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Clinical Trial
. 2025 Jan;60(1):69-78.
doi: 10.1038/s41409-024-02445-6. Epub 2024 Nov 6.

Impact of cytopenias and early versus late treatment with ruxolitinib in patients with steroid-refractory acute or chronic graft-versus-host disease

Zahra Mahmoudjafari  1 , Valkal Bhatt  2 , John Galvin  2 , Zhenyi Xue  2 , Robert Zeiser  3 , Franco Locatelli  4   5 , Gérard Socié  6 , Mohamad Mohty  7
Affiliations
Clinical Trial

Impact of cytopenias and early versus late treatment with ruxolitinib in patients with steroid-refractory acute or chronic graft-versus-host disease

Zahra Mahmoudjafari et al. Bone Marrow Transplant. 2025 Jan.

Abstract

REACH2 and REACH3 were randomized, multicenter, open-label phase 3 studies comparing the selective Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib versus investigators' choice of best available therapy (BAT) in steroid-refractory (SR) acute (REACH2) or chronic (REACH3) graft-versus-host disease (aGVHD/cGVHD). Moderate-severe aGVHD/cGVHD can progress rapidly; thus, key clinical considerations driving management of patients with SR-aGVHD/SR-cGVHD are prompt treatment initiation and concomitant cytopenias. These post hoc analyses of REACH2/REACH3 describe the impact of timing of treatment initiation after SR-aGVHD/SR-cGVHD diagnosis and development of concomitant cytopenias on treatment outcomes. Ruxolitinib initiation within 3 days from SR-aGVHD diagnosis yielded an extended duration of response and higher Day 28 complete response rates compared with initiation ≥7 days after SR-aGVHD diagnosis (median 178 vs 167 days and 36.6% vs 25.0%, respectively). For patients with SR-cGVHD, Week 24 overall response was not impacted by time to treatment (54.5% vs 42.6% for <14 vs >28 days). Clinically relevant cytopenias were manageable, allowing for maintenance of dose intensity (median 20 mg/d), and did not impact the favorable efficacy outcomes from ruxolitinib treatment. This analysis highlights the practical importance of considering earlier ruxolitinib initiation after SR diagnosis in GVHD and the benefits of ruxolitinib treatment compared with BAT even for patients with cytopenias.

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Conflict of interest statement

Competing interests: ZM: Advisory board participation: AstraZeneca, BMS, Genentech, Janssen, KITE, Pfizer. RZ: Consulting fees and speaker bureau: Incyte, Medac, Mallinckrodt Pharmaceuticals/Therakos, Neovii, Novartis, Sanofi. FL: Consulting fees and speaker bureau: Amgen, Gilead, Miltenyi, Novartis, Sanofi, SOBI. GS: Consulting fees and speaker bureau: Allovir, Incyte, Novartis, Sanofi. MM: Declared no competing interests. VB, JG, and ZX are employees and shareholders of Incyte. Ethical approval and consent to participate: Based on the retrospective post hoc analysis design of this study, no additional ethical approval or consent to participate was required. However, the REACH trials on which this study were based were designed and conducted in accordance with the International Council for Harmonisation Guideline for Good Clinical Practice, Declaration of Helsinki, and local regulatory requirements. Study protocols were approved by institutional review boards at each site. Patients or their guardians provided written informed consent for participation in the original REACH trials.

Figures

Fig. 1
Fig. 1. Overall response rate and best overall response by treatment initiation subgroup.
a ORR: CR + PR at Day 28 (SR-aGVHD). b ORR: CR + PR at Week 24 (SR-cGVHD). Values at the top of graphs indicate OR (95% CI) for ruxolitinib vs BAT. BAT best available therapy, CR complete response, OR odds ratio, ORR overall response rate, PR partial response, SR-aGVHD steroid-refractory acute graft-versus-host disease, SR-cGVHD steroid-refractory chronic graft-versus-host disease.
Fig. 2
Fig. 2. Duration of response in patients treated with ruxolitnib or BAT.
a DOR in patients with SR-aGVHD. b DOR in patients with SR-cGVHD. BAT best available therapy, DOR duration of response, IQR interquartile range, NE not evaluable, SR-aGVHD steroid-refractory acute graft-versus-host disease, SR-cGVHD steroid-refractory chronic graft-versus-host disease.
Fig. 3
Fig. 3. Time to ruxolitinib treatment initiation subgroup comparisons for responses and duration of response.
a ORR and BOR for patients with SR-aGVHD. b DOR for patients with SR-aGVHD. c ORR and BOR for patients with SR-cGVHD. d DOR for patients with SR-cGVHD. OR odds ratio, SR-aGVHD steroid-refractory acute graft-versus-host disease, SR-cGVHD steroid-refractory chronic graft-versus-host disease. a, c Values at the top of graphs indicate OR (95% CI) for early versus late or very late treatment initiation.
Fig. 4
Fig. 4. Effect of cytopenias on responses in patients with SR-aGVHD treated with ruxolitinib or BAT.
a ORR at Day 28. b Durable response at Day 56, defined as the proportion of all patients who achieved a CR or PR at Day 28 and maintained a CR or PR at Day 56. c Median duration of response. ANC absolute neutrophil count, BAT best available therapy, CR complete response, Hb hemoglobin, IQR interquartile range, NE not evaluable, NR not reached, OR odds ratio, ORR overall response rate, PLT platelet count, PR partial response, SR-aGVHD steroid-refractory acute graft-versus-host disease, WBC white blood cell count. * Cytopenias were defined as low blood counts between baseline and Week 4; low blood cell counts were defined as: WBC, <5 × 109 cells/L; ANC, <1 × 109 cells/L; PLT, <30 × 109 cells/L; Hb, <8 g/dL.
Fig. 5
Fig. 5
Hematologic laboratory values in patients with SR-aGVHD. ANC absolute neutrophil count, BAT best available therapy, Hb hemoglobin, PLT platelet count, SR-aGVHD steroid-refractory acute graft-versus-host disease, WBC white blood cell count.
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