Ghurye, Vineta

Abstract Introduction: Approximately 75% of myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol in the treatment of anemia in MF demonstrate responses in anemia of 30-55%. Ruxolitinib has demonstrated improvement in MF related splenomegaly, symptom burden, and even survival yet improvements in cytopenias are uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia. Methods: This is a pre-planned interim analysis of a Simon optimum two-stage phase II trial designed to include a minimum of 10 and a maximum of 27 patients. Participants received ruxolitinib 10mg (plat >75 x10x9) BID or 5mg (plat <75 x10 x9) BID with danazol 200mg orally TID. Dose escalation was allowed after completion of 28 days for lack of response or for disease progression. Patients without progression were continued for 6 cycles at 56 days each. Treatment modifications were based on adverse events including thrombocytopenia, leukopenia, and elevation in creatinine and transaminases. Treatment responses were evaluated by the IWG-MRT response criteria (Blood 2013). Patient reported outcome questionnaires (MPN-SAF and EORTC QLQ-C30) were administered at baseline, prior to treatment cycles, and at study discontinuation. Results: Patients: Ten of the 12 evaluable patients enrolled (median age 70.5, range 57-78, M:F ratio 4:1) are included in this analysis. Eight patients had primary MF (PMF), 1 had post essential thrombocytosis (ET) MF, and 1 had post polycythemia vera (PV) MF. Jak2 V617F mutation was positive in 30%. At the time of enrollment 40% had received an erythrocyte transfusion in the last month and all were DIPSS Int-2 or higher. Median baseline hemoglobin was 9.0 g/dL (range 8.3 - 12.4). Median baseline platelet level was 172 x10 (9)/L (range 56 - 346). Most (90%) had received prior therapy and many were refractory to multiple lines of therapy prior to enrollment. Three (30%) patients had previously participated in a JAK inhibitor clinical trial. Tolerability: Among 6 patients who have completed treatment, median duration of treatment was 39 days (range 24-287) with treatment discontinuation due to progression of disease in 2 patients, allogeneic stem cell transplant in 1, alternative treatment in 1, unrelated adverse event (hyponatremia) in 1, and unrelated death (leukemic transformation with intracranial hemorrhage) in 1. Hematologic Grade 3 or > adverse events included anemia (60%), neutropenia (20%), and leukopenia (10%). Non-hematologic Grade 3 or > adverse events included electrolyte abnormalities (20%), edema (10%), infection (10%), and intracranial hemorrhage (10%). Efficacy: Treatment response per IWG-MRT response criteria included stable disease (SD) in 8/10 (80%), clinical improvement in 1/10 (10%), and progressive disease (PD) in 1 (10%). The median change in hemoglobin and platelet count from baseline was -0.05 g/dL (range -0.5 - 1.8) and 28.5 x10(9)/L (range -143 – 118) respectively, however 4/10 (40%) and 7/10 (70%) had improvement at some point during treatment in level of anemia and/or thrombocytopenia. The median follow-up time was 2 months (range 0.9-9.4). Among 6 patients with a baseline and at least one post-baseline MPN-SAF TSS, 2/6 (30%) of patients had at least a 10-point (clinically meaningful) improvement, with 1 of the 2 achieving the stricter 50% improvement from baseline. Responses might have been confounded due to impact of prior therapies. Conclusions: On interim analysis, ruxolitinib and danazol combination therapy demonstrates modest additional clinical benefit, however in a group of exceedingly high risk MF patients with significant anemia and prior single agent JAK inhibitor failures. Preliminary data suggests improvement in anemia and/or thrombocytopenia in some treated patients however only one clinical improvement per IWG-MRT criteria was observed. Combination therapy was well tolerated with no major incremental toxicity attributable to the addition of danazol. Maturation of data is needed to fully evaluate efficacy of ruxolitinib and danazol combination therapy prior to continuation of accrual. Disclosures Mascarenhas: Incyte Corporation: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Tibes:Seattle Genetics, Inc.: Research Funding. Mesa:Incyte: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; Ns Pharma: Research Funding; Celgene: Research Funding; Lilly: Research Funding; Cti: Research Funding.

