Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

Abstract

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.

Figure 1.

Best cGVHD response. The best cGVHD response was measured based on the 2005 NIH response criteria in patients with cGVHD (N = 42). The 5 patients who had no response assessment during the study are included in the denominator in this intent-to-treat analysis. Reasons for discontinuing the study before a response assessment included toxicity (n = 4) and noncompliance with study drug (n = 1).PD, progressive disease; SD, stable disease.

Figure 2.

Change in corticosteroid doses over time. Median change in weekly average of daily corticosteroid doses for responders over time. Responders include patients with a best overall response of CR and PR (n = 28). Nonresponders include patients with stable disease, patients with progressive disease, and patients who were not evaluable for response (n = 14).

Figure 3.

Improvement in cGVHD symptoms and severity. Change in clinician-assessed and patient-reported severity of cGVHD over time.

Figure 4.

Pharmacodynamic analyses of BTK and ITK from peripheral blood samples. (A) IgE-induced basophil activation. Activated basophils (CD123⁺, HLA-DR⁻, CD63⁺) from 32 patients are shown as a percentage of total basophils (CD123⁺, HLA-DR⁻). (B) PLCγ1 activation in CD4 T cells as measured by phosphorylation of Y783 (in red), as well as ITK occupancy (in blue) from 4 patients. Treatment day and hour post–ibrutinib administration are denoted as day number (D) − hour (0 or 4); 0 hour denotes a predose sample.

Figure 5.

Heat map of change in biomarker levels from baseline by time after ibrutinib dose. Heat map of chemokines, cytokines, or factors associated with fibrosis that showed a significant change in levels for at least 1 time point posttreatment. The values at each time point are expressed as a proportion of the baseline value and depicted as a heat map. *P < .05; **P < .01; ***P < .001; ****P < .0001. CXCL9, C-X-C motif chemokine ligand 9; CXCL10, C-X-C motif chemokine ligand 10; EGF, epidermal growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-g, interferon-γ; IL-1a, interleukin-1α; IL-8, interleukin-8; MCP-1, monocyte chemotactic proteins 1; MCP-3, macrophage-derived chemokine, monocyte chemotactic proteins 3; MDC, macrophage-derived chemokine; MIP-1a, macrophage-inflammatory proteins 1α; MIP-1b, macrophage-inflammatory proteins 1β; sCD25, soluble CD25; TNFa, tumor necrosis factor-α.