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• W3092168310 abstract "Aims: Combining Navitoclax (Nav) with Ruxolitinib (Rux) may overcome resistance to JAK2 inhibition, providing a disease-modifying treatment for myelofibrosis (MF). The efficacy and safety of Nav+Rux in MF patients was evaluated. Methods: Eligible adults diagnosed with MF received ≥ 12wk of Rux treatment and have splenomegaly requiring new treatment. Patients continued stable dose of Rux and Nav was initiated at 50mg QD, escalating to 300mg based on tolerability. Primary endpoint was percentage reduction in spleen volume (SV) from baseline. Secondary endpoints included total symptom score (TSS) and bone marrow fibrosis (BMF), anemia response, and safety. The Human ExplorerMAPTM v1.0 panel assessed changes in cytokine levels from baseline at wk 12, 24, and 48. Results: As of 18/11/2019, 34 patients received ≥ 1 dose Nav+Rux; JAK2 and CALR mutations were in 79% and 21%, respectively and 17/33 had high molecular risk. Median duration of prior Rux treatment was 21 months. Median baseline SV was 1,665cm3. Seven patients had RBC transfusion (Tn) within 12wk prior to study, with 2 Tn dependent (TD) per IWG. Median duration of Nav was 330 days; 27 patients remain on study; 30 were evaluable. Reduction in SV ≥35%(SVR35) from baseline showed in 13(43%) patients, with 9(30%) achieving SVR35 at wk 24; 8/32 (25%) had grade ≥1 reduction in BMF. TSS reduction in 11/17 patients at wk 24, with ≥50% reduction in 6. Four of 7 patients had ≥12 wk Tn-free period. Of the 2 TD patients, 1 became Tn independent ongoing for 34 wk. Most common adverse events (AEs) were thrombocytopenia (85%) and diarrhea (68%). Most common grade ≥3 AEs were thrombocytopenia (44%), reversible and manageable with dose modification, and anemia (27%). Serious AEs (SAEs) occurred in 8 patients (24%). No serious episodes of bleeding occurred. Most analyzed cytokines (10/18) modulated by Rux in JAK2 inhibitor-naive patients were modulated on introduction of Nav. At wk 12, modulation of AXL, beta-2 microglobulin, E-selectin, IGFBP7, and MPO directly associated with SV response. Data will be updated at presentation. Conclusion: Nav+Rux was well-tolerated and led to clinically meaningful SVR, reductions in TSS and BMF, and cytokine modulation. Apoptotic induction with Nav may be a treatment option for MF patients to prevent or reverse JAK2 resistance and modify MF. Abstract was previously published at EHA25 Combining Navitoclax (Nav) with Ruxolitinib (Rux) may overcome resistance to JAK2 inhibition, providing a disease-modifying treatment for myelofibrosis (MF). The efficacy and safety of Nav+Rux in MF patients was evaluated. Eligible adults diagnosed with MF received ≥ 12wk of Rux treatment and have splenomegaly requiring new treatment. Patients continued stable dose of Rux and Nav was initiated at 50mg QD, escalating to 300mg based on tolerability. Primary endpoint was percentage reduction in spleen volume (SV) from baseline. Secondary endpoints included total symptom score (TSS) and bone marrow fibrosis (BMF), anemia response, and safety. The Human ExplorerMAPTM v1.0 panel assessed changes in cytokine levels from baseline at wk 12, 24, and 48. As of 18/11/2019, 34 patients received ≥ 1 dose Nav+Rux; JAK2 and CALR mutations were in 79% and 21%, respectively and 17/33 had high molecular risk. Median duration of prior Rux treatment was 21 months. Median baseline SV was 1,665cm3. Seven patients had RBC transfusion (Tn) within 12wk prior to study, with 2 Tn dependent (TD) per IWG. Median duration of Nav was 330 days; 27 patients remain on study; 30 were evaluable. Reduction in SV ≥35%(SVR35) from baseline showed in 13(43%) patients, with 9(30%) achieving SVR35 at wk 24; 8/32 (25%) had grade ≥1 reduction in BMF. TSS reduction in 11/17 patients at wk 24, with ≥50% reduction in 6. Four of 7 patients had ≥12 wk Tn-free period. Of the 2 TD patients, 1 became Tn independent ongoing for 34 wk. Most common adverse events (AEs) were thrombocytopenia (85%) and diarrhea (68%). Most common grade ≥3 AEs were thrombocytopenia (44%), reversible and manageable with dose modification, and anemia (27%). Serious AEs (SAEs) occurred in 8 patients (24%). No serious episodes of bleeding occurred. Most analyzed cytokines (10/18) modulated by Rux in JAK2 inhibitor-naive patients were modulated on introduction of Nav. At wk 12, modulation of AXL, beta-2 microglobulin, E-selectin, IGFBP7, and MPO directly associated with SV response. Data will be updated at presentation. Nav+Rux was well-tolerated and led to clinically meaningful SVR, reductions in TSS and BMF, and cytokine modulation. Apoptotic induction with Nav may be a treatment option for MF patients to prevent or reverse JAK2 resistance and modify MF. Abstract was previously published at EHA25" @default.
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• W3092168310 date "2020-09-01" @default.
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• W3092168310 title "MPN-038: Navitoclax in Combination with Ruxolitinib in Patients with Primary or Secondary Myelofibrosis: A Phase 2 Study" @default.
• W3092168310 doi "https://doi.org/10.1016/s2152-2650(20)30493-6" @default.
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