A phase I clinical trial of ruxolitinib in combination with nilotinib in chronic myeloid leukemia patients with molecular evidence of disease

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.

Keywords: Chronic myeloid leukemia; Molecular disease; Nilotinib; Ruxolitinib.

Conflict of interest statement

Declarations of interest

KS serves on Speakers Bureau and consults for Novartis; JPI consults for and serves on advisory boards for Novarits; LN also declares Novartis. LH, ES, FK, KH, and AN have no conflicts of interest to declare.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Figures

Fig. 1.

Patient responses over time. (A) Quantitative real-time PCR results, using international scale. (B) Patients’ molecular responses over the 6-month period of the clinical trial are shown according to the international scale (IS).

Fig. 2.

Flow cytometry plot of plasma inhibitory assay for patient number 11, indicating that pSTAT5 (Y694) and pSTAT3 (Y705) are less in the day-28 samples (notated as EOS [end of study]) than in the pre-dose samples.