Complete Resolution of Extensive Chronic Graft-Versus-Host Disease with Ibrutinib in Relapsed Mantle Cell Lymphoma

We here in document a complete response of extensive chronic graft-versus-host disease (cGvHD) to a Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib. A 41 year old Caucasian female with stage IVA mantle cell lymphoma (MCL) received four cycles of R-CHOP (rituximab, cyclophosphamide, vincristine and prednisone) and two cycles of RICE (rituximab, ifosphamide, carboplatin and etoposide) without a significant response. Four cycles of bendamustine and rituximab (BR) effected a partial response with persistent PET positive disease. For primary refractory MCL she underwent mismatched unrelated donor allogeneic hematopoietic stem cell transplantation in December 2011 receiving conditioning with cyclophosphamide (60 mg/kg × 2), total body irradiation (1200 cGy), alemtuzumab (10 mg × 3) and total of 6.6 ×106/kg CD-34+ cells. Tacrolimus is used for graft-versus-host disease (GvHD) prevention. Platelets and neutrophils engrafted on days 11 and 14 respectively and she developed grade III acute GvHD involving the skin and gut on day 17 of transplantation that persisted beyond 100 days posttransplant. Her chronic GvHD (cGvHD) was treated with steroids, but remained active and extensive. Despite active and persistent cGvHD with 100% donor chimerism, in July 2012 she was found to have persistent biopsy proven MCL in the stomach that was treated with external beam radiation (3000 cGy). Subsequent progression in bone marrow and para-aortic lymph nodes in April 2013 was treated with 2cycles BR with excellent partial response but neurotoxicity precluded continued treatment. By December 2013, the patient had extensive cGvHD manifesting as scleromatous skin thickening, oral ulcers and sclerosis of the buccal mucosa, ocular dryness and diarrhea. She was started on ibrutinib 560 mg once daily for primary refractory MCL. After two months of therapy, cGvHD had begun to improve. Oral steroids were reduced and ultimately stopped after six months of ibrutinib; after seven months, all cGvHD manifestations resolved completely. A complete remission for MCL was documented at two months of ibrutinib initiation. Currently she continues to be on daily 560mg ibrutinib without cGvHD exacerbation for 34 months; MCL remained in CR for only one year (Figure 1). Overall survival from the initial MCL diagnosis is now 76 months.