Evaluation of genetic and epigenetic determinants of response in patients with accelerated and blast phase Myeloproliferative Neoplasm (MPNs)

The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders, which include polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). MPNs carry an inherent risk of progression to advanced MPN, consisting of accelerated- phase disease (AP; 10-19% blasts in the peripheral blood or bone marrow), as well as blast phase disease (BP; ≥ 20% blasts in the peripheral blood or bone marrow). The prognosis of patients with advanced MPN remains quite poor, with median survival of 2.6 months. Importantly, chemotherapy regimens used to treat Acute Myeloid Leukemia (AML) such as standard induction chemotherapy (which are often used in advanced MPN) appear to have limited efficacy in this setting. Thus, the treatment of advanced MPN is a major unmet clinical need. We recently carried out a phase I/II study to test the safety and efficacy of combination therapy with the JAK1/2 inhibitor Ruxolitinib and the hypomethylating agent Decitabine in patients with advanced MPN (MPD-RC 109 study; NCT02076191). This combination (RUX-DAC) was based on data demonstrating synergy between these drugs in in vitro preclinical studies. 46 patients were accrued to the phase I and II studies. 37 patients were response evaluable. Complete response (CR) occurred in 10%, Complete Response with incomplete count recovery (CRi) in 24%, Partial Response (PR) in 24%. 42% of patients had no response to therapy. Using samples available from the MPD-RC 109 study, as well as samples from a contemporaneous clinical trial of 28 patients with advanced MPN treated with the RUX-DAC regimen carried out at the MD Anderson Cancer Center (NCT02257138), and samples collected from advanced MPN patients treated with the RUX-DAC regimen as a standard of care at Memorial Sloan Kettering Cancer Center, we seek to assess and validate genetic and epigenetic determinants of response to RUX-DAC in this cohort of homogenously treated advanced MPN patients. Specifically, we seek to assess whether the mutational profile of advanced MPN patients explains and predicts response to therapy. We further seek to assess whether alterations in genomic architecture in advanced MPN occur in patients who respond to therapy. Finally, we seek to determine if the baseline global methylation profile correlates with response to therapy, as has been demonstrated for other myeloid malignancies. Data resulting from these studies could be used to guide therapeutic decisions and identify patients for whom combination RUX-DAC therapy has the highest likelihood of procuring a response, as well as to open new lines of biologic and therapeutic inquiry into this disease. Project Number: 1R21CA313410-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Raajit Rampal (+1 co-PI) | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $444,590 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CDPT-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11352898