Outcome Of Patients (pts) With Myelofibrosis (MF) After Ruxolutinib (Rux) Therapy

Ruxolitinib (Rux) is a potent, specific oral JAK1 and JAK2 inhibitor that is approved therapy for patients (pts) with intermediate- or high-risk MF. Its clinical benefit is seen in the majority of pts, as a marked and sustained improvement in splenomegaly and/or disease-associated symptoms. Rux therapy also prolongs the life-span of pts with advanced MF. Nonetheless, the prognosis of the minority of MF pts who either fail to primarily respond or lose clinical response over time to Rux has not been examined so far.

To assess the outcome of pts with MF after a reasonable course of Rux therapy has been completed. This is important in relation to pts who might benefit from other strategies in this clinical setting, such as allogeneic stem cell transplantation (AlloSCT) or clinical studies with investigational agents.

Data from all pts with a diagnosis of MF who received Rux therapy at MDACC from Jun.2007 until Sep, 2011 were analyzed. Of those, 79 pts discontinued Rux but also provided adequate data during follow-up for this analysis.

Median age was 67 years (range, 40-84) and 56 pts (71%) were primary MF. Per International Prognostic Scoring System (IPSS), at baseline (BL), 8 (10%) pts had intermediate (int)-1, 19 (24%) int-2, and 52 (66%) high-risk MF. Per Dynamic (D)-IPSS, 19 (24%) pts were int-1, 49 (62%) int-2, and 11 (14%) high-risk. Karyotype was diploid in 45 pts (57%). The JAK2V617F mutation was identified in 62 pts (78%), with a median allele burden of 54%. At BL, median spleen size was 18 cm (range, 0-36); 3 pts had prior splenectomy; 25 pts (32%) were RBC transfusion-dependent. Median BL platelet count was 257 x 10⁹/L (range, 100-1183). Rux was given for a median of 19 months (mo; range, 2-5+). Clinical improvement in splenomegaly per IWG, i.e., a 50% or greater reduction of splenic length by palpation, was observed in 40 pts (53%) for a median of 32 mo (range 6-57). In addition, 36 pts (46%) with post-BL assessments experienced a clinical benefit with up to 50% reduction in splenomegaly and improvement in symptoms. Only 3 pts had “primary” refractory disease. The characteristics of pts at the time of Rux discontinuation are shown in Table 1: 19 pts (24%) had int-1, 49 (62%) int-2, and 11 (14%) high-risk disease, by D-IPSS. Reasons for stopping Rux in 76 pts who initially responded to this medicine were: loss of clinical benefit in 53 pts (70%), transformation into acute myeloid leukemia in 6 pts (8%), progression in comorbidities in 4 pts (5%), limiting myelosuppression in 4 pts (5%), AlloSCT in 4 pts (5%), pts’ personal request in 3 (4%), and splenectomy in 2 (3%). The median overall survival (OS) after Rux discontinuation was 6 mo with estimated 1- and 2-year OS rates of 34% and 25%, respectively. After a median follow-up of 10 mo from stopping Rux, 27 (34%) pts remain alive. There was no difference in survival depending upon D-IPSS categories (p=0.71).

The outcome of pts with MF who experience either ‘primary’ failure (∼4%) of or loss of clinical benefit (∼96%) from Rux therapy is poor, with a median survival of only 6 mo. The D-IPSS risk model is not predictive of their outcome.

Cortes:Incyte: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Verstovsek:Incyte: Research Funding.