 (95%CI 3.2 – 6.5) and 7.8 (95%CI 2.8 – 12.8) months, respectively (p=0.467)]. After a median follow-up of 6.1 months (IQR xx – xx) from the start of combined regimen, 37 patients (57.8%) died, 2 (3.1%) were lost to follow-up and 25 (39.1%) were alive. Median overall survival (OS) of the whole cohort was 7.2 months (95%CI 4.8-9.7), without differences between MPN-BP and AML-MDS groups [8.0 (95%CI 5.0 – 10.9) and 6.8 (95%CI 4.3 – 9.3) months, respectively (p=0.717, Figure 1)]. Patients with any type of response to the combination regimen had a significantly longer OS compared to patients with progressive/stable disease [11.6 (95%CI 8.2 – 14.9) and 5.4 (95%CI 2.8 – 7.9) months, respectively (p=0.006)].

Conclusions: Our real-life data confirm that HMA + VEN combination could have a role in these two very challenging subsets of secondary AML, with achievement of ORR > 50% in patients unfit for intensive approaches: however, this treatment is affected by severe hematological and infective toxicities and the response duration is short, leading to a persistently poor median OS. Larger cohorts of patients and a longer follow-up are needed to assess factors predictive of CR/iCR achievement, while the addition of other targeted therapies should be explored.