MAJIC-PV Trial Confirms Clinical Benefit of Ruxolitinib in Polycythemia Vera

Treatment with ruxolitinib (Jakafi) generated superior responses vs treatment with best available therapy (BAT) in patients with hydroxycarbamide-intolerant or -resistant polycythemia vera (PV), according to findings from the phase 2 MAJIC-PV trial (ISRCTN61925716).¹ 

At a median follow-up of 4.8 years and a data cutoff of April 2022, 43% (n = 40) of evaluable patients who received ruxolitinib achieved a complete response (CR) vs 26% (n = 23) of those who received BAT (odds ratio, 2.12; 90% CI, 1.25-3.60; P = .02).

Previously, the phase 3b RESPONSE-2 trial (NCT02038036), which evaluated ruxolitinib vs BAT in patients with inadequately controlled PV without splenomegaly, showed that 22% of patients in the ruxolitinib arm achieved durable hematocrit control by week 260. Additionally, during the 5-year follow-up period, the median hematocrit level in the ruxolitinib arm remained below 45%. Patients in the BAT arm could cross over to the ruxolitinib arm after week 28 and up to week 80 if BAT was ineffective or not tolerated.²

“In MAJIC-PV, there was no preplanned crossover to ruxolitinib, and patients were followed for 60 months, which enabled important novel clinical and biological outcome data to be assessed,” lead study author, Claire N. Harrison, DM, FRCP, of Guy’s and St Thomas’ NHS Foundation Trust in London, United Kingdom (UK), and coauthors, wrote in a paper of the data that was published in the Journal of Clinical Oncology.¹

Between August 2012 and August 2016, MAJIC-PV recruited 190 patients who were resistant or intolerant to hydroxycarbamide and randomized 180 of these patients to receive either ruxolitinib (n = 93) or BAT (n = 87). This trial was conducted at 38 sites in the UK and included patients at least 18 years of age with high-risk PV that was intolerant or resistant to hydroxycarbamide. Patients in the ruxolitinib arm received the agent at a starting dose of 10 mg twice daily or 5 mg twice daily for those with baseline platelet counts of 100 x 109/L to 200 x 109/L.

Patients in the BAT arm were permitted to change BAT therapies. Although crossover from the BAT arm to the ruxolitinib arm was not allowed, 10 patients in the BAT arm received ruxolitinib as BAT.

Patients were assessed twice weekly for 3 months, then 6 times a week until 12 months, then 4 times a month thereafter. Patients in the ruxolitinib arm could continue treatment beyond 1 year if they achieved a CR or partial response (PR) at 12 months.

The primary outcome for this trial was CR within 1 year per European LeukemiaNet criteria, which included hematocrit levels below 45% without venesection for 3 months, platelet counts of 400 x 109/L or fewer, white blood cell counts of 10 x 109/L or fewer, and normal spleen size. The key secondary outcomes were PR rates, duration of response, safety, histologic and molecular responses, quality of life, progression-free survival (PFS), overall survival (OS), and event-free survival (EFS).

In the overall study population, the median age was 66 years, and 58% (n = 105) of patients were male. In total, 30% (n = 54), 44% (n = 80), and 26% (n = 46) of patients were resistant to, intolerant to, or both resistant and intolerant to hydroxycarbamide.

The median duration of treatment was 1568 days in the ruxolitinib arm and 1220 days in the BAT arm. The mean ruxolitinib dose was 10 mg twice daily, and dose intensity increased over time. Patients in the BAT arm most frequently received hydroxycarbamide (32%), interferon (15%), and hydroxycarbamide plus interferon (12%).

Additionally, patients in the ruxolitinib arm achieved a superior CR duration compared with those in the BAT arm (HR, 0.38; 95% CI, 0.24-0.61; P < .001).

In total, 54% (n = 50) and 67% (n = 58) of patients in the ruxolitinib and BAT arms, respectively, achieved a best response of PR. Of these patients, 45 and 50 in the ruxolitinib and BAT arms, respectively, had hematocrit levels under 0.45 and had been venesection free for 3 months at the time of their first PR. The overall response rates were 97% and 93% in the ruxolitinib and BAT arms, respectively.

Regarding hematological responses, the patients in the ruxolitinib arm required 83 total venesections vs 307 total venesections in the BAT arm, and 29% (n = 27) and 52% (n = 45) of patients in the ruxolitinib and BAT arms, respectively, had at least 1 venesection. Of the 47 paired samples, 29 from the ruxolitinib arm and 18 from the BAT arm, that were available for 1-year histologic response, the investigators observed no CRs.

Additional results demonstrated that ruxolitinib treatment significantly improved thromboembolic EFS but not hemorrhage-free EFS (HR, 0.56; 95% CI, 0.32-1.00; P = .05). When controlled for sex and treatment, time to first thrombotic event within the first 3 years on the trial was associated with the average number of yearly venesections (sub-distribution HR, 1.20; 95% CI, 1.08-1.33; P < .001).

