Outcomes of Patients with IDH1/2 Mutated Accelerated/Blast-Phase Myeloproliferative Neoplasms in the Era of IDH Inhibitors

Introduction: Myeloproliferative neoplasms (MPN) carry a variable risk of progression to accelerated phase (AP) or blast phase (BP), which is associated with poor overall survival (OS). Isocitrate dehydrogenase (IDH) mutations are associated with the progression of MPNs to AP/BP and are characterized as high-risk mutations. The IDH1 inhibitors ivosidenib and olutasidenib and the IDH2 inhibitor enasidenib are approved for use in acute myeloid leukemia (AML) and reports have demonstrated the efficacy of IDH inhibition in IDH1/2-mutated MPN AP/BP (Patel et al, BJH 2020; Chifotides et al, Blood Adv 2020, Gangat et al, BJH 2023). Our group previously reported on a cohort of 202 patients (pts) diagnosed with MPN AP/BP with modern myeloid therapies and found a median OS (mOS) of 0.86 years (Patel et al, Blood Adv 2024); here we describe the treatment patterns and survival of pts with IDH1/2-mutated MPN AP/BP.

Methods: In this multicenter, retrospective study, adult pts with IDH1/2-mutated MPN AP/BP diagnosed after 1/1/2017 were included. Patient demographic, disease characteristics, treatment, and survival data were collected. Response was characterized by European LeukemiaNet (ELN) 2017 criteria and 2012 MPN-BP criteria. OS was evaluated with Kaplan-Meier analysis.

Results: Thirty-five pts with IDH1/2-mutated MPN AP/BP were identified (9 with AP, 26 with BP). Median age was 69.5 years old and 54% were male. Thirty pts had race and ethnicity data, of which 90% identified as White and 4% identified as Hispanic. MPN AP/BP arose from polycythemia vera in 20% of pts, essential thrombocythemia in 26%, primary myelofibrosis in 26%, MPN not otherwise specified in 23% and other in 5%. Regarding incidence of driver mutations, JAK2 was noted in 74% of pts, MPL in 9%, CALR in 9% and 11% were triple-negative. Ten pts (29%) underwent allogeneic stem cell transplant for MPN AP/BP.

All pts underwent next generation sequencing (NGS) at diagnosis of MPN AP/BP; 11 (31%) had an IDH1 mutation and 24 (69%) had an IDH2 mutation. Non-driver co-mutations with frequency >10% included SRSF2 (43%), ASXL1 (37%), DNMT3A (17%), TP53 (17%), TET2 (14%), and EZH2 (11%). Thirty pts had at least 1 adverse risk mutation by ELN 2022 criteria.

We then analyzed responses based on frontline (1L) treatment approach along with survival for the entire cohort and stratified by 1L treatment. By ELN 2017 criteria a response was characterized as achievement of complete remission (CR), CR with incomplete count recovery (CRi), or partial remission (PR). Ten pts received intensive chemotherapy (IC) with an overall response rate (ORR) of 40% (3 CR, 1 CRi). For hypomethylating agent (HMA) + venetoclax (VEN)-based therapy (HMA+VEN) (n=9) ORR was 67% (2 CR, 4 CRi), for HMA-based therapy (HMA monotherapy or HMA+JAKi) (n=8) ORR was 50% (3 CRi, 1 PR), and for IDH inhibitor (IDHi)-based (HMA+IDHi or IDHi), (n=6) the ORR was 33% (1 CRi, 1 PR).

Response by 2012 MPN-BP criteria in pts with available data was also reported. Response was characterized by achievement of complete molecular response (CMR), complete cytogenetic response (CCR), acute leukemia response (ALR)-complete (ALR-C), or ALR-partial (ALR-P). ORR were 57% (1 CCR, 3 ALR-C) with IC (n=7), 57% (3 ALR-C, 1 ALR-P) with HMA + VEN (n=7), 50%(2 ALR-C, 2 ALR-P) with HMA-based (n=8) and 67% (1 ALR-C, 3 ALR-P) with IDHi-based (n=6).

Median OS (mOS) for the entire cohort was 2.2 years; of note the mOS for pts (n=30) with 1+ ELN22 adverse-risk co-mutations was 2.6 years. Median OS by frontline therapy was 1.5 years for IC, 1.1 years for HMA + VEN, 2.2 years for HMA-based, and 2 years for IDHi-based with no statistically significant difference (p=0.9976).

We also analyzed outcomes of IDHi-based therapy in the relapsed/refractory (R/R) setting. Eight pts received IDHi-based therapy (1 IDH1 and 7 IDH2) with an ORR of 25% by ELN2017 (2 CRi). When using 2012 MPN-BP criteria, ORR was 50% (2 ALR-C, 2 ALR-P). Median OS from time of IDHi initiation in the R/R setting was 1.1 years.

Conclusions: In our cohort of pts with IDH1/2-mutated MPN-AP/BP, mOS was 2.2 years and was not impacted by the presence of adverse-risk ELN22 mutations. There was no significant difference in mOS based on frontline treatment, although mOS was numerically longest in the HMA-based and IDH inhibitor based groups. IDH inhibitors also retained efficacy in the R/R setting with an ALR-C/ALR-P rate of 50% and mOS of 1.1 years.