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Early Outcomes of Ruxolitinib in the Treatment of Steroid Refractory Graft-versus-host Disease on Liver Transplant Recipients

Kakadia, Sunilkumar MD1; Trotta, Holly DNP2; Kurczek, Leslie PharmD2; Burdine, Lyle MD, PhD2; Veeraputhiran, Muthu MD1; Giorgakis, Emmanouil MD, MSc2

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doi: 10.1097/TP.0000000000003252
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We read with great interest the report by Endo et al on the application of ruxolitinib, a novel Janus kinase subtype 1-2 inhibitor, on the treatment of graft-versus-host disease (GVHD) after liver transplantation (LT).1,2 We hereby report the cases of 2 patients who received ruxolitinib for the treatment of steroid-refractory LT-GVHD.

GVHD is a rare post-LT complication.3,4 Left untreated, it has a mortality rate of up to 85%. There is currently no consensus on LT-GVHD treatment. Treatment options have been limited, inconsistent, and almost universally disappointing, often leading into bone marrow failure and fatal sepsis.3,4 Corticosteroids are the mainstay of the treatment; however, LT-GVHD is commonly steroid refractory.3,4 We hereby report the cases of 2 patients who received ruxolitinib for the treatment of steroid-refractory LT-GVHD.

Case 1. A 63-y-old male with hepatitis C cirrhosis and hepatocellular carcinoma underwent LT following donation after circulatory death. Five weeks post-LT, he developed generalized erythematous maculopapular rash, pancytopenia, and diarrhea. Punch biopsy showed lichenoid interface dermatitis with cluster of differentiation (CD)3, as well as CD8 T lymphocytic infiltration. Sigmoid mucosal biopsy showed apoptotic cells. Peripheral blood subset flow-cytometric chimerism showed CD3 94% donor and CD33 <1%, confirming donor cells engraftment. The patient was diagnosed with LT-GVHD. Initial treatment included 1 mg/kg IV methylprednisolone (MP) twice daily (bid) and immunoglobulin (IVIG), with partial improvement. Ruxolitinib (5 mg bid) was introduced, which was increased to 10 mg bid (2 wk), and then decreased to 10 mg daily for another week (25 d total). Follow-up flow-cytometric analysis showed CD3 donor DNA chimerism reduction to 37% and 21% at 3 and 8 wk, respectively. The patient was started on glecaprevir/pibrentasvir for hepatitis C viremia, with seronegativity achieved after 8 wk. He was also started on weekly rituximab/IVIG for Epstein-Barr viremia. The patient became aplastic at 2½ mo postdiagnosis. Ruxolitinib was reinstated at 5 mg bid (for 34 d) while he was maintained on 20 mg IV MP daily. The patient died 5 mo post LT-GVHD diagnosis while awaiting allogenic hematopoietic stem cell transplant.

Case 2. A 53-y-old male s/p LT for nonalcoholic steatohepatitis, who developed LT-GVHD 4 wk postoperatively. Peripheral blood short tandem repeated testing showed 27% CD3 and <1% CD33 donor DNA. After a course of IV MP (1 mg/kg bid) with little response, he was started on ruxolitinib (5 mg advanced to 10 mg bid), with gradual resolution of his symptoms. Ruxolitinib was discontinued on day 40. Peripheral blood CD3 donor DNA chimerism improved from 31% to 7%. Patient recovered from infections and cytopenias and has been doing well 25 wk since his LT-GVHD diagnosis. He remains on tacrolimus (target trough level 5 ng/mL) and prednisone 15 mg daily.

On both cases, we succeeded favorable initial response to ruxolitinib. None of the patients had received basiliximab or lymphocyte depletion on induction.

In summary, no consensus exists in the optimal GVHD treatment, although recent reports describe achievement of partial to complete LT-GVHD remission with ruxolitinib.1,5 Its addition to the LT-GVHD armamentarium gives promise for tackling this rare but devastating complication.

References

1. Endo Y, Oshima G, Hibi T, et al. Achievement of durable and complete remission of graft-versus-host disease after liver transplantation with ruxolitinib: a case report. Transplantation. 2019; 10311e375–e377doi:10.1097/TP.0000000000002904
2. US Healthcare ProfessionalsIntervene with Jakafi.2020Available at https://hcp.jakafi.com/. Accessed March 2, 2020
3. Murali AR, Chandra S, Stewart Z, et al. Graft versus host disease after liver transplantation in adults: a case series, review of literature, and an approach to management. Transplantation. 2016; 100122661–2670doi:10.1097/TP.0000000000001406
4. Perri R, Assi M, Talwalkar J, et al. Graft vs. host disease after liver transplantation: a new approach is needed. Liver Transpl. 2007; 1381092–1099doi:10.1002/lt.21203
5. Jacobs MT, Olson M, Ferreira BP, et al. The use of ruxolitinib for acute graft-versus-host disease developing after solid organ transplantation. Am J Transplant. 2020; 202589–592doi:10.1111/ajt.15579
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