Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide

Abstract

Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P = .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in CALR-positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.com as #ISRCTN61925716.

Figure 1.

Doses of ruxolitinib throughout the MAJIC-ET trial. This figure shows the mean dose of ruxolitinib throughout the MAJIC-ET trial. The mean dose intensity for ruxolitinib during year 1 was 19 mg twice daily.

Figure 2.

Trial consort diagram at 2-year follow-up. Death was recorded as such regardless of prior discontinuation or withdrawal. Patients were clustered as withdrawals regardless of prior discontinuations. **Note: 1 BAT patient started treatment 1 year after randomization; 1 other BAT patient did not have a recorded response within 1 year. Both have been excluded from primary analysis, but included in the follow-up.

Figure 3.

Changes in ET-related symptom burden during year 1 of the MAJIC-ET trial. (A) A waterfall plot of maximum percentage change in the MPN-10 TSS score; dotted line indicates 50% reduction in TSS. (B) The mean MPN-10 TSS throughout the first year of the trial; there was a consistent trend for reduction for ruxolitinib. (C) The mean MPN-10 score for itching during the first 12 months of the MAJIC-ET trial.