Outcome of Patients with Accelerated and Blast-Phase Myeloproliferative Neoplasms Ineligible for Intensive Chemotherapy or Allogeneic Hematopoietic Cell Transplantation Treated By Azacitidine Alone or in Combination – a FIM Study

Background: Accelerated-phase (AP) or blast-phase (BP) myeloproliferative neoplasms (MPN) are associated with poor prognosis with better survival in patients who can proceed to allogeneic hematopoietic cell transplantation (HCT). However, some patients are ineligible for intensive therapy related to age, comorbidities, or clinical manifestations from disease; and non-curative therapies such as hypomethylating agents (HMA) can be considered. Some studies suggested that combining HMA with either ruxolitinib or venetoclax could be an interesting approach in this context. To assess the relationship between treatment modalities and outcome, we report herein a French national multicenter cohort of patients with AP/BP MPN ineligible for intensive therapy who received azacitidine (AZA) alone or in combination.

Methods: For this academic retrospective study, 149 evaluable patients >60 years old, ineligible for intensive chemotherapy or allogeneic HCT, diagnosed with AP/BP, treated with AZA alone (n=60) or in combination (n=89) with first cycle started between January 2019 and October 2023 were included from 28 centers.

Results: The median age of the overall population of patients was 75 years (interquartile range [IQR]: 71-79). With a median follow-up of 1.25 years (IQR: 0.57-2.10) after treatment initiation in survivors, 113 deaths were observed and median overall survival of the full cohort was 0.67 years (0.50-1.08) with a three-year OS of 13%. Among disease characteristics, OS was lower in patients with BP (n=112; median 0.52 years [0.42-0.75] vs. 1.50 [1.09-2.21] in AP patients, P=0.03), complex karyotype (n=52; median 0.50 years [0.33-0.67] vs. 1.09 [0.66-1.50], P=0.005), and TP53 mutation (n=28; median 0.67 years [0.32-1.08] vs. 0.92 [0.52-1.59], P=0.009). Importantly, patients with AZA monotherapy were more likely to have a complex karyotype (53% vs. 30%, P=0.009) and a TP53 mutation (44% vs. 19%, P=0.007). Progression of AML was the main cause of death (71%) followed by infection (16%) without significant differences between AZA monotherapy and AZA combination subgroups (77% vs. 65% and 13% vs. 18%, respectively, P=0.44). AZA combinations included venetoclax (VEN; 51 patients), ruxolitinib (RUXO; 27 patients), and both venetoclax and ruxolitinib (9 patients) while two patients received IDH inhibitors. Patients treated with AZA-VEN were more likely to have BP disease (94% vs. 44% vs. 67% in patients receiving AZA-VEN, AZA-RUXO, and AZA-VEN-RUXO, respectively, P<0.001), had a shorter time to progression (5 vs. 9 vs. 15 years, P=0.040), and less likely to have splenomegaly (36% vs. 67% vs. 67%, P=0.019). With a median of 4 cycles received, the overall response rate was 60% in the whole cohort (complete remission, 31%; partial response, 29%) with similar results between patients receiving AZA as monotherapy or in combination (54% and 64%, respectively, P=0.64). Overall response rates were non-significantly lower in patient treated with AZA-RUXO in comparison to those with AZA-VEN combinations (55% vs. 70%; P=0.25). OS was non-significantly lower in patients receiving AZA monotherapy (median 0.58 years [0.50-1.08] vs. 0.84 [0.52-1.21] in patients receiving AZA combinations, P=0.12). When analyzing AZA combinations separately, patients treated with AZA-RUXO had higher OS (median 1.50 years [0.50-not reached] vs. 0.75 years [0.33-1.21] vs. 0.84 years [0.35-not reached] in patients receiving the AZA-VEN and the AZA-VEN-RUXO combinations, P=0.015). The better OS with the AZA-RUXO combination was especially observed in the subgroup of patient with BP MPN without complex karyotype and/or TP53 mutation. After adjustment for blast count at progression (HR=1.02 [1.01-1.03], P<0.001) and complex karyotype (HR=2.11 [1.36-3.27], P<0.001), the AZA-RUXO combination was associated with higher OS (HR=0.53 [0.29-0.99], P=0.046).

Conclusion: The outcome of patients with AP/BP MPN ineligible for intensive chemotherapy remains poor. The more favorable outcome of AP patients might advocate for earlier diagnosis and treatment initiation. These data suggest that an AZA-RUXO combination may be associated with improved outcome in patients with AP/BP MPN ineligible for intensive chemotherapy, as compared to AZA monotherapy or AZA-VEN combination. New therapeutic options are urgently needed, especially in patients with complex karyotype and/or TP53 mutations.