A phase I clinical trial of ruxolitinib in combination with nilotinib in chronic myeloid leukemia patients with molecular evidence of disease. (November 2018)

• Record Type: Journal Article
• Authors: Sweet, Kendra; Hazlehurst, Lori; Sahakian, Eva; Powers, John; Nodzon, Lisa; Kayali, Fadi; Hyland, Kelly; Nelson, Ashley; Pinilla-Ibarz, Javier
• Is Part Of: Leukemia research. Volume 74(2018)
• Page Start: 89
• Page End: 96
• Publication Date: 2018-11
• Subjects: Chronic myeloid leukemia -- Nilotinib -- Ruxolitinib -- Molecular disease; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2018.10.002
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: Inhibition of pSTAT3 may alter the bone marrow and sensitize CML stem cells to TKI. Ruxolitinib and nilotinib can be safely combined in patients with chronic-phase CML. Molecular responses after combination therapy are encouraging. Abstract: Purpose: Preclinical evidence indicates that the bone marrow microenvironment provides a protective niche for leukemic stem cells, allowing them to evade the effects of BCR-ABL tyrosine kinase inhibitors (TKIs), but that targeting of the JAK-STAT pathway with the JAK2 inhibitor ruxolitinib increases TKI-induced apoptosis. A phase I clinical trial (NCT01702064) investigated the tolerability and safety of treating chronic-phase chronic myeloid leukemia patients with ruxolitinib in combination with the BCR-ABL TKI nilotinib and explored initial efficacy evidence. Experimental design: Eleven patients already treated with single-agent nilotinib (300–400 mg twice daily) commenced combination therapy, and molecular responses were evaluated after 6 months. Three ruxolitinib dose cohorts were studied: 5 mg, 10 mg, and 15 mg twice daily. Results: One patient experienced a grade 3/4 adverse event (hypophosphatemia) and 36% of patients experienced grade 1/2 anemia. Of 10 patients who were evaluable for responses, 40% had undetectable BCR-ABL transcripts, as measured by quantitative RT-PCR after 6 months. Plasma inhibitory assay results revealed a decrease in phospho-STAT3 levels after treatment with ruxolitinib. The recommended phase 2 dose of ruxolitinib was 15 mg BID. Conclusions: Overall, this combination was safe and well-tolerated, and the molecular responses were encouraging, thereby warranting further investigation in a phase 2 trial.