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Randomized Controlled Trial
. 2017 Oct 26;130(17):1889-1897.
doi: 10.1182/blood-2017-05-785790. Epub 2017 Aug 9.

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

Claire N Harrison  1 , Adam J Mead  2 , Anesh Panchal  3 , Sonia Fox  3 , Christina Yap  3 , Emmanouela Gbandi  3 , Aimee Houlton  3 , Samah Alimam  1 , Joanne Ewing  4 , Marion Wood  5 , Frederick Chen  6 , Jason Coppell  7 , Nicki Panoskaltsis  8 , Steven Knapper  9 , Sahra Ali  10 , Angela Hamblin  11 , Robyn Scherber  12   13 , Amylou C Dueck  14 , Nicholas C P Cross  15 , Ruben Mesa  13 , Mary Frances McMullin  16
Affiliations
Randomized Controlled Trial

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

Claire N Harrison et al. Blood. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: C.N.H. has participated in advisory boards for Novartis, CTI, Baxaltra, and Celgene; was on speakers bureau for Novartis, CTI, Baxaltra, Shire, Gilead, INCYTE; received honoraria from Novartis, Shire CTI, Gilead, Baxaltra, INCYTE; and received research funding and travel, accommodation, and expenses from Novartis. A.J.M. has participated in advisory boards for Novartis, CTI, and Baxaltra; received honoraria from Novartis, Gilead, Shire, and Baxaltra; and also received research funding and travel, accommodation, and expenses from Novartis. F.C. and J.C. have received travel, accommodation, and expenses from Novartis. S.K. has participated in advisory boards for Novartis; received honoraria from Novartis, Shire, and Gilead; and received travel accommodation and expense from Novartis and Celgene. S. Ali received honoraria from Novartis and participated in advisory boards for Novartis. A.H. has participated in advisory boards for Novartis and was on the speakers bureau from Gilead. N.C.P.C. has participated in advisory boards for Novartis and received honoraria from Novartis and research support from Novartis. R.M. has consulted for Novartis, Ariad, and Galena and received research funding from Incyte, Gilead, CTI, NS Pharma, Celgene, and Promedior. M.F.M. has participated in advisory boards for Novartis and Gilead; received honoraria from Novartis, Shire, and Celgene; and received travel, accommodation, and expenses from Novartis. The remaining authors declare no competing financial interests.

Figures

Figure 1.
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.
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.
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.
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Comment in

References

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