Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis

Highlights

• Ruxolitinib associated cytopenias often limit tolerance to therapy.

• Ruxolitinib and danazol therapy demonstrated hematologic stabilization.

• Combination therapy did not improve response per IWG-MRT criteria.

• Therapy was generally well tolerated.

• Combination therapy may be useful in heavily pretreated MF patients.

Abstract

Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol. Fourteen intermediate or high-risk MF patients were enrolled at 2 institutions. Responses per IWG-MRT criteria were stable disease in 9 patients (64.2%) clinical improvement in 3 (21.4%) all of which were spleen responses, partial response in 1 (7.1%) and progressive disease in 1 (7.1%). Despite limited IWG-MRT response, stabilization of anemia and thrombocytopenia was demonstrated. In JAK inhibitor naïve patients, 4/5 (80%) had stable or increasing hemoglobin. Of the 9 patients on prior JAK inhibitor, 5 patients (55.5%) and 8 patients (88.9%) had stable or increasing hemoglobin or platelet levels, respectively. Adverse events possibly related included grade 3 or greater hematologic toxicity in ten patients (71.4%) and non-hematologic toxicity in two patients (14.3%). Although combination therapy did not lead to increased hematologic response per IWG-MRT criteria, hematologic stabilization was observed and may be clinically useful.

Introduction

Myelofibrosis (MF) is a chronic Philadelphia negative myeloproliferative neoplasm characterized by cytopenias, splenomegaly, profound symptom burden, and marrow fibrosis. [1] Anemia is a common manifestation of MF [2]. Since the discovery of the JAK2 V617F mutation [3], [4], [5], [6], targeted therapies with JAK inhibitors, like ruxolitinib, have demonstrated improvements in splenomegaly, symptom burden, and potentially overall survival. [7], [8] Despite this, an improvement in cytopenias with ruxolitinib therapy is uncommon and cytopenias may paradoxically worsen with therapy. Exacerbation of cytopenias by ruxolitinib has been a primary cause of dose reduction and clinical trial discontinuation leading to decreased access to JAK inhibition in a population of patients who may derive the most benefit. Other JAK inhibitors have been demonstrated to be less myelosuppressive but have other dose limiting toxicities [9], [10]. Treatment approaches with erythropoietin stimulating agents or immunomodulatory agents is commonly employed for MF associated anemia with limited success[11], [12], [13], [14], [15]. Previous studies have indicated that danazol is an effective agent for the treatment of anemia in MF with anemia response in up to 37% of treated patients [16], [17]. Combination therapy is an emerging strategy in the treatment of MF patients with multiple pathophysiologic targets in hopes of enhancing efficacy and decreasing toxicity associated with JAK inhibitor therapy [18]. As such, it is hypothesized that combination therapy of danazol with JAK inhibition may modulate cytopenias observed with JAK inhibitor therapy. Thus, we designed a phase II multicenter study to evaluate the overall efficacy per IWG-MRT criteria, hematologic best overall response, and tolerability of combination therapy with ruxolitinib and danazol in intermediate/high-risk MF patients with anemia.