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Acute myeloid leukemia

A phase 1/2 study of ruxolitinib and decitabine in patients with post-myeloproliferative neoplasm acute myeloid leukemia

Leukemia volume 34, pages 2489–2492 (2020)Cite this article

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Leukemic or blast phase transformation occurs in ~2.3–14.4% of patients with polycythemia vera at 10 years and 5.5–18.7% at 15 years; the corresponding rates for essential thrombocythemia have been reported as 0.7–3% and 2.1–5.3%, respectively [1]. This devastating complication is more common among patients with primary myelofibrosis, reaching an actuarial probability of 20.6% at 100 months from diagnosis in one study [2]. Post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) carries a dismal prognosis, with median survival in the 3–5 month range, with the best outcomes seen in the small minority of patients who are able to achieve complete remission (CR) or CR with incomplete count recovery (CRi) and proceed to allogeneic hematopoietic cell transplantation (allo-HCT) [3].

Both ruxolitinb [4] and decitabine [5] have single-agent activity in post-MPN AML, albeit modest, and synergism between these agents has been demonstrated in preclinical studies [6]. Based on these considerations, we designed a single institution, phase 1/2 study of the combination of ruxolitinib and decitabine, intended for outpatient administration, in patients with post-MPN AML (NCT02257138). The phase 1 portion was open to all patients with relapsed/refractory AML (with an emphasis on recruiting patients with post-MPN AML, who could be treatment-naive) and used a standard “3 + 3” dose escalation schema to determine the recommended phase 2 dose (RP2D) of the combination. The phase 2 portion enrolled only patients with blast phase MPN (post-MPN AML) or AML arising from a myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Ruxolitinib was administered orally twice daily (bid) continuously; four dose levels (10, 15, 25, and 50 mg bid) were evaluated in the phase 1 portion. Decitabine was administered intravenously at a dose of 20 mg/m2/day on days 1–5 in each cycle; cycle length was 4–6 weeks depending on speed of count recovery. Dose limiting toxicities (DLTs) were evaluated in cycle 1 of the phase 1 portion only. Grade ≥3 non-hematologic toxicities, with certain exceptions and qualifiers, and any grade 4 hematologic toxicity lasting ≥42 days from the first day of the last cycle of therapy with a bone marrow cellularity of ≤5% and no evidence of leukemia qualified as DLTs. Prior ruxolitinib for MPN was allowed in both phases of the study; prior azacitidine was not permitted in the phase 2 portion, in which all patients had to be previously untreated for their AML. Standard response criteria for AML, as well as more recently published consensus response criteria for blast phase MPN [7], were utilized for response adjudication. The study employed the Bayesian approach of Thall et al. [8], with stopping rules built in for both efficacy (futility) and toxicity monitoring. A maximum of 18 (DLT-evaluable) patients could be enrolled to the phase 1 portion, and a maximum of 24 to the phase 2 portion (not including patients in the phase 1 portion treated at the RP2D). Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0. The study was approved by the MD Anderson Institutional Review Board and all participants provided written informed consent.

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Acknowledgements

This study was supported, in part, by Incyte Corporation and by the MD Anderson Cancer Center Support Grant from the National Cancer Institute (National Institutes of Health), P30 CA016672.

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Prithviraj Bose, Srdan Verstovsek, Jorge E. Cortes, Susan Tse, Yvonne Gasior, Nitin Jain, Elias J. Jabbour, Zeev Estrov, Yesid Alvarado, Courtney D. DiNardo, Naveen Pemmaraju, Steven M. Kornblau, Tapan M. Kadia, Naval G. Daver, Kiran Naqvi, Nicholas J. Short, Lucia Masarova, John Villareal, Sherry A. Pierce, Guillermo Garcia-Manero, Hagop M. Kantarjian & Farhad Ravandi

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Graciela Nogueras-Gonzalez & Xuelin Huang

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  1. Prithviraj Bose
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Correspondence to Farhad Ravandi.

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Conflict of interest

PB, SV, NP, NGD, and FR report receipt of honoraria/consulting fees and research support from Incyte Corporation. NJ and TMK report research support from Incyte Corporation. EJJ reports receipt of consulting fees from Incyte Corporation. The other authors have no conflict of interest relevant to this article to disclose.

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Bose, P., Verstovsek, S., Cortes, J.E. et al. A phase 1/2 study of ruxolitinib and decitabine in patients with post-myeloproliferative neoplasm acute myeloid leukemia. Leukemia 34, 2489–2492 (2020). https://doi.org/10.1038/s41375-020-0778-0

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