Graft-versus-host disease (GVHD) is a life-threatening complication that can develop after allogeneic hematopoietic cell transplant (HCT); symptoms of GVHD include skin rashes and mouth ulcers.1 Allogeneic HCT is used to treat acute and chronic leukemias, although it is employed across a variety of acquired and inherited diseases.2 In the United States, approximately 10,000 people receive HCT each year, with overall incidence of GVHD between 30% and 60%, and a mortality rate of 50%.3

Corticosteroids are the standard treatments for chronic GHVD (cGHVD), either alone or with cyclosporine; corticosteroids are, however, associated with adverse events linked to immune suppression. Though combination therapy allows for a lower corticosteroid dose, the combination may not improve overall mortality, transplantation-related mortality, recurrent malignancy, or discontinuation of therapy.4 Ibrutinib shows promise as an effective approach in symptom management, and was granted Breakthrough Therapy Designation and Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of cGVHD in those who fail systemic therapies.5

Ibrutinib functions as a Bruton’s tyrosine kinase (BTK) inhibitor and an IL-2 inducible T cell kinase (ITK) inhibitor, the former of which is FDA-approved. As a BTK inhibitor, ibrutinib inhibits signaling of B cell pathways. As an ITK inhibitor, it targets TH2 cells and disrupt T cell activity. These dual mechanisms suit ibrutinib for treating cGVHD, which is mediated by both B cell and CD4 T cell pathways.6,7

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The multicenter, open-label, phase 2, single-arm study (ClinicalTrials.gov Identifier: NCT02195869) consisted of 42 patients who were steroid-dependant or had refractory cGVHD, each of whom received 420 mg of ibrutinib daily until cGVHD progression or unacceptable toxicity.

At median follow-up of about 14 months, the primary outcome of overall response rate (ORR) was approximately 67%, with 21% of patients having complete responses and 45% of patients having partial responses. More than 70% of patients had a sustained response of at least 20 weeks, and 48% had sustained response of at least 32 weeks.8

Another study objective was to lower corticosteroid dose. Twenty-one of the 28 responders had their doses reduced to less than 0.15 mg/kg per day, reducing corticosteroid-mediated immunosuppression.

The most common adverse events were fatigue (57% of patients), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Serious adverse event occurred in 22 patients, including grade 3 or worse pneumonia (6 patients), septic shock (2 patients), and pyrexia (2 patients). Two fatal events, 1 due to multilobular pneumonia and 1 due to bronchopulmonary aspergillosis, were reported. Five patients discontinued therapy for progressive cGVHD and 14 for adverse effects.

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Ibrutinib shows promise in reducing both the severity of symptoms and steroid dose related to cGVHD, particularly after systemic therapy. More studies are, however, needed to establish ibrutinib’s efficacy and safety in more severe cases, its place in the treatment algorithm, and duration of treatment required for symptom control. 

References

  1. Ibrutinib relieves chronic graft-versus-host disease symptoms. National Cancer Institute website. https://www.cancer.gov/news-events/cancer-currents-blog/2017/ibrutinib-stem-cell-transplant-gvhd. Published January 11, 2017. Accessed February 15, 2017.
  2. Gyurkocza B, Rezvani A, Storb RF. Allogeneic hematopoietic cell transplantation: the state of the art. Expert Rev Hematol. 2010;3(3):285-99.
  3. Barton-burke M, Dwinell DM, Kafkas L, Johnson E. Graft-versus-host disease: a complex long-term side effect of hematopoietic stem cell. Cancer Network website. http://www.cancernetwork.com/hematologic-malignancies/graft-versus-host-disease-complex-long-term-side-effect-hematopoietic-stem-cell. Published October 1, 2008. Accessed February 16, 2017.
  4. Cragg L, Blazar BR, Defor T. A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease. Biol Blood Marrow Transplant. 2000;6(4A):441-7.
  5. Late-breaking phase 2 ibrutinib study in chronic graft-versus-host-disease (cGVHD) showed complete or partial response in up to two-thirds of steroid dependent or refractory patients [news release]. Janssen; December 6, 2016. http://www.janssen.com/late-breaking-phase-2-ibrutinib-study-chronic-graft-versus-host-disease-cgvhd-showed-complete-or. Accessed February, 2017.
  6. Dubovsky JA, Flynn R, Du J, et al. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest.;124(11):4867-76.
  7. Ibrutinib [package insert]. Pharmacyclics LLC and Janssen Biotech, Inc.; 2017. https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing_information.pdf.
  8. Miklos D, Cutler CS, Arora M, et al. LBA-3 multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Paper presented at: American Society of Hematology (ASH) 58th Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA.

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Hematologic Cancers