A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis

Abstract

Myelofibrosis is a hematological malignancy with a median survival of approximately 5 to 7 years. Allogeneic stem cell transplantation is the only therapeutic modality that provides a cure for myelofibrosis patients. Recently, ruxolitinib has been shown in 2 phase 3 studies to be effective in reducing splenomegaly and improving symptoms in myelofibrosis patients. Although conventional markers of disease burden (marrow histopathological features, cytogenetic and molecular markers, and reversal of cytopenias) were not uniformly improved, a survival advantage in favor of ruxolitinib therapy was demonstrated. The use of historical control cohorts to compare survival was implemented in 2 different analyses of patients enrolled in the phase 1/2 studies and has further added fuel to the controversy surrounding the significance of this survival advantage. Ruxolitinib therapy results in a dramatic reduction in circulating proinflammatory cytokine levels, which has been associated with improvement in symptoms and performance status and may provide a link to improved survival. We analyze the various data published and place in perspective the significance of the prolongation of survival associated with ruxolitinib therapy. This critical review of these data may allow physicians to more rationally assess the benefits that can be anticipated with the appropriate use of this therapy.

MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis

“…The immune effect of the conditioning may play an important role in the success that will be encountered with new protocols that are being designed to include ruxolitinib or other JAK 1/2 inhibitors (MPD-RC114). [42][43][44][45] In fact, these agents are being investigated in AHSCT not only because they can rapidly reduce constitutional symptoms and spleen size thanks to a marked suppression of proinflammatory cytokines 8 but also for a possible immunosuppressive activity that may limit GVHD. 46 Because of these considerations and the high rate of graft failure in unrelated transplants prepared with FluMel/ATG observed in this study, the MPD-RC has recently launched a new prospective study combining ruxolitinib with a fludarabine/busulfan ATG RIC regimen.…”

“…Clinical trials with small-molecule JAK1/2 inhibitors have proven beneficial in reducing the degree of splenomegaly and suppressing constitutional symptoms in a large fraction of patients with MF, but treatment with these agents does not extensively affect the degree of marrow fibrosis or eliminate molecular or cytogenetic abnormalities. 7,8 The only therapeutic option that can reverse the marrow fibrosis in MF patients 9,10 is allogeneic hematopoietic stem cell transplantation (AHSCT). Initially, AHSCT with myeloablative conditioning regimens was shown to be curative, especially in younger patients, thanks to a graft-versus-tumor effect from donor lymphocytes.…”

Rescue of a primary myelofibrosis model by retinoid-antagonist therapy

“…Other treatment options are largely supportive and do not alter the course of the disorder (9). Recently the US Food and Drug Administration approved ruxolitinib (a JAK 1/2 inhibitor), supporting a view that transcriptional activation may be at the core of the disease (10,11).…”

Elevation of the Hepatitis B Virus DNA during the Treatment of Polycythemia Vera with the JAK Kinase Inhibitor Ruxolitinib

“…Ruxolitinib effectively reduced splenomegaly, relieved constitutional disease symptoms and improved the overall survival of patients with MF (1). In addition to MF, the clinical investigation of ruxolitinib for the treatment of polycythemia vera is ongoing.…”