Abstract Introduction: Most myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol for the treatment of anemia in MF demonstrate responses in anemia. In prior randomized-controlled studies, ruxolitinib demonstrated improvements in splenomegaly, symptom burden, and even survival yet improvements in cytopenias were uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia. Methods: This was a Simon optimum two-stage phase II trial. Eligible subjects received ruxolitinib, a JAK 1/JAK2 inhibitor, at 10mg (plat >75 x10x9) BID or 5mg (plat <75 x10 x9) BID) representing initial dose reduction for JAK inhibitor naïve patients to minimize cytopenias, in combination with tapered danazol up to 200mg orally TID. Dose escalation was allowed after completion of 28 days for lack of response or for disease progression. Pts without progression continued for 6 cycles at 56 days each. Treatment modifications were allowed for either medication based on emergent adverse events (AE). Treatment responses were evaluated every cycle by IWG-MRT criteria (Blood 2006). Patient reported outcome questionnaires (MPN-SAF, EORTC QLQ-C30) were administered at baseline, prior to treatment cycles, and at study discontinuation. Results: Patients: Fourteen pts enrolled (9 Mayo Arizona, 5 Mount Sinai). Median (Med) age 70.5 (range 43-78), M:F ratio 1.8:1. Ten primary MF, 2 post-essential thrombocythemia MF, and 2 post-polycythemia vera MF. JAK2 V617F positive in 42.9%. DIPSS Low in 1 pt, Int-1 in 1pt, Int-2 in 8 pts, High in 2 pts, and unknown in 2pts. Transfusion dependence in 35.7% at baseline. Med baseline hemoglobin (hgb) was 9.0 g/dL (R: 8.3 - 12.4), platelet (plt)157 x109/L (R:143 - 520). Thirteen pts received prior therapy, with 9 pts (64.2%) on a JAK inhibitor within 3 months of study entry. Tolerability: Nine pts (64.2%) ended active treatment, due to progression of disease in 2 pts (22.2%), adverse event (AE) in 2, pt preference in 2, stem cell transplant in 1, unrelated death in 1, and comorbidity in 1. Med duration of therapy: 91 days (range 24-287). AEs regardless of attrition included: hematologic grade 3 or >: anemia in 7 pts (50%), neutropenia in 2 (14.3%), leukopenia in 1 (7.1%), and thrombocytopenia in 2 (14.3%). Non-hematologic grade 3 or >: electrolyte abnormalities in 3 pts (21.4%), infection in 2 (14.3%), edema in 1(7.1%), hypertension in 1 (7.1%), and intracranial hemorrhage in 1 (7.1%). Efficacy: Of the 5 JAK inhibitor naïve pts, 4 had stable or increasing hgb levels with therapy despite new ruxolitinib therapy. Of the 9 pts on prior JAK inhibitor (5 ruxolitinib, 4 other), 5 (55.5%) and 7 (77.7%) patients had stable or increasing hgb or plt levels, respectively. See Table #1. Four pts (28.6%) had at least 50% improvement from baseline on MPN-SAF TSS (95% CI 8.4%-58.1%). Overall treatment response: (IWG-MRT) stable disease (SD) in 10 pts (71.4%), clinical improvement (CI) in 3 (21.4%) all of which were spleen responses, and progressive disease (PD) in 1 (7.1%). Trial was halted secondary to lack of anemia response. Table 1. Patient Specific Response Patient IWG-MRT Response: Study Cycles (N): Prior therapy (within 3 mo) Hemoglobin Response*: (initial, final g/dL) Platelet Response*: (initial, final 10(9)/L) Ruxolitinib 1 CI-Spleen 5 D (8.8, 7.6) S (221,212) 2 SD 4 D (10.3,7.9) S (54,46) 3 SD 2 S (8.8,8.9) S (82,101) 4 SD 3 I (8.9,9.8) S (441,458) 5 SD 3 S (9.6, 9.5) I (161, 231) JAK Inhibitor: 6 SD 5 Momelotinib S (9.0, 9.2) S (132,113) 7 SD 1 NS-018 D (8.3, 7.1) D (120,43) 8 SD 3 NS-018 D (10.1,9.0) D (138,111) 9 SD 2 LY2784544 S (8.7,9.1) S (56,21) Other: 10 CI-Spleen 9 Procrit I (10.5,11.9) S (153,198) 11 CI-Spleen 7 None I (8.9,10.2) D (338,133) 12 PD 1 Hydroxyurea S (12.4, 12.2) D (310, 82) 13 SD 1 Procrit D (10.1, 8.6) D (192, 71) 14 SD 1 Hydroxyurea S (9.1,8.9) D (346,119 *S=stable (Hgb +/- 0.5g/dL, Plt +/- 50x109, D=decreasing, I=increasing. Conclusions: Although overall well tolerated, the addition of danazol to ruxolitinib therapy has modest incremental efficacy by IWG-MRT criteria. Clinical improvement was observed in 21.4% of treated patients, however responses were limited to spleen reduction. The degree to which danazol may stabilize expected cytopenias is interesting and may require further investigation. Disclosures Hoffman: Promedior: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Gilead: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Research Funding.