Molecular Characteristics and Patterns of Progression of IDH2-Mutated, Philadelphia-Chromosome Negative, Advanced-Phase Myeloproliferative Neoplasms Treated with Enasidenib

Background:

Myeloproliferative neoplasms (MPNs) that progress to an accelerated phase (AP) or blast phase (BP) have poor outcomes with median overall survival (OS) of 3-5 months. Approximately 20% of AP/BP, Philadelphia-chromosome negative (Ph-negative) MPNs have an IDH1 or IDH2 mutation. Ivosidenib and enasidenib are IDH1 and IDH2 inhibitors, respectively, that have been FDA-approved for use in acute myeloid leukemia (AML). We previously reported on encouraging clinical outcomes in IDH2-mutated MPN-AP/BP pts treated with enasidenib (Patel et al. BJH 2020). We report on additional follow-up of this cohort with a focus on molecular characteristics and patterns of progression.

Methods:

Retrospective chart review was done to identify pts with Ph-negative IDH1/2-mutated MPN-AP/BP that were treated with ivosidenib or enasidenib from 1/1/2009-4/1/2020. Response was assessed using the the 2012 Post-MPN AML Consortium (2012 MPN-BP) criteria (Mascarenhas et al. Leuk Res 2012). Adverse event data and OS from initiation of IDH inhibitor therapy were collected. In addition, co-occurring molecular mutations from next-generation sequencing (NGS) and variant allele frequency (VAF) data were collected.

Results:

92 pts with various myeloid neoplasms and IDH1 or IDH2 mutations were identified. Within this cohort there were 8 pts with Ph-negative, IDH1/2-mutated, MPN-AP/BP who received treatment with an IDH inhibitor. Pt characteristics are summarized in Table 1. Median age was 69 years, median Charlson Comorbidity Index (CCI) was 6, and all pts had an ECOG 1 or 2 performance status. 7 pts had MPN-BP and 1 had MPN-AP; all 8 were IDH2-mutated and received treatment with enasidenib. All 8 pts had a canonical MPN mutation (7 JAK2, 1 MPL). In addition, pts had a median of 2 co-occurring mutations (co-mutations) (range, 1-4) (Table 2).

Overall response rate (ORR) using 2012 MPN-BP criteria was 75%, and 1-year OS was 50%. Of the 6 pts who had a response, 2 discontinued enasidenib due to adverse effects, 3 discontinued due to progression/relapse of disease, and 1 pt continues on treatment. NGS data were available for 4 pts at best response; IDH2 became undetectable in 2 pts (1 with a partial acute leukemia response (ALR-P), 1 with a complete acute leukemia response (ALR-C)) while 2 had persistence despite clinical responses (1 ALR-P, 1 ALR-C). The median number of co-mutations at best response was 1 (range, 0-4); no new co-mutations were noted. 3 pts had NGS repeated at time of progression/relapse. One pt’s previously undetectable IDH2 mutation became detectable again, one had persistence of the mutation, and in the third pt the IDH2 mutation remained undetectable. All three pts acquired additional mutations at time of relapse, with a median of 4 co-mutations (range, 4-5) (Figure 1). Of note, canonical MPN mutations persisted in all pts at best response and at relapse.

Conclusions:

Canonical MPN mutations persist during IDH inhibitory therapy even if the IDH mutation becomes undetectable. Additional pathogenic mutations may be acquired at relapse. It remains unclear if these pathogenic mutations arise in the same clone carrying the canonical MPN mutation or from an ancestral clone or from an entirely unrelated clone. We aim to utilize single-cell RNA sequencing to study this issue further. Combination-therapy approaches capable of inducing deep molecular responses of the MPN clone in addition to the IDH-mutated clone should be prospectively evaluated.