Phase I study of ruxolitinib in previously treated patients with low or intermediate-1 risk myelodysplastic syndrome with evidence of NF-kB activation.

Autor: Abaza Y; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Hidalgo-Lopez JE; Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., Verstovsek S; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Jabbour E; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Ravandi F; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Borthakur G; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Estrov Z; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Alvarado Y; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Burger J; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Schneider H; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Soltysiak KA; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Wei Y; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Kantarjian HM; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Bueso-Ramos CE; Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., Garcia-Manero G; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA. Electronic address: ggarciam@mdanderson.org.
Jazyk: angličtina
Zdroj: Leukemia research [Leuk Res] 2018 Oct; Vol. 73, pp. 78-85. Date of Electronic Publication: 2018 Sep 14.
DOI: 10.1016/j.leukres.2018.09.004
Abstrakt: Therapeutic options for patients with lower-risk myelodysplastic syndrome (MDS) who have failed prior therapies are limited particularly after hypomethylating agent. Several studies have indicated that deregulation of innate immunity signaling is critical in the pathogenesis of MDS. This process involves Toll-like receptor stimulation, cytokine overexpression, and nuclear factor-kB (NF-kB) activation. Since ruxolitinib, a JAK1/JAK2 inhibitor, suppresses NF-kB expression, we conducted a phase 1 dose-escalation study to determine the safety and efficacy of ruxolitinib in previously treated lower-risk MDS patients with evidence of NF-kB activation. Nineteen patients, 8 with chronic myelomonocytic leukemia and 11 with MDS, were enrolled. No dose limiting toxicity was observed and the maximum tolerated dose was 20 mg twice daily. Responses were restricted to MDS patients with an overall response rate of 22% [hematological improvement in platelets (HI-P) = 2, hematological improvement in erythrocytes (HI-E) = 1, partial cytogenetic response (PCyR) = 1]. Of these patients, 2 relapsed (HI-P and PCyR) and 2 continue to be in HI-P and HI-E, respectively, with ongoing therapy. Meaningful improvement in bone marrow dysplasia was only seen in a patient who achieved HI-E. Phosphorylated p65 (pp65) decreased in 6 of 15 patients (40%) including the 2 patients with continued response to treatment and increased in a patient who relapsed after a short-lived HI-P. This suggests potential correlation between reduction in pp65 expression and response duration. In conclusion, ruxolitinib was well-tolerated in previously treated lower-risk MDS patients with evidence of NF-kB activation and resulted in low but significant frequency of responses. (NCT01895842).
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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