Ibrutinib for the Treatment of Steroid-Refractory Chronic Graft-Versus-Host Disease After Transplant

The Bruton tyrosine kinase inhibitor ibrutinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of several B-cell malignancies and, according to results from a phase II study presented by David Miklos, MD, it may also be a potential treatment option for hematopoietic cell transplantation patients with chronic GVHD (cGVHD) whose disease has not responded to corticosteroids.

Early data from this trial served as the basis for the FDA’s decision in June 2016 to grant ibrutinib breakthrough therapy and orphan designation for the treatment of cGVHD after the failure of one or more lines of systemic therapy. Forty-two patients (median age = 56 years; range = 19-74 years) with cGVHD who had been treated with a median of two prior regimens (range = 1-3) received ibrutinib 420 mg. Median duration of cGVHD before study entry was 13.7 months (range = 1.1-63.2 months).

At a median follow-up of 13.9 months, two-thirds of patients (n=28) responded to ibrutinib treatment (defined according to the 2005 National Institutes of Health consensus response criteria), including nine who achieved a complete response (CRs; 21%) and 19 who achieved a partial response (PRs; 45%). Seventy-one percent (n=20/28) and 48 percent (n=12/25) sustained responses of ≥20 and ≥32 weeks, respectively.

Five patients discontinued treatment due to progressive cGVHD, and another 14 patients discontinued due to adverse events (AEs). The most common AEs were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Grade ≥3 AEs occurring in three or more patients included pneumonia (n=6), fatigue (n=5), and diarrhea (n=4). Serious AEs occurred in 22 patients (52%); grade ≥3 serious AEs were reported in 17 patients (40%), including pneumonia (n=5), septic shock (n=2), and pyrexia (n=2). Two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis) were reported.

“Managing the ibrutinib-associated side effects will be important as we learn how to advise our patients going forward using this drug,” Dr. Miklos said, noting that the AE rates with ibrutinib did not differ from the AE rates seen with corticosteroids alone. “Also, 13 patients have been on ibrutinib for more than two years. They are coming off the therapy [without cGVHD recurrence], which is exciting because it means people are stopping all immune-suppressive therapies, which, of course, is the goal.”

In an accompanying exploratory biomarker study, the researchers found that pro-inflammatory, chemotactic, and fibrotic factors (including the GVHD-associated biomarkers IFNγ, TNFα, IP-10, and CXCL9) decreased while patients were receiving ibrutinib. These results were “consistent with decreasing inflammation and improving patients’ immune reconstitution,” Dr. Miklos said.

The study had no comparator arm, which limits its findings, the researchers noted. Dr. Miklos added that a randomized, controlled trial comparing upfront treatment with ibrutinib or high-dose steroids in patients with cGVHD and other trials are questioning whether ibrutinib could prevent cGVHD when used as maintenance therapy post-transplant.


Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Abstract LBA-3. Presented at the 2016 ASH Annual Meeting, December 6, 2016; San Diego, California.