Outcomes of Patients with Accelerated/Blast-Phase Myeloproliferative Neoplasms in the Current Era of Myeloid Therapies

Background: Philadelphia-chromosome negative (Ph neg) myeloproliferative neoplasms (MPN) that progress to an accelerated phase (AP) or blast phase (BP) have poor outcomes with a median survival of less than one year (Odenike, Blood 2018; Tam et al, JCO 2009). Since 2017 there have been a number of FDA-approved therapies for acute myeloid leukemia (AML) that have been utilized in MPN-AP/BP. We aim to characterize outcomes of patients (pts) with MPN-AP/BP in the current era of myeloid therapies via a multi-center retrospective analysis.

Methods: Retrospective chart review was performed at participating institutions to identify pts with pathology-confirmed Ph neg MPN-AP/BP diagnosed in 2017 or later. All patients that met inclusion criteria were included. Response was assessed using both 2017 European Leukemia Net AML (2017 ELN) criteria (Dohner et al, Blood 2017 and 2012 Post-MPN AML Consortium (2012 MPN-BP) Criteria (Mascarenhas et al. Leuk Res 2012). Overall survival from diagnosis of MPN-AP/BP was calculated utilizing Kaplan-Meier analysis.

Results: This analysis includes 80 pts treated at three institutions with a data analysis cut-off of 7/1/22. Sixteen pts had MPN-AP and 64 pts had MPN-BP at time of progression. Median age at diagnosis of MPN-AP/BP was 68.9 years old. Amongst the 80 pts, chronic-phase MPN (cMPN) treatments included hydroxyurea (59%), JAK inhibitor (34%), Interferon (4%), hypomethylating agent (HMA) (5%), and allogeneic stem-cell transplant (allo-SCT) (4%). Driver mutations in pts with cMPN included JAK2 (66%), CALR (14%), and MPL (10%) with 8% of pts having triple-negative disease. Sixty-six patients had next-generation sequencing (NGS) performed at time of MPN-AP/BP diagnosis. Frequencies of high-risk mutations as defined by MIPSS70 v2.0 (Tefferi et al, JCO 2018) were as follows: ASXL1 (32%), SRSF2 (23%), IDH2 (18%), U2AF1 (8%), EZH2 (5%), and IDH1 (5%). Other frequent co-occurring mutations detected at time of MPN-AP/BP diagnosis were TP53 (21%), TET2 (18%), DNMT3A (11%), and RUNX1 (9%). Table 1 summarizes additional pt demographics.

Initial therapies for MPN-AP/BP included intensive chemotherapy (IC) (n=32), HMA+Venetoclax (VEN) (n=23), HMA-based therapy (n=16), and IDH inhibitor (n=3) with 5 pt continuing best supportive care and 1 pt proceeding directly to allo-SCT. Specific therapies are summarized in Table 2A. Twelve pts were treated on clinical trial (6 HMA backbone, 3 IC backbone, 2 HMA-VEN, 1 IDH inhibitor). Overall response rate (ORR) was defined as pts achieving a complete molecular response (CMR), complete cytogenetic response (CCR), acute leukemia response-complete (ALR-C), or acute leukemia response-partial (ALR-P) by 2012 MPN BP Criteria. ORR was 53% in IC group, 65% in HMA+VEN group, and 31% in HMA-based group. Response to 1^st line therapy by both 2012 MPN-BP and 2017 ELN criteria is summarized in Table 2A. Therapies utilized in the 2^nd-line and beyond (2L+) setting included IC (n=15), HMA-VEN (n=22), HMA-based therapy (n=7), IDH inhibitor (n=5), FLT3 inhibitor (n=1), and investigational monotherapies (n=2). Six of these therapies were administered in the context of a clinical trial (2 HMA-VEN, 2 investigational monotherapies, 1 IC backbone, 1 IDH inhibitor). ORR was 73% in IC group, 41% in HMA+VEN group, and 43% in HMA-based group. Response to 2L+ therapies is summarized in Table 2B. Twenty-one pts underwent allo-SCT for MPN-AP/BP (1 prior to MPN-AP/BP-directed therapy, 10 after first-line therapy, and 10 after 2L+ therapy). There were 5 relapses after allo-SCT. Median overall survival (mOS) for the entire 80 pt cohort was 0.73 years (Figure 1A). Survival analysis based on 1^st line MPN-AP/BP therapy demonstrated a mOS of 0.59 years for IC, 0.59 years for HMA+VEN, and 1.11 years for HMA-based (Figure 1B). A mOS of 1.33 years was seen in pt that underwent allo-SCT.

Conclusions: Despite the rapidly changing landscape of therapies for myeloid malignancies, survival remains short in patients with MPN-AP/BP with a mOS of 0.73 years for the entire cohort. Patients that underwent allo-SCT had a mOS of 1.33 years. In addition, only 16% of therapies were administered in the context of a clinical trial in the first-line setting and 12% in the 2L+ setting, highlighting the need for the development of novel investigational approaches. Future directions include collection of patient data from 8 participating institutions with planned multivariate analyses.

Patel:Servier/Agios: Research Funding; Celgene/BMS: Research Funding; Kronos Bio: Research Funding; Pfizer: Research Funding; AbbVie: Consultancy. Bradley:Geron Corporation: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abaza:Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; ALX Oncology: Research Funding. Garcia:AbbVie, Genentech, AstraZeneca, Prelude and Pfizer: Other: Clinical trial support (institutional) , Research Funding; AbbVie: Research Funding; AbbVie, Astellas, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board . Shallis:Bristol Myers Squibb and Gilead Sciences, Inc: Honoraria; Gilead Sciences, Inc.: Honoraria. Gupta:AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Roche: Other: Participation on a Data Safety or Advisory board; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria. Pettit:AbbVie, CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Biomedicines, Image Biosciences, Kura Oncology, Macogenics, PharmaEssentia, Protagonis: Research Funding. Odenike:Abbvie; Impact Biomedicines; Celgene; Novartis; BMS; Taiho Pharmaceutical; CTI; Threadwell therapeutics; Bristol-Myers Squibb/Celgene (Inst): Consultancy; Celgene (Inst); Incyte (Inst); Astex Pharmaceuticals (Inst); NS Pharma (Inst); Abbvie (Inst); Janssen Oncology (Inst); OncoTherapy Science (Inst); Agios (Inst); AstraZeneca (Inst); CTI BioPharma Corp (Inst); Kartos Therapeutics (Inst); Aprea AB (Inst): Research Funding.

outcomes of patients treated with investigational therapies while on trial are part of this retrospective analysis