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Myeloproliferative Neoplasms
EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis
Ferrata Storti Foundation
Haematologica 2019 Volume 104(5):947-954
Alessandro M. Vannucchi,1 Peter A. W. te Boekhorst,2 Claire N. Harrison,3 Guangsheng He,4 Marianna Caramella,5 Dietger Niederwieser,6
Françoise Boyer-Perrard,7 Minghui Duan,8 Nathalie Francillard,9
Betty Molloy,10 Monika Wroclawska10 and Heinz Gisslinger11
1Center for Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero Universitaria Careggi, University of Florence, Italy; 2Erasmus Medical Center, Rotterdam, the Netherlands; 3Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, London, UK; 4No. 1 Hospital of Nanjing Medical University, China; 5ASST Grande Ospedale Metropolitano, Milano, Italy; 6Department of Hematology and Medical Oncology, University of Leipzig, Germany; 7Centre Hospitalier Universitaire d’Angers, France; 8Peking Union Medical College Hospital, Beijing, China; 9Novartis Pharma S.A.S, Rueil Malmaison, France; 10Novartis AG, Basel, Switzerland and 11Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria
ABSTRACT
EEXPAND (phase Ib, dose-finding study) evaluated the starting dose of ruxolitinib in patients with myelofibrosis with baseline platelet
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counts of 50-99×10 /L. The study consisted of dose-escalation and
safety-expansion phases. Based on the baseline platelet counts, patients were assigned to stratum 1 (75-99x109/L) or stratum 2 (50-74x109/L), with the primary objective of determining the maximum safe starting dose (MSSD); key secondary objectives included safety and efficacy. At week 48 data cutoff (stratum 1, n=44; stratum 2, n=25), 24.6% (17 out of 69) of patients were still receiving treatment. The MSSD was established as ruxolitinib 10 mg twice daily in both strata. Thrombocytopenia [grade 4 (stratum 1, n=1; stratum 2, n=2)] was the only reported dose-limiting toxicity (study drug related) at 10 mg twice daily. In the MSSD cohort (stratum 1, n=20; stratum 2, n=18), adverse events (regardless of study drug relationship) led to treatment discontinuation in 15.0% and 33.3% of patients in stratum 1 and stratum 2, respectively, and dose adjust- ment/interruption in 45.0% and 66.7% of patients in stratum 1 and stra- tum 2, respectively. Three cases of on-treatment deaths were reported at the MSSD. Spleen response was achieved at week 48 in 33.3% and 30.0% of patients in stratum 1 and stratum 2, respectively. Improvements in the Total Symptom Score were also observed. In this study, ruxolitinib demonstrated acceptable tolerability in both the strata at the MSSD of 10 mg twice daily. (Registered at: clinicaltrials.gov identifier: 01317875).
Introduction
Myelofibrosis (MF) is a rare, chronic, Philadelphia chromosome-negative myelo- proliferative neoplasm caused by clonal proliferation of pluripotent hematopoietic stem cells.1,2 The common clinical presentations associated with MF include splenomegaly due to extramedullary hematopoiesis, progressive bone marrow fibrosis with cytopenias, and debilitating constitutional symptoms (e.g., fatigue, night sweats, and fever), which substantially diminish the quality of life.3-6 The dys- regulated activation of the Janus kinase (JAK)/signal transducer and activator of tran- scription pathway is the hallmark of MF and can result from mutations in JAK2, in the cytokine receptor, or in other components of the signaling pathway.7,8
Ruxolitinib, a potent and selective oral JAK1/JAK2 inhibitor, was approved for the treatment of intermediate- and high-risk patients with MF based on two random- ized, phase III studies: COMFORT-I (n=309; clinicaltrials.gov identifier: 00952289) and
Correspondence:
ALESSANDRO M. VANNUCCHI amvannucchi@unifi.it
Received: August 16, 2018. Accepted: November 13, 2018. Pre-published: November 15, 2018.
doi:10.3324/haematol.2018.204602
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/5/947
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