Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls

Abstract

Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with longterm therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P ‫؍‬ .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P ‫؍‬ .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with > 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit. (Blood. 2012;120(6):1202-1209)

A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis

“…28 Here we observed a similar improvement in survival for patients who had larger spleen size reductions, both by volume as assessed by MRI and palpable spleen length, compared with patients who had increased splenomegaly or no change from baseline. The positive correlation of greater on-treatment spleen size reduction with a reduced risk of death that was observed in the combined ruxolitinib group was not observed for patients in the combined control group, thus precluding use of spleen size reduction as a general surrogate marker for survival, independent of treatment.…”

High concordance in grading reticulin fibrosis and cellularity in patients with myeloproliferative neoplasms

“…[26][27][28] The JAK1/JAK2 inhibitor ruxolitinib is a novel agent that has been shown to ameliorate clinical symptoms and splenomegaly and prolong survival in patients with primary myelofibrosis, post-thrombocythemic myelofibrosis and post-polycythemic myelofibrosis. [29][30][31][32][33][34][35] Although prior therapies used to treat primary myelofibrosis (hydroxyurea and interferon) have shown little or no effect on bone marrow fibrosis grade, 36,37 treatment with ruxolitinib has been associated with reduction and even complete resolution of bone marrow fibrosis. 38,39 The selective JAK2 inhibitor fedratinib has also shown efficacy in treating patients with primary myelofibrosis, post-thrombocythemic myelofibrosis, and post-polycythemic myelofibrosis and similarly shows evidence of reduced reticulin fibrosis in treated patients.…”

Ruxolitinib: a potent and selective Janus kinase 1 and 2 inhibitor in patients with myelofibrosis. An update for clinicians

“…For ruxolitiniband placebo-treated patients respectively, the probability of survival (95% CI) beyond 48 weeks was 0.98 (0.92-0.99) and 0.90 (0.81-0.95) for patients with baseline hemoglobin values at least 10 g/dl and 0.84 (0.72-0.91) and 0.77 (0.63-0.86) for patients with baseline hemoglobin less than 10 g/ day [Verstovsek et al 2011]. This was also shown in a comparison between the MD Anderson cohort of the phase I/II ruxolitinib-treated patients (n = 107) and a matched historical cohort (n = 310) with clinical characteristics that would have allowed them to participate in the phase I/II study of ruxolitinib [Verstovsek et al 2012a]. The survival of patients with high-risk MF that were treated with ruxolitinib was found to be significantly longer than that of the matched control group (p = 0.005), primarily because of a highly significant advantage in overall survival of patients in the high-risk group (p = 0.006).…”