A multivariable logistic regression model, fitted to include treatment arm, sex, baseline hemoglobin, number or prior therapies, thrombosis history, hydroxycarbamide resistance or intolerance, and splenomegaly generated an odds ratio of 2.03 (90% CI, 1.09-3.78; P = .06).

The ruxolitinib arm also trended toward improved PFS, with a 3-year PFS rate of 84% (95% CI, 74%-90%) vs 75% (95% CI, 63%-83%) in the BAT arm.

The 3-year OS rates were 88% (95% CI, 79%-93%) and 87% (95% CI, 77%-93%) in the ruxolitinib and BAT arms, respectively.

A superior EFS was observed in patients who achieved a CR within 1 year (HR, 0.41; 95% CI, 0.21-0.78; P = .01) and in those who received ruxolitinib (HR, 0.58; 95% CI, 0.35-0.94; P = .03).

At baseline, the median JAK2 V617F variant allele fraction (VAF) was 64% in the ruxolitinib arm and 58% in the BAT arm. The investigators performed JAK2 V617F longitudinal quantification in 127 eligible patients, 70 from the ruxolitinib arm and 57 from the BAT arm. At 12 months, 32% (n = 20/63) and 30% (n = 15/50) of these patients in the ruxolitinib and BAT arms, respectively, had over a 25% VAF reduction, and 14% (n = 9/63) and 18% (n = 9/50) of these patients in the ruxolitinib and BAT arms, respectively, had over a 50% VAF reduction. At median follow-ups of 48 months and 36 months, 56% (n = 39/70) and 25% (n = 14/57) of evaluable patients in the ruxolitinib and BAT arms, respectively, achieved over a 50% VAF reduction (P < .001).

Overall, the median time to molecular response was 36 months in the ruxolitinib arm and not reached in the BAT arm. Molecular response at 12 months was associated with improved outcomes, as 24% of responders experienced events at 12 months vs 43% of nonresponders (P = .005). In the overall population and the ruxolitinib arm, but not the BAT arm, molecular responses at the last sample tested were associated with improved PFS (overall, P = .001; ruxolitinib arm, P = .001), EFS (P = .001; P = .006), and OS (P = .01; P = .04).

In the overall population, 59% (n = 98/167) of patients had a single driver mutation. The presence of additional mutations was associated with age (P = .04), and the most common additional driver mutations were TET2 and ASXL1. Patients with additional driver mutations had impaired EFS (treatment-, age-, and sex-adjusted HR, 1.92; 95% CI, 1.16-3.19; n = 167; P = .01). ASLX1 mutations were predictive for adverse EFS outcomes (n = 167; HR, 3.02; 95% CI, 1.47-6.17; P = .003) after adjusting for age, sex, and TET2 mutations. Additionally, at 12 months, in 14 patients, 8 of whom had JAK2 V617F molecular response data, ASXL1 mutations were overrepresented in JAK2 V617F molecular nonresponders (n = 8).

In total, 147 patients, 76 from the ruxolitinib arm and 71 from the BAT arm completed at least a baseline symptom assessment, and 39 total patients completed the 60-month symptom assessment. Baseline symptom scores were similar between the 2 arms, with the exception of weight loss per the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), which was 1.7 (standard deviation, 2.8) in the ruxolitinib arm and 0.7 (standard deviation, 1.7) in the BAT arm (P = .02). The mean total symptom score (TSS) was 52 months in the ruxolitinib arm. Additionally, patients in the BAT arm experienced worsened symptom burden that improved to baseline at 56 months.

A total of 115 patients had MPN-SAF TSS scores at baseline and at least 1 other time point. Of these patients, 61% (n = 36/59) and 30% (n = 17/56) of those in the ruxolitinib and BAT arms, respectively, had at least a 50% TSS reduction at 1 or more time points (P = .001). Statistically significant symptom reduction at more than 5 time points favoring ruxolitinib occurred for fatigue, night sweats, early satiety, itching, weight loss, and bone pain.

The most common adverse effects were gastrointestinal disorders, infections, and vascular disorders. In total, 27 and 12 grade 3/4 infection events, including respiratory infections, genitourinary infections, and cutaneous herpes zoster, occurred in the ruxolitinib and BAT arms, respectively. No infection-related deaths or atypical infections occurred. Additionally, squamous cell skin cancer occurred in 11 patients, all of whom received ruxolitinib treatment.

“Overall, MAJIC-PV confirms evidence that ruxolitinib is associated with improved treatment efficacy, for hematologic control and symptom responses, and significantly extends currently available data demonstrating novel benefits for ruxolitinib improving thrombosis-free survival and EFS in high-risk hydroxycarbamide-intolerant or -resistant PV,” the study authors concluded.

References

1. Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib versus best available therapy for polycythemia vera intolerant or resistant to hydroxycarbamide in a randomized trial. J Clin Oncol. Published online May 1, 2023. doi:10.1200/JCO.22.01935
2. Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480-e492. doi:10.1016/S2352-3026(22)00102-8