TP53 mutations and Complex Karyotype in Newly-Diagnosed Blast/Accelerated Phase MPN Are Associated with Ephemeral Response to Treatment with Venetoclax + HMA and Poor Survival

Background

Blast or accelerated phase myeloproliferative neoplasm (MPN-BP/AP) carries a dismal prognosis, with 3-year survival estimates of <5% (BCJ 2023;108). Patients with MPN-BP/AP were excluded from venetoclax (Ven) plus hypomethylating agent (HMA) clinical trials for acute myeloid leukemia (NEJM 2020;383:617). In the current retrospective study, we examined response patterns and long-term survival of newly-diagnosed MPN-BP/AP patients who received treatment with Ven+HMA, outside of clinical trials.

Methods

Newly-diagnosed patients with MPN-BP/AP treated with Ven+HMA at the Mayo Clinic, between March 2019 and May 2024, were retrospectively reviewed. Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Cytogenetic and molecular studies were performed by conventional karyotype and next-generation sequencing, respectively. All patients received at least one cycle of Ven+HMA (azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 days 1-5). Response was assessed according to the 2022 European Leukemia Net criteria (Blood 2022;140:1345). Standard statistical analyses were performed using JMP Pro (Version 17.1.0).

Results

Patient characteristics

70 patients (median age 73 years, 59% males, 48% splenomegaly >14 cm, 4% isolated myeloid sarcoma) with newly-diagnosed MPN-BP (n=58) or AP (n=12) received Ven+HMA with (n=13) or without (n=57) concomitant JAK2 inhibitor. Driver mutation distribution was 69% JAK2, 21% CALR, 6% MPL, and 4% triple negative. Mutations involved ASXL1 (31%), TP53 (28%), TET2 (28%), RUNX1 (25%), SRSF2 (18%), IDH2 (12%), U2AF1 (11%), DNMT3A (9%), IDH1 (7%), and K/NRAS (7%). Karyotype was abnormal in 50 (76%) of 66 informative cases, of which 28 (56%) were complex (CK). Median TP53 mutation variant allele frequency (VAF) was 30% (8-96%) and all evaluable cases displayed CK (n=18).

Response and Survival

Complete remission (CR; 21%) or CR with incomplete count recovery (CRi; 19%) was documented in 28 (40%) patients with residual MPN in 18 (64%) patients. Median response duration was 5.5 months (1-60 months). After a median follow up of 7 months (1-62 months), 48 (69%) deaths, 13 relapses (46%), and 15 (21%) allogeneic stem cell transplants (ASCT; 12 in CR/CRi) were recorded. Median overall survival (OS) was 9 months and was superior with ASCT (median 22 vs. 8 months; p=0.01). In univariate analysis, transplant-censored survival was superior with CR/CRi (12 vs. 5 months; p<0.01) and IDH1 mutation (33 vs. 8 months; p=0.04) and inferior with CK (7 vs. 10 months; p=0.05), TP53 mutation (5 vs. 10 months; p<0.01), post polycythemia vera myelofibrosis (post-PV MF) (3 vs. 9 months; p=0.01), and splenomegaly >14 cm (5 vs. 16 months; p<0.01). Multivariable analysis confirmed the negative survival impact of not achieving CR/CRi (HR 3.8; p<0.01) and presence of TP53 mutation (HR 4.0; p<0.01); median survival (1/3-year survival rate) was 3 months (10%/0%) in TP53 mutated patients not achieving CR/CRi (n=11) vs. 27 months (65%/28%) in TP53 unmutated cases achieving CR/CRi (n=19) (p < 0.01). Median survival in patients with TP53 mutations or CK who achieved CR/CRi (n=7; 7 months) was inferior to that in treatment responders without TP53 mutations or CK (n=18; 23 months; p=0.01).

CR/CRi rates in the presence vs. absence of TP53 mutations were 42% vs. 39% (p=0.80) and of CK (25% vs. 50% (p=0.04). Importantly, responses in the presence of TP53 mutations or CK were too short-lived to allow successful bridging to ASCT (median 2 vs. 9 months; p<0.01). Additional predictors of inferior treatment response included splenomegaly >14 cm (24% vs. 53%; p=0.01), and post-PV MF (0% vs. 46%; p<0.01) while SRSF2 (67% vs. 34%; p=0.04) and IDH2 mutations (75% vs. 35%; p=0.03) were associated with favorable response. In multivariable analysis, CK (p=0.04) and splenomegaly >14 cm (p=0.01) remained independent predictors of inferior response. The use of concomitant JAK2 inhibitor therapy did not impact treatment response (CR/CRi 46% vs. 39%; p=0.62) or survival (median 9 vs. 8 months; p=0.71).

Conclusions

TP53 mutations and CK undermine the value of Ven+HMA, with or without concomitant JAK2 inhibitor, in enabling successful bridging of newly-diagnosed MPN-BP/AP to ASCT. An alternative treatment approach is advised, in the particular scenario, while the observed 3-year survival rate of 28%, in treatment responders without TP53 mutations, is encouraging.

Gangat:DISC Medicine: Consultancy, Other: Advisory Board ; Agios: Other: Advisory Board. Begna:Novartis: Membership on an entity's Board of Directors or advisory committees. Litzow:Abbvie: Research Funding; Amgen: Research Funding, Speakers Bureau; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Sanofi: Research Funding; Beigene: Speakers Bureau; Biosight: Other: Data Safety Monitoring Committee. Mangaonkar:BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Badar:pfizer: Other: Advisory board; Morphosys: Other: Advisory Board; Takeda: Other: advisory board . Patnaik:Epigenetix: Research Funding; Polaris: Research Funding; StemLine: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Solu therapeutics: Research Funding.