Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
29
09
2020
accepted:
26
04
2021
revised:
25
03
2021
pubmed:
22
5
2021
medline:
29
1
2022
entrez:
21
5
2021
Statut:
ppublish
Résumé
Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45-88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.
Identifiants
pubmed: 34017073
doi: 10.1038/s41375-021-01261-x
pii: 10.1038/s41375-021-01261-x
pmc: PMC8632662
doi:
Substances chimiques
Nitriles
0
Pyrazoles
0
Pyrimidines
0
ruxolitinib
82S8X8XX8H
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3455-3465Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
Références
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.
doi: 10.1182/blood-2016-03-643544
Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228:273–87.
doi: 10.1111/j.1600-065X.2008.00754.x
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.
doi: 10.1016/S0140-6736(05)71142-9
Kralovics R, Passamonti F, Buser AS, Teo S-S, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–90.
doi: 10.1056/NEJMoa051113
Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233–45.
doi: 10.1146/annurev.med.60.041707.160528
Mesa RA, Niblack J, Wadleigh M, Verstovsek S, Camoriano J, Barnes S, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109:68–76.
doi: 10.1002/cncr.22365
Ballen KK, Shrestha S, Sobocinski KA, Zhang M-J, Bashey A, Bolwell BJ, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transpl. 2010;16:358–67.
doi: 10.1016/j.bbmt.2009.10.025
McLornan D, Szydlo R, Koster L, Chalandon Y, Robin M, Wolschke C, et al. Myeloablative and reduced-intensity conditioned allogeneic hematopoietic stem cell transplantation in myelofibrosis: a retrospective study by the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transpl. 2019;25:2167–71.
doi: 10.1016/j.bbmt.2019.06.034
Tefferi A. Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2018;93:1551–60.
doi: 10.1002/ajh.25230
Barbui T, Tefferi A, Vannucchi AM, Passamonti F, Silver RT, Hoffman R, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32:1057–69.
doi: 10.1038/s41375-018-0077-1
Tefferi A. Anemia in myelofibrosis-prevalence, the U2AF1 connection, new treatments. Blood Cancer J. 2017;7:648.
doi: 10.1038/s41408-017-0032-9
Cervantes F, Correa JG, Hernández-Boluda JC. Alleviating anemia and thrombocytopenia in myelofibrosis patients. Expert Rev Hematol. 2016;9:489–96.
doi: 10.1586/17474086.2016.1154452
Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Gugliemelli P, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8:15.
doi: 10.1038/s41408-018-0054-y
Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, et al. Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22:437–8.
doi: 10.1038/sj.leu.2404914
Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895–901.
doi: 10.1182/blood-2008-07-170449
Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: A study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115:1703–8.
doi: 10.1182/blood-2009-09-245837
Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29:392–7.
doi: 10.1200/JCO.2010.32.2446
Cervantes F. How I treat myelofibrosis. Blood. 2014;124:2635–42.
doi: 10.1182/blood-2014-07-575373
Harrison C, Mesa R, Ross D, Mead A, Keohane C, Gotlib J, et al. Practical management of patients with myelofibrosis receiving ruxolitinib. Expert Rev Hematol. 2013;6:511–23.
doi: 10.1586/17474086.2013.827413
Bose P. Advances in potential treatment options for myeloproliferative neoplasm associated myelofibrosis. Expert Opin Orphan Drugs. 2019;7:415–25.
doi: 10.1080/21678707.2019.1664900
Oh TS, Talpaz M, Gerds AT, Gupta V, Verstovsek S, Mesa R, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4:4282–91.
doi: 10.1182/bloodadvances.2020002662
JAKAVI (ruxolitinib) Summary of Product Characteristics. 2019. Novartis Pharm GmbH, Nuremberg, Germany. https://www.ema.europa.eu/en/documents/product-information/jakavi-epar-product-information_en.pdf . Accessed 13 December, 2019.
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799–807.
doi: 10.1056/NEJMoa1110557
Harrison C, Kiladjian J-J, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787–98.
doi: 10.1056/NEJMoa1110556
Al-Ali HK, Stalbovskaya V, Gopalakrishna P, Perez-Ronco J, Foltz L. Impact of ruxolitinib treatment on the hemoglobin dynamics and the negative prognosis of anemia in patients with myelofibrosis. Leuk Lymphoma. 2016;57:2464–7.
doi: 10.3109/10428194.2016.1146950
ClinicalTrials.gov. NCT02966353. Efficacy and safety of ruxolitinib in the treatment of anemic myelofibrosis patients. (REALISE). Novartis Pharmaceuticals. https://clinicaltrials.gov/ct2/show/NCT02966353?term=NCT02966353&draw=2&rank=1 . Accessed 17 Dec 2019.
Tefferi A, Cervantes F, Mesa R, Passamonti F, Verstovsek S, Vannucchi AM, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122:1395–8.
doi: 10.1182/blood-2013-03-488098
U.S. Department of Health and Human Services. CTCAE 4.03. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf . Accessed 17 Dec 2019.
Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117–27.
doi: 10.1056/NEJMoa1002028
Palandri F, Palumbo GA, Bonifacio M, Tiribelli M, Benevolo G, Martino B, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017;8:79073–86.
doi: 10.18632/oncotarget.18674
Al-Ali HK, Griesshammer M, le Coutre P, Waller CF, Liberati AM, Schafhausen P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101:1065–73.
doi: 10.3324/haematol.2016.143677
Al-Ali HK, Griesshammer M, Foltz L, Palumbo GA, Martino B, Palandri F, et al. Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Br J Haematol. 2020;189:888–903.
doi: 10.1111/bjh.16462
McMullin MF, Harrison CN, Niederwieser D, Demuyinck H, Jäkel N, Gopalakrishna P, et al. The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis. Exp Hematol Oncol. 2015;4:26.
doi: 10.1186/s40164-015-0021-2
Gupta V, Griesshammer M, Martino B, Foltz L, Tavares R, Al-Ali HK, et al. Analysis of predictors of response to ruxolitinib in patients with myelofibrosis in the phase 3b expanded-access JUMP study. Leuk Lymphoma. 2021;62:918–26.
Mead AJ, Milojkovic D, Knapper S, Garg M, Chacko J, Farquharson M, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. Br J Haematol. 2015;170:29–39.
doi: 10.1111/bjh.13379