Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial

Abstract

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.

FIG 1.

CONSORT diagram. BAT, best available therapy; CR, complete response; PR, partial response; RUX, ruxolitinib.

FIG 2.

Ruxolitinib induces durable responses and improves major EFS in PV. Kaplan-Meier plots of (A) duration of complete remission, stratified by treatment arm; (B) time to discontinuation of first treatment, stratified by treatment arm; (C) EFS, stratified by treatment arm; and (D) EFS according to the primary end point. P value obtained from a Cox model adjusting for sex and, where indicated, treatment. BAT, best available therapy; CR, complete response; EFS, event-free survival; HR, hazard ratio; RUX, ruxolitinib.

FIG 3.

Molecular analysis and clinical correlates. (A) Waterfall plot displaying the percentage change in JAK2V617F VAF at the latest time point in comparison with baseline. Bars are colored according to BAT (blue) and ruxolitinib (red). ^aPatients with additional driver mutations. (B) The percentage of HSPCs that were JAK2V617F+ by single-cell genotyping at BL and latest FU. Three ruxolitinib-treated patients showing a >90% reduction in JAK2V617F VAF in peripheral blood at the latest time point were selected for analysis. For patients (1) and (2), CD34+CD38+ (n = 237 and n = 218 cells analyzed, respectively) and CD34+CD38– (n = 70 and n = 90 cells analyzed, respectively) HSPCs are shown separately. For patient (3), total CD34+ cells (n = 125) are shown. (C) EFS with patients stratified according to molecular response at 12 months (orange, NR defined as <50% JAK2 VAF reduction; purple, partial responder defined as >50% JAK2 VAF reduction). Shaded areas represent 95% CIs. (D) Heatmap of extended gene panel mutation analysis of baseline samples. The rows in the graph represent individual gene mutations colored by the type of mutation together with the VAF for mutant JAK2, and the columns represent patients in the study. (E) EFS for patients stratified according to presence or absence of additional driver mutations (gray, all patients; purple, patients with a single driver mutation; orange, those with additional driver mutations). (F) EFS stratified according to presence or absence of an ASXL1 mutation (gray, all patients; purple, ASXL1-unmutated; orange, ASXL1-mutated). BAT, best available therapy; BL, baseline; EFS, event-free survival; FU, follow-up; HR, hazard ratio; HSPCs, hematopoietic stem and progenitor cells; NR, nonresponder; PR, partial response; VAF, variant allele fraction.

FIG 4.

Symptom responses. Change in MPN TSS, blue is BAT, red is ruxolitinib. Shaded areas indicate 95% CIs. ^aSignificant difference between the arms. BAT, best available therapy; MPN, myeloproliferative neoplasm; RUX, ruxolitinib; TSS, total symptom score.