Examining Ibrutinib as Secondline Therapy for cGVHD

On August 2, 2017, the U.S. Food and Drug Administration (FDA) approved the Bruton tyrosine kinase inhibitor ibrutinib as a secondline treatment for adult patients with chronic graft-versus-host disease (cGVHD), making it the first FDA-approved therapy for this indication.

The FDA’s decision was based on data from an open-label, multicenter, phase Ib/II trial of patients with cGVHD whose disease had not responded to at least one systemic corticosteroid-based therapy. In a study published in Blood, David Miklos, MD, PhD, from Stanford Cancer Institute at Stanford University in California, and colleagues reported the safety and efficacy results of this single-arm trial, in which nearly three-quarters of patients with active cGVHD had a sustained response to ibrutinib.

The high frequency of sustained responses was accompanied by “meaningful reductions” or discontinuation in corticosteroid use, the authors reported.

The investigators enrolled 42 patients (median age = 56 years; range = 19-74 years) who had cGVHD after undergoing allogeneic hematopoietic cell transplantation for a variety of underlying malignancies. Patients had received a median of two prior regimens (range = 1-3 regimens). Mouth and skin were the most frequently involved organs, and 36 patients (85%) had evidence of cGVHD in two or more organs.

Based on results from the phase I, dose-finding portion of the study, patients received ibrutinib 420 mg daily until cGVHD progression. At last follow-up, 12 patients (29%) were still receiving ibrutinib, and 30 (71%) had discontinued treatment (most commonly due to adverse events [AEs; n=14], cGVHD progression [n=5], or patient decision [n=6]). Treatment duration ranged from 5.6 to 24.9 months for the 12 patients who continued treatment.

Response was assessed according to the National Institutes of Health’s cGVHD criteria every 12 weeks.

At a median follow-up of 13.9 months (range = 0.5-24.9 months), 28 patients responded to treatment, for an overall response rate (ORR) of 67 percent, including:

  • 9 patients with a complete response (21%)
  • 19 patients with a partial response (45%)
  • 7 patients with stable disease (17%)
  • 2 patients with progressive disease (5%)

Five patients discontinued treatment and left the study before a 12-week response assessment. When these patients were excluded from the analysis, the ORR increased to 76 percent.

The investigators observed similar response rates among all patients, regardless of organ involvement.

Of the 28 responders, 20 (71%) had a sustained response for ≥20 weeks (the study’s primary endpoint). “This cGVHD study is the first to report sustained response as an efficacy endpoint,” the authors noted. “This endpoint is clinically relevant because [patients with] cGVHD generally require therapy for an extended period and short-term responses do not allow for resolution of disabling symptoms or tapering of corticosteroids.”

Median corticosteroid dose in responders decreased from 0.29 mg/kg/day (range = 0.06-1.30 mg/kg/day) at baseline to 0.12 mg/kg/day (range = 0.0-0.18 mg/kg/day) at week 49. Additionally, five responders could completely discontinue corticosteroids during response to ibrutinib treatment, and 26 patients (62%) tapered down to a corticosteroid dose of <0.15 mg/kg/day. “Our results suggest that ibrutinib may have a steroid-sparing effect, which could reduce the morbidity associated with long-term corticosteroid use,” the authors explained.

The most common treatment-emergent AEs (reported in ≥10% of patients) included fatigue (n=24), diarrhea (n=15), muscle spasms (n=12), nausea (n=11), and bruising (n=10), most of which were grade 1 or 2. The most common grade ≥3 AEs were pneumonia (n=6), fatigue (n=5), and diarrhea (n=4).

Any-grade infectious complications were reported in 29 patients (69%), including 15 (36%) grade ≥3 events.

Two patients had a relapse of their underlying malignancy (one with acute lymphocytic leukemia and one with prolymphocytic leukemia). AEs led to dose reductions in 13 patients (31%) and treatment discontinuation in 14 patients (33%).

Seven patients died during the study. Two deaths were related to AEs (multilobular pneumonia and bronchopulmonary aspergillosis) while the patients were on ibrutinib; the other five deaths occurred after the patients discontinued ibrutinib.

In an accompanying exploratory biomarker analysis, the researchers found that pro-inflammatory, chemotactic, and fibrotic factors (including the cGVHD-associated biomarkers IFNγ, TNFα, IP-10, and CXCL9) decreased following ibrutinib therapy, “suggesting that ibrutinib could be impacting resolution of allogeneic inflammation at the cellular level,” the authors explained.

The study was limited by its single-arm design and small patient population. The authors added that a randomized, controlled trial comparing upfront treatment with ibrutinib or high-dose steroids in patients with cGVHD is underway.

The study was supported by Pharmacyclics LLC, a subsidiary of AbbVie (the manufacturers of ibrutinib).

The authors report financial support from Pharmacyclics LLC.


Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017 September 18. [Epub ahead of print]