Phase 2 study of ruxolitinib and decitabine in patients with myeloproliferative neoplasm in accelerated and blast phase

Abstract

Myeloproliferative neoplasms (MPN) that have evolved into accelerated or blast phase disease (MPN-AP/BP) have poor outcomes with limited treatment options and therefore represent an urgent unmet need. We have previously demonstrated in a multicenter, phase 1 trial conducted through the Myeloproliferative Neoplasms Research Consortium that the combination of ruxolitinib and decitabine is safe and tolerable and is associated with a favorable overall survival (OS). In this phase 2 trial, 25 patients with MPN-AP/BP were treated at the recommended phase 2 dose of ruxolitinib 25 mg twice daily for the induction cycle followed by 10 mg twice daily for subsequent cycles in combination with decitabine 20 mg/m2 for 5 consecutive days in a 28-day cycle. Nineteen patients died during the study follow-up. The median OS for all patients on study was 9.5 months (95% confidence interval, 4.3-12.0). Overall response rate (complete remission + incomplete platelet recovery + partial remission) was 11/25 (44%) and response was not associated with improved survival. We conclude that the combination of decitabine and ruxolitinib was well tolerated, demonstrated favorable OS, and represents a therapeutic option for this high-risk patient population. This trial was registered at www.clinicaltrials.gov as #NCT02076191.

Conflict of interest statement

Conflict-of-interest disclosure: J.O.M. has received research funding from Incyte, Novartis, Merck, CTI Biopharma, Roche, Kartos, Celgene, Janssen, AROG, Merus, and Promedior and consulting fees from Novartis, Roche, Celgene, CTI Biopharma, and Incyte. R.K.R. has received consulting fees from Constellation, Incyte, Celgene, Promedior, CTI, Jazz Pharmaceuticals, Blueprint, Stemline, and research funding from Incyte, Constellation, and Stemline. E.H. has served as an advisor and received research support from Blueprint Medicines and Novartis Oncology. E.S.W. has served as advisory/consultant role for AbbVie, Arog, Astellas, Celyad, Jazz, Kite, Kura, Pfizer, Macrogenics, and PTC Therapeutics. M.K. has received research funding from Incyte, Celgene, Constellation, and Blueprint and consulting fees from La Jolla Pharmaceutical. R.A.M. has received consulting fees from Novartis, Sierra Oncology, and La Jolla and research support from Celgene, Incyte, AbbVie, Samus, and Genentech. A.G. has received research funding from Incyte, Celgene, CTI Biopharma, Roche, Sierra Oncology, and Imago Biosciences and consulting fees from Celgene, Pfizer, Kartos, CTI Biopharma, Galecto, and Promedior. C.N.A. has received research funding from Pfizer, Actinium, and AstraZeneca, and consulting fees from Nkarta, Tetraphase, Bayer, Jazz, Seattle Genetics, Cardinal Health, and ArcherDX. O.O. has received consulting fees from AbbVie, Celgene, Impact Biomedicines, and Incyte; and research funding from AbbVie, Astra Zeneca, Agios, Celgene, CTI-Biopharma, Janssen, Incyte, Kartos, NS-Pharma, Oncotherapy Sciences, and Sierra Oncology. R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Loxo, Imago, C4 Therapeutics, and Isoplexis, which each include an equity interest; he receives research support from and consulted for Celgene, Incyte, and Roche; has received research support from Prelude Therapeutics; has consulted for Novartis and Janssen; and has received honoraria from Lilly and Amgen for invited lectures and from Gilead for grant reviews. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Genomic data from patient specimens at time of clinical trial enrollment. (A) Genomic profile of somatic mutations in baseline samples, as detected by next-generation sequencing data. Each column represents a patient (n = 24) and each row in the top panel represents a gene that carries at least 1 pathogenic or likely pathogenic mutation (n = 38). The upper bar plot indicates the number of somatic mutation(s) per patient, colored according to the type of the alteration, as described in the legend. The right bar plot shows the number of somatic mutations per gene. The frequency of mutations in the cohort is listed on the left border of the figure. The clinical response to treatment is displayed in the annotation bar at the lower axis of the figure according to the legend. (B) Distribution of mutations across all genes in the cohort. The bars are colored according to the proportion of patient’s response to the treatment. Color code: complete remission with incomplete hematologic recovery (blue); partial response (orange); no response (NR; red); response not evaluable (N/E; gray).

Figure 2.

Duration of treatment by disease group. Corresponding clinical responses are indicated by symbols. End of response is defined as peripheral blood blast count exceeding baseline value. Overall survival time is also noted in the figure.

Figure 3.

Maximum percentage change in peripheral blood blasts by disease group. Median blast count reduction of 54.8% (−100% to 71.4%), across all patients, was observed.

Figure 4.

Maximum change in spleen size by disease group. The median reduction in spleen size across both MPN-AP/BP cohorts was −70.5% (range, −100% to 0%).

Figure 5.

Survival analysis of MPN-AP/BP patients treated with combination decitabine and ruxolitinib. (A) OS from the time of study enrollment. The median OS for all patients on study was 9.5 (95% CI, 4.3-12.0) months. (B) OS by TP53 status. Median OS for TP53 mutated patients was 7.6 (95% CI, 4.3-NE) and 9.6 (95% CI, 3.6-NE) months in TP53 nonmutated patients (P = .78).

Figure 6.

Baseline and dynamic changes in cytokine levels in patients with MPN-AP/BP treated with combination decitabine and ruxolitinib. (A) Heatmap of evaluated cytokines for MPN-AP/BP baseline samples, C1D8, C2D1, and control samples. Cytokines are normalized across the comparison groups. Each row constitutes 1 cytokine, with the data for individual patients organized in columns. Green and red denote markers that are present at lower and higher levels, respectively. (B) Log2 fold changes shown for evaluated cytokines. Comparisons consisted of baseline vs control, C1D8 vs baseline, and C2D1 vs baseline.