Mason, Emily F

Background: Myelodysplastic/Myeloproliferative neoplasms (MDS/MPN) represent a group of rare hematologic malignancies, distinguished by their concurrent dysplastic and proliferative features. Patients with these neoplasms have an increased risk of acute leukemia transformation and often present with extramedullary and constitutional symptoms. The only approved therapies for MDS/MPNs are hydroxyurea, decitabine (oral decitabine/cedazuridine and parenteral decitabine) or azacitidine (parenteral) for pts with CMML. Given the rarity and the heterogeneity of MDS/MPNs, prospective studies focusing specifically on MDS/MPN have been uncommon, and refining treatment strategies has been difficult. ABNL-MARRO ( A Basket study of Nove l therapy for untreated MDS/MPN and Relapsed/ Refractory Overlap Syndromes) is an international cooperative effort that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides a framework for collaborative studies around the world to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response (Moyo TK et.al BMC Cancer. 2022). Methods: ABNL-MARRO 001 (AM-001) is an open-label, phase 1b/2 study testing the treatment combination of ASTX727 (days 1-5), a fixed dose oral combination pill containing 35 mg of the DNMTi decitabine (DEC) and 100 mg of the cytidine deaminase inhibitor cedazuridine (CED), together with a series of active agents in myeloid disease (see Figure 1a) for MDS/MPN. In arm A, ASTX727 is combined with itacitinib 300 mg (days 1-28), a selective JAK1 inhibitor in newly diagnosed and relapsed/refractory (R/R) pts. Here we report results from the 3+3 dose de-escalation phase 1b portion used to determine the recommended Phase 2 dose (RP2D) in arm A. Dose-limiting toxicities (DLTs) were assessed in cycle 1. Disease response was assessed by the MDS/MPN IWG response criteria (Savona et.al., Blood. 2015). Results: Seven patients were enrolled with a median age 75 (range 32-82) years with newly diagnosed (4 pts) or R/R (3 pts) MDS/MPN. Three patients had CMML, 2 had MDS/MPN-U, and 2 had refractory MDS/MPN RST. One patient was not DLT evaluable given severe disease-induced cytopenia, and was not included in the assessment (patient 4 in Figure 1b). The majority of pts experienced a treatment-emergent adverse event (TEAE) of any grade; the most common (≥30% of pts) were thrombocytopenia (50%), neutropenia (30%), and constipation (30%); 50% of pts experienced a Grade ≥3 TEAE; the most common was neutropenia (30%). No DLTs were reported, and these AEs were consistent with what has been reported in the use of ASTX727 (Savona et al. Blood. 2022). One patient achieved a CR, and two additional patients had the best overall response of optimal marrow response after receiving 6 cycles of treatment. All patients are alive with a median follow-up of 12 months (range 6-17 months). The clinical responses and time-on-treatment of all pts in phase 1b are summarized in Figure 1b. Summary/Conclusion: Based on the preliminary results of the phase 1b study, the dosing schedule of 35 mg DEC / 100 mg CED daily for 5 days in combination with itacitinib 300 mg daily for 28 days was selected as the RP2D as it balanced clinical efficacy with an acceptable and manageable safety profile. This regimen and dose are being utilized in a 28-day cycle in the ongoing global, multi-center phase 2 study (NCT04061421).

Abstract Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.