Graft-versus-host disease (GVHD) remains a rare (1%–2%) but life-threatening complication after liver transplantation.1 Moreover, there is no definite treatment protocol,2 and although corticosteroids are mainstays of GVHD treatment, their response rates are low (16%).1 Furthermore, the majority of post-liver transplantation GVHD is steroid-refractory, although data on treatment strategies for steroid-refractory GVHD (SR-GVHD) are lacking.
Ruxolitinib, a selective Janus kinase (JAK) I/II inhibitor, which is used to treat primary myelofibrosis and polycythemia vera, has recently been shown to have suppressive activity against GVHD after allogeneic hematopoietic stem cell transplantation.3,4 Despite its potential adverse effects, such as cytopenia, reactivation of viral infection, and bacterial or fungal infections, previous studies have indicated that Ruxolitinib is well tolerated. Here, we present the first case report, to the best of our knowledge, of a patient who exhibited a durable and complete response induced by a JAK I/II inhibitor for GVHD after liver transplantation.
A 27-year-old man with primary sclerosing cholangitis underwent deceased donor liver transplant surgery. The donor was a 46-year-old woman; the HLA class, determined via serological methods, was HLA-A 24/-, B 52/-, DR15/15, and the blood group was AB rhesus-positive. Liver transplantation was performed without complications. On postoperative day 5, the HLA typing of the recipient was reported to be HLA-A24/-, B61/52, DR12, and DR15, which indicated a donor-dominant 1-way match in 3 loci. On day 35, he developed a systemic rash and severe diarrhea. Colonoscopy on day 38 revealed diffuse mucosal erythema, and biopsy from the ascending colon showed evidence of cytomegalovirus (CMV) infection. Despite administering ganciclovir (250 mg q12h) for CMV colitis, his diarrhea persisted. Skin biopsy was performed on day 49 (Figure 1A–B), which demonstrated basal cell layer vacuolization with lymphocytic infiltration in the dermis and apoptotic cells without eosinophil infiltration and CMV-infected cells. All these findings, together with the clinical course, were consistent with GVHD diagnosis ruling out drug eruption and viral rash. Based on these tests, we diagnosed him with grade IV GVHD with biopsy-proven skin lesions and gastrointestinal tract involvement. Additionally, chimerism testing of T cells in peripheral blood using X-Y chromosome flow cytometry5 on day 48 demonstrated the proportion of donor-derived T cell as 34%, which was consistent with GVHD (Figure 1E).
After confirming the diagnosis, treatment was initiated with a pulsed intravenous corticosteroid (methylprednisolone 500 mg bolus on day 50 that was tapered by 100 mg per day for 5 days, followed by 50 mg/day) in combination with ganciclovir (250 mg q12h) for CMV colitis. His clinical symptoms persisted; thus, 2 courses (days 53–57 and days 80–84) of rabbit antithymocyte globulin (Thymoglobulin, Sanofi, France) were administered at a dose of 2.5 mg/day for 5 consecutive days. Tacrolimus (target trough level of 4–6 ng/mL) and mycophenolate mofetil (MMF) (250 mg q12h) were continued, weekly injections of 10 mg/kg intravenous infliximab were administered on days 59 and 73, and oral budesonide was initiated at a dose of 9 mg/day on day 92. Despite these treatments, the patient’s condition deteriorated with approximately 3000 mL/day of diarrhea and rapidly progressing exfoliation that affected his entire body surface. These symptoms rendered the patient bedridden. Follow-up colonoscopy on day 83 showed diffuse mucosal erythema with patchy granulomatous changes and spotted aphthous lesions, which were worse than those reported in previous studies. The ascending colon biopsy revealed crypt apoptotic cells without any CMV-infected cells (Figure 1B). Chimerism testing on day 78 demonstrated an increased proportion of donor-derived T cell as 96% (Figure 1E). He also developed generalized tonic-clonic seizures caused by human herpesvirus 6 encephalitis on day 94. Finally, ruxolitinib (5 mg/day) was orally administered on day 104, following the failure of prior treatments. The patient rapidly and significantly responded to ruxolitinib, which improved severe diarrhea and skin exfoliation within few days (Figure 1C–D). When ruxolitinib was initiated, tacrolimus (target trough level of 4–6 ng/mL), methylprednisolone (100 mg daily), and MMF (500 mg q12h) were initially continued at the same dose. Tacrolimus was terminated on day 124 to mitigate the risk of infection. MMF was discontinued on day 148 because of gastrointestinal intolerance. Methylprednisolone was tapered and then terminated on day 180 as per our institution’s protocol. Sulfamethoxazole/trimethoprim was administered as prophylaxis for Pneumocystis jiroveci infection. Chimerism testing of T cells in peripheral blood (Figure 1E) and a skin biopsy specimen demonstrated complete resolution of GVHD on day 440. The patient was discharged on day 472. Since then, he has been alive and well for >2 years taking ruxolitinib 5 mg/day as the only immunosuppressive agent. Ruxolitinib was well tolerated, and no adverse events, such as opportunistic infections or myelosuppression, were noted. His liver function has been consistently stable, and he has never experienced acute rejection throughout the clinical course.
To the best of our knowledge, we documented a first-time recovery of a patient who was successfully treated by a JAK I/II inhibitor from post-liver transplantation SR-GVHD. Potential side effects of ruxolitinib included bacterial or fungal infections, reactivation of viral infections (eg, CMV, Epstein-Barr virus), cytopenia, liver dysfunction, and neurologic complaints. Although our patient already had human herpesvirus 6 encephalopathy and CMV colitis before the administration of ruxolitinib, no specific adverse events developed after ruxolitinib treatment. The pharmacological effect of ruxolitinib against GVHD is poorly understood. Further evaluations are needed to elucidate the functional mechanisms of ruxolitinib for the treatment of GVHD, in addition to appropriate dose regimens to be used with patients with SR-GVHD following liver transplantation.
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