ISSN 1866-8836
Клеточная терапия и трансплантация

Case report: effect of Jak-2 kinase inhibitor discontinuation on chronic steroid-refractory graft-versus-host disease in liver

Kseniya P. Yakimovich, Olga V. Pirogova, Oleg V. Goloshchapov, Elena I. Darskaya, Sergey N. Bondarenko, Ivan S. Moiseev, Boris V. Afanasyev
R. M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, Chair of Hematology, Transfusiology and Transplantology, First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation

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Cellular Therapy and Transplantation (CTT)
Volume 7, Number 3
Contents 

Summary

Introduction

The incidence of steroid-refractory graft versus host disease (SR-GVHD) is a one-half of patients with a mortality rate of 70%. Janus kinase (JAK) 1/2 inhibitors might be considered as a salvage therapy. However, there is a scarcity of relevant information about optimal duration and taping strategy of Jak-2-inhibitors. Our aim was to present a clinical case of a liver SR-GVHD after haploidentical HSCT (haplo-HSCT) in a young patient with Gilbert syndrome who developed decrease of liver function tests following discontinuation of Jak-2 kinase inhibitor therapy. Medical records, laboratory and instrumental data were reviewed when analyzing the results. GVHD severity was scored according to the 2014 NIH Consensus Criteria.

Case report

A 28-year-old male patient with acute myeloid