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Clinical Trial
. 2021 Dec;35(12):3455-3465.
doi: 10.1038/s41375-021-01261-x. Epub 2021 May 20.

Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study

Francisco Cervantes  1 , David M Ross  2 , Atanas Radinoff  3 , Francesca Palandri  4 , Alexandr Myasnikov  5 , Alessandro M Vannucchi  6 , Pierre Zachee  7 , Heinz Gisslinger  8 , Norio Komatsu  9 , Lynda Foltz  10 , Francesco Mannelli  6 , Francesco Passamonti  11 , Geralyn Gilotti  12 , Islam Sadek  12 , Ranjan Tiwari  13 , Evren Zor  14 , Haifa Kathrin Al-Ali  15
Affiliations
Clinical Trial

Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study

Francisco Cervantes et al. Leukemia. 2021 Dec.

Erratum in

Abstract

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.

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Conflict of interest statement

FC has served on speakers’ bureaus and advisory boards for Celgene and Novartis. DMR has received consultancy fees, honoraria, and research funding from Novartis, consultancy fees and honoraria from Bristol-Myers Squibb and Celgene, and research funding from Celgene. FPal has received speaker’s honoraria from Novartis. AMV has served on speakers’ bureaus for Gilead and Shire, and has served on the board of directors, speakers’ bureaus or advisory committees for and received research funding from Novartis. HG has received consultancy fees, honoraria, and research funding from, and served on speakers’ bureaus for AOP ORPHAN and Celgene, has received consultancy fees, honoraria, and research funding from Novartis, has received honoraria from and has served on speakers’ bureaus for Janssen Cilag. NK has received research funding from Fuso Pharmaceutical Industries and Wako Pure Chemical Industries, has received research funding from and has served on speakers’ bureaus for PharmaEssentia and Takeda, and has served on speakers’ bureaus for Novartis. LF has received consultancy fees from Pfizer, research funding from Constellation, Gilead, Incyte, and Promedior, and consultancy fees, honoraria, and research funding from Novartis. FPas has served on speakers’ bureaus for Novartis and Celgene/BMS. GG, IS, RT, and EZ are employees of Novartis. HKA-A has received consultancy fees, honoraria, and research funding from Novartis and Celgene, honoraria from Alexion, and consultancy fees and honoraria from Gilead. AR, AM, PZ, FM declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Diagram of up-titration procedure in the REALISE phase 2 study.
b.i.d. twice daily, BSL baseline spleen length, PLT platelets, RUX ruxolitinib, SL spleen length.
Fig. 2
Fig. 2. Total daily dose of ruxolitinib over time.
Total daily doses were achieved as follows: 5 mg qd; 5 mg b.i.d.; 5 mg qd and 10 mg qd; 10 mg b.i.d.; 15 mg b.i.d.; 20 mg b.i.d. b.i.d twice daily; qd once daily. *Three patients started the study at a 10 mg qd. Two of these were dosing errors that were corrected within 5 and 6 days. The third was a physician decision for a patient who did not continue with the next phase of the study due to progressive disease and was not included in subsequent analyses.
Fig. 3
Fig. 3. Spleen and symptom response.
Best response according to spleen length (A) and MFSAF score change (B) from baseline for individual patients. Note: patient 44 achieved a best MFSAF score of +200.7%. MFSAF Myelofibrosis Symptom Assessment Form.
Fig. 4
Fig. 4. Evolution of hemoglobin and platelets.
Median hemoglobin (A) and platelet (B) levels over time. Boxes indicate 25th–75th percentiles and median daily dose is indicated as a horizontal line. Whiskers indicate 10th–90th percentiles. Values outside this range are not displayed. X marks indicate values 1.5x the IQR above Q3 and 3x the IQR below Q1. Continuous line indicates IQR of change in total daily dose from starting dose. IQR interquartile range, Q1 first quartile; Q3 3rd quartile.
Fig. 5
Fig. 5. Transfusion requirements.
Mean number of RBC units received during the study in patients who were transfusion-dependent or transfusion-independent at baseline (A) and spleen responders and non-responders at any time during the study (B). BSL baseline spleen length; RBC red blood cells.
See this image and copyright information in PMC

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