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Multicenter Open-Label Phase 2 Study of Ibrutinib in Chronic Graft-versus-Host Disease (cGVHD) After Failure of Corticosteroids

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem-cell transplantation. There are no approved therapies for patients with cGVHD who fail corticosteroids, and this condition remains an unmet medical need. Both B and T cells play a role in the pathophysiology of cGVHD. In preclinical models, ibrutinib (ibr) reduced the severity of cGVHD through its inhibition of Bruton’s tyrosine kinase and interleukin-2–inducible T-cell kinase.1 Indeed, ibr has recently been granted a breakthrough therapy designation (BTD) for cGVHD after failure of 1 or more lines of systemic therapy, which was supported by early data from a phase 2 study that evaluated the efficacy and safety of ibr in patients with cGVHD who have failed corticosteroids and are in need of additional therapy. Miklos and colleagues now present the final results of that study.

Patients who had received ≤3 prior regimens (which included corticosteroids, tacrolimus, photochemotherapy, rituximab, mycophenolate, cyclosporine, sirolimus, or other immunosuppressants) for cGVHD and had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4 were treated with daily ibr 420 mg until cGVHD progression or unacceptable toxicity. The primary end point was cGVHD response based on the 2005 NIH consensus response criteria. Secondary end points included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety end points. Of 42 patients treated with ibr, at a median follow-up of 13.9 months, the overall response rate (ORR) was 67% (28/42 patients; 9 [21%] complete remission, 19 [45%] partial remission), with 20/28 (71%) responders showing a sustained response of ≥5 months. In patients with 2 or more involved organs at baseline, 80% responded in at least 2 organs, and 56% of those with 3 or more involved organs at baseline responded in at least 3 organs. Overall, 26 patients (62%) achieved corticosteroid doses <0.15 mg/kg/d while on ibr, and 5 responders were able to discontinue corticosteroid therapy altogether during the study.

Median overall clinician-assessed cGVHD severity score decreased from 7 at baseline (n = 41) to 4 at week 25 (n = 20) and 3 at week 49 (n = 15). A corresponding decrease in median patient-assessed overall cGVHD score from 7 at baseline (n = 42) to 5 at week 25 (n = 18) and 4 at week 49 (n = 14) was reported. Improvement in the Lee cGVHD symptom score was reported for 12 (43%) and 17 (61%) of 28 responders by month 6 and overall, respectively, compared with 1 of 9 nonresponders (11%) by month 6 and overall. Analysis of soluble plasma proinflammatory cytokines (eg, interferon-gamma, CD25, TNF-alpha), chemokines (eg, MDC, MCP-3, IL-8, IP-10, CXCL9), and factors associated with tissue growth and fibrosis (eg, epidermal growth factor and granulocyte-macrophage colony-stimulating factor) from all treated patients showed a significant decrease over time with ibr.

The most common adverse events (AEs) were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Grade ≥3 AEs occurring in >3 patients were pneumonia (n = 6), fatigue (n = 5), and diarrhea (n = 4). Serious AEs (SAEs) occurred in 22 patients (52%); grade ≥3 SAEs reported in 17 patients (40%) included pneumonia (n = 5), septic shock (n = 2), and pyrexia (n = 2). Two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis) were reported. Five patients (12%) discontinued therapy for progressive cGVHD and 14 (33%) for AEs, including fatigue (n = 3) and pneumonia (n = 2). Twelve patients (29%) continued ibr; their treatment duration ranges from 5.6 to >25 months.

The authors conclude that with an ORR of 67% and a sustained ORR for ≥20 weeks of 71%, treatment with ibr resulted in clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD. Most responders were able to reduce steroid dose to an acceptable minimal level. Reported AEs were consistent with those for ibr in B-cell malignancies and patients with cGVHD. Observed response rates in this pretreated, high-risk population support further study of ibr for frontline treatment of cGVHD, for which a phase 3 study is now underway.

Miklos D, et al. ASH 2016. Abstract LBA3.

  1. Dubovsky JA, et al. J Clin Invest. 2014;124:4867-4876.
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Last modified: August 30, 2021