Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2018 Nov:74:89-96.
doi: 10.1016/j.leukres.2018.10.002. Epub 2018 Oct 9.

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

Kendra Sweet  1 , Lori Hazlehurst  2 , Eva Sahakian  2 , John Powers  2 , Lisa Nodzon  2 , Fadi Kayali  3 , Kelly Hyland  4 , Ashley Nelson  4 , Javier Pinilla-Ibarz  2
Affiliations
Clinical Trial

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

Kendra Sweet et al. Leuk Res. 2018 Nov.

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.

PubMed Disclaimer

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.

Figures

Fig. 1.
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.
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.
See this image and copyright information in PMC

References

    1. Rowley JD, Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining, Nature 243 (5405) (1973) 290–293. - PubMed
    1. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O’Brien SG, Druker BJ, Investigators I, Long-term outcomes of imatinib treatment for chronic myeloid leukemia, N. Engl. J. Med 376 (10) (2017) 917–927. - PMC - PubMed
    1. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque C, Shah NP, Chuah C, Casanova L, Bradley-Garelik B, Manos G, Hochhaus A, Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial, J. Clin. Oncol 34 (20) (2016) 2333–2340. - PMC - PubMed
    1. Gambacorti-Passerini C, Brummendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, Durrant S, Kantarjian HM, Khoury HJ, Zaritskey A, Shen ZX, Jin J, Vellenga E, Pasquini R, Mathews V, Cervantes F, Besson N, Turnbull K, Leip E, Kelly V, Cortes JE, Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: minimum 24-month follow-up, Am. J. Hematol 89 (7) (2014) 732–742. - PMC - PubMed
    1. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Muller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H, Investigators P, A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias, N. Engl. J. Med 369 (19) (2013) 1783–1796. - PMC - PubMed

Publication types

MeSH terms

Associated data