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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 II trial of ruxolitinib (JAK1/2 inhibitor) vs Best Available Therapy (BAT) in ET and polycythemia vera (PV) patients resistant or intolerant to HC. Here findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 & 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 two complete molecular responses (CMR) and one partial molecular response (PMR) in CALR positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in one CMR patient, presumably due to the emergence of a different clone raising questions about the relevance of CMR in ET patients. Grade 3&4 anemia occurred in 19% & 0% of ruxolitinib vs 0% (both grades) BAT arm, grade 3&4 thrombocytopenia in 5.2% & 1.7% of ruxolitinib vs 0% (both grades) of BAT treated patients. Rates of discontinuation or treatment switching did not differ between the two trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET.

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases. © 2013 Nature America, Inc. All rights reserved.

MAJIC-ET is a phase 2 study comparing ruxolitinib (RUX) to best available therapy (BAT) in hydroxycarbamide resistant/intolerant (HC-RES/INT) essential thrombocythaemia (ET). The presence of additional non-driver mutations at baseline, in particular TP53 and SF3B1, were predictive for increased risk of disease transformation in this cohort (EHA-4276). Now, we expand the mutation analysis up to 5 years to evaluate clonal evolution after prolonged treatment and correlate with clinical outcome. Driver mutation (JAK2/CALR/MPL) allele burdens were quantified using targeted next-generation sequencing and non-driver mutation analysis was performed using an ISO accredited Illumina TruSeq Custom Amplicon Panel, including 31 gene mutation hotspots & exons (~36,000 bp, 287 amplicons). Data was censored in January 2017 with 47.3% (n=52) randomised to BAT & 52.7% (n=58) to RUX. Overall, 49.1% were JAK2-mutated, 30% CALR-mutated, 4.5% MPL-mutated and 16.4% triple-negative (TN). At 12 months (m), molecular responses (MR) occurred rarely with complete MR (CMR) in 2 patients (pts) and partial MR (PMR) in 3 pts. MR were exclusively seen in RUX-treated pts. 54% (50/92) of those with driver mutations had a >12m allele burden analysis. Median sample time was 48m after trial entry (24 - 60m). There was no significant change in allele burden in the overall cohort. A new JAK2 V617F mutation (allele burden of 6%) was detected at 36m in a "TN" pt at baseline. Of the 5 pts achieving a molecular response at 12m, 2 of these subsequently lost their molecular response; a JAK2-mutated pt achieving CMR at 12m but at 52m had an allele burden of 4% (now PMR) and a CALR-mutated pt with PMR (allele burden 65 to 9%) at 12m, switched from RUX due to toxicity and subsequently lost their MR at 60m (allele burden of 44%), associated with clonal evolution (gain of a new ASXL1 mutation). New MRs occurred in only 2 pts; PMR in a MPL-mutated pt on pegylated-interferon and in a CALR-mutated pt on RUX. 4 pts with a baseline allele burden of Analysis of non-driver mutations was performed on latest TP samples in 51 pts (46%) at a median of 40m after trial entry (6 - 60m). Additional non-driver mutations were present in 30% (33/110) of the cohort at baseline (EHA-4276). In 94% of pts with non-driver mutations at baseline, these were still detected at the latest TP (median 38m, 12 - 52m). There was a We report for the first time a comprehensive longitudinal mutational analysis of HC-RES/INT ET patients within the context of a clinical trial. In this cohort, we found that MR was rare, both early and late in the course of treatment. Initial MR was often not sustained and may signify clonal evolution. As the presence of SF3B1 and TP53 mutations at trial entry predicted for disease progression, we anticipate that the new SF3B1 and TP53 mutations identified at later TP will also increase risk of subsequent transformation during longer follow-up. These data highlight the clinical utility of longitudinal molecular analysis of patients with HC-RES/INT ET. Disclosures Harrison: Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Mead:ARIAD: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Cell Therapeutics: Consultancy; Celgene: Research Funding; Elstar: Research Funding; Evotek: Research Funding.