Molecularly Targeted Combination Therapy for Advanced Phase Myeloproliferative Neoplasm: MPN-RC 119

Background: Patients with myeloproliferative neoplasms (MPNs) that develop accelerated (AP) or blast phase (BP) disease have poor outcomes and limited treatment options. The median overall survival (OS) for patients with MPN-BP is 3-5 months (Mesa, Blood 2005; Mascarenhas, CLML 2016), and 12 months for patients with MPN-AP. Myelofibrosis (MF) patients with 5-9% blasts in the peripheral blood (PB) have a similar outcome as patients with MPN-AP (Massarova, CLML 2021).

IDH mutations occur in 20-25% of patients with MPN-BP and the acquisition of these mutations is associated with both an increased risk of leukemic transformation and reduced OS (Dunbar, blood 2020).

IDH2R140Q-Jak2V617F mice treated with a combination of JAK1/2 inhibitor (ruxolitinib) and an IDH2 inhibitor (enasidenib) showed complete resolution of splenomegaly, normalization of blood counts, and blast resolution (McKenney, JCI 2018).

Here we report the preliminary results of the first molecularly targeted therapy for MPN AP/BP patients harboring IDH2 mutations utilizing combination treatment with ruxolitinib and enasidenib.

Methods: A phase 2, multicenter trial of combined ruxolitinib and enasidenib is being conducted in patients with MPN-AP/BP or MF in chronic phase (CP) with 4-9% PB blasts and an IDH2 Mutation (NCT04281498). MPN-AP/BP and MF-CP Patients receive enasidenib 100mg and 50mg daily respectively, with dose increases after cycle 1 for MF-CP. Initial ruxolitinib doses were determined based on platelet counts at enrollment for patients without previous ruxolitinib treatment or continuation of current treatment dose. Response assessment occurred every 3 cycles for MPN-AP/BP using modified Cheson criteria and every 6 cycles for MF-CP using IWG/ELN criteria.

Results: Six patients have been enrolled (5 MPN-AP/BP and 1 MF-CP). 50% were male with a median age of 74 years (range 58-81). (Table 1). Patients were treated for a median of 5.5 cycles (1-13) with a median follow up of 26 weeks (2.7-53).

At the time of reporting, two patients remain on trial. Four discontinued treatment; disease progression (n=1), physician discretion (n=1, after no response observed after 3 cycles), allogeneic stem cell transplant (n=1), withdrew consent (n=1).

Grade 3/4 adverse events (AEs) were reported in five of the six (83%) patients. All grade 4 AEs were hematological events, as well as the majority of the grade 3 AEs. One patient (16.7%) had grade 3 liver function test abnormalities, one patient (16.7%) had grade 3 hyperbilirubinemia and one patient (16.7%) had grade 3 neutropenic fever. QT prolongation and evidence of a differentiation syndrome were not observed. AEs are summarized in Table 2.

Of the five MPN-AP/BP patients, one pt was not evaluable for response (removed after 1 cycle due to disease progression). The ORR was 50% in the evaluable cohort and 40% in the intention to treat analysis. Two patients achieved complete remission (CR). One patient achieved CRi after 3 cycles and has maintained the response after 13 cycles, one patient achieved CRi after 3 cycles, and CR after 4 cycles, and has maintained the response after 9 cycles. Two patients had stable disease after 3 and 6 cycles.

Conclusion: Combination treatment with ruxolitinib and enasidenib appear safe with manageable toxicity profile. The majority of grade 3/4 AEs were hematologic as expected in this advanced patient population. Results are encouraging and warrant continued evaluation of this IDH2 mutant defined poor prognostic group. Trial enrollment is ongoing and mature results will be presented at the meeting.

Bar-Natan:BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Incyte: Research Funding. Mascarenhas:Kartos: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sierra Oncology: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy; GSK: Consultancy; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Research Funding; Janseen: Research Funding; Prelude Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy; Merus: Research Funding; Forbius: Research Funding; Imago: Consultancy; Roche: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gerds:Kratos Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Accurate Pharmaceuticals: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imago BioSciences: Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys/Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Samus: Consultancy, Research Funding; AbbVie: Research Funding; Genotech: Research Funding; Promedior: Research Funding; Blueprint: Consultancy; Geron: Consultancy; Celgene: Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Roche: Consultancy; LaJolla Pharmaceutical: Consultancy; CTI: Research Funding; Bristol Myers Squibb: Consultancy; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; AOP: Consultancy; Novartis: Consultancy; Imago: Research Funding. Gupta:Roche: Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board. Kremyanskaya:Kronos: Research Funding; Incyte: Consultancy, Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; BMS: Research Funding; Chimerix: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Kura: Research Funding; Ionis: Research Funding. Hoffman:Novartis: Other: Chair DSMB; Scholar Rock: Research Funding; Abbvie: Other: Chair DSMB, Research Funding; Novartis: Research Funding; Ionis: Consultancy; Protagonist Therapeutics: Consultancy; Repare: Research Funding; Silence Therapeutics: Consultancy; Turning Point: Research Funding. Rampal:Zentalis: Consultancy, Research Funding; CTI: Consultancy; Sierra Oncology: Consultancy; Jazz Pharmaceuticals: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunimoto Dainippon: Consultancy; Disc Medicines: Consultancy; Galecto: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy; Stemline: Consultancy, Research Funding; Promedior: Consultancy; Stemline: Consultancy, Research Funding; Gilead: Consultancy; Novartis: Consultancy; Celgene/BMS: Consultancy; Incyte: Consultancy, Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding.

Enasidenib is approved for AML, we are conducting a trial that includes patients with high features chronic phase MF.