Successful Treatment of Steroid-refractory Acute Graft-versus-host Disease With Ruxolitinib in a Liver Transplant Recipient

Graft-versus-host disease (GVHD) after liver transplantation (LT) is a rare complication with >85% mortality.1 It results from the proliferation of immunocompetent donor T-cell lymphocytes that recognize recipient tissues as foreign, leading to inflammatory alloimmune attack and tissue damage.2 It typically manifests 2–6 wk posttransplantation with fever, maculopapular rash, diarrhea, and pancytopenia. Frontline treatment consists of high-dose corticosteroids along with a decrease in maintenance immunosuppression, whenever possible. However, responses are usually weak and short-lasting. There is no standard second-line therapy; the typical outcome of steroid-refractory disease is rapid demise. Here, we present a case of post-LT steroid-refractory acute GVHD successfully treated with ruxolitinib. A 57-y-old man with a history of Crohn’s disease, hypothyroidism, and alcohol-induced cirrhosis underwent an orthotopic LT from a male donor. Standard immunosuppression consisted of induction with methylprednisolone (500 mg on day 0, 250 mg on day 1, and 125 mg on day 2) and basiliximab 20 mg on day 0, and maintenance with tacrolimus starting on day 4 and mycophenolate mofetil 1 g twice daily starting on day 0. He presented 40 d after transplantation with a 5-d history of fever, >3 L/d of diarrhea, diffuse abdominal pain, and a generalized erythematous maculopapular rash (Figure 1A). White blood cell count was 0.21 × 109/L, absolute neutrophil count was 0.07 × 109/L, hemoglobin was 6.9 g/dL, and platelet count was 444 × 109/L. Mycophenolate mofetil was discontinued because of abdominal pain and neutropenia. Histological examination of a skin biopsy showed basal vacuolar change with dyskeratotic keratinocytes, consistent with GVHD. Flexible sigmoidoscopy showed marked crypt apoptosis, glandular destruction, including apoptotic crypt abscesses, and detached granulation tissue, consistent with GVHD. Other causes of diarrhea, including infections, Crohn’s flare, and drug side effects, were ruled out. Peripheral blood chimerism studies using restriction fragment length polymorphisms revealed 73% CD3 (T cell) and 0% CD33 (myeloid) donor chimerism. Examination of a bone marrow aspiration and biopsy revealed markedly reduced myelopoiesis. Marrow restriction fragment length polymorphisms showed 25% CD3 and 0% CD33 donor chimerism. A diagnosis of post-LT acute GVHD (grade 4) was established.FIGURE 1.: Skin rash at presentation and absolute neutrophil count over time. A, Images of the generalized skin rash at presentation. B, Absolute neutrophil count over time. Time is relative to the transplant day. G-CSF, granulocyte colony-stimulating factor; MMF, mycophenolate mofetil; MPN, methylprednisolone; POD, postoperative day.He was started on methylprednisolone 2 mg/kg/d while tacrolimus was continued. Due to persistent diarrhea after 3 wk of high-dose steroids, ruxolitinib 10 mg twice daily was initiated for the treatment of steroid-refractory GVHD and as a steroid-sparing agent. With the resolution of rash, gastrointestinal symptoms, and neutropenia and complete clearance of donor T cells as evident from a decline of peripheral blood donor CD3 chimerism to 0%, steroids were tapered down to a low-dose maintenance (5 mg/d) during a course of 9 wk and ruxolitinib was discontinued after 6 mo. Ruxolitinib was well tolerated, with no significant adverse effects. The patient is currently asymptomatic with normal blood counts while maintained on tacrolimus and prednisone (5 mg/d). The treatment course is summarized in Figure 1B. Ruxolitinib is an oral JAK1/2 inhibitor that modulates cytokine signals driving T-cell proliferation and inflammation in GVHD.3 Ruxolitinib is an approved treatment for steroid-refractory GVHD after allogeneic hematopoietic cell transplantation, with a complete response rate of 30% to 40%.4 However, it has been rarely used in post-LT GVHD.5 Our report represents one successful case and highlights the importance of early tissue biopsy and donor chimerism, followed by prompt treatment. We recommend starting ruxolitinib as soon as steroid refractoriness is demonstrated and before severe complications have occurred.