McMullin, Mary Frances

ABSTRACT Myelofibrosis is characterized by perturbation of the JAK/STAT pathway and upregulation of anti‐apoptotic factors leading to myeloproliferation, bone marrow fibrosis (BMF), extramedullary hematopoiesis, splenomegaly, and cytopenias. Navitoclax, a potent oral B‐cell lymphoma (BCL)‐X L /BCL‐2 inhibitor, promotes apoptosis of malignant myelofibrosis cells. Herein, we present results of Cohort 3 of the Phase 2 REFINE study (NCT03222609), which evaluated efficacy and safety of navitoclax plus ruxolitinib in JAKi‐naïve patients with myelofibrosis. JAKi‐naïve patients with primary or secondary myelofibrosis (≥ 18 years with splenomegaly, DIPSS intermediate‐2 and high‐risk myelofibrosis, and ECOG 0–2) and platelet count > 100 × 10 9 /L were enrolled and treated with navitoclax 100 mg once daily (QD) or 200 mg QD according to platelet count (≤ 150 × 10 9 /L or > 150 × 10 9 /L, respectively). Ruxolitinib was given twice daily (dose per label). Primary endpoint: spleen volume reduction of ≥ 35% (SVR 35 ) at week 24. Secondary endpoints: ≥ 50% reduction in total symptom score (TSS 50 ) at week 24, change in grade of BMF, anemia response, and safety. Thirty‐two patients received ≥ 1 dose of navitoclax plus ruxolitinib. Median (range) duration of follow‐up was 44 months (5–58). 63% (20/32) of patients achieved SVR 35 at week 24; median (range) time to first SVR 35 was 12 weeks (11─48). Of 24 evaluable patients, 21% achieved ≥ 50% reduction in driver gene variant allele frequency (VAF). Of 27 evaluable patients, 11 (41%) achieved TSS 50 at week 24; median (range) time to first TSS 50 of 3 weeks (0─16). BMF improved from baseline by ≥ 1 grade in 13/27 patients (48%) at any time on study. Anemia response rates were 38% (5/13) for transfusion‐independent and 100% (2/2) for transfusion‐dependent patients. No bleeding events or deaths were attributed to navitoclax. These findings suggest navitoclax plus ruxolitinib has a tolerable safety profile and provides clinically meaningful improvements for JAKi‐naïve patients with myelofibrosis. Trial Registration NCT03222609.

PURPOSE Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

Abstract The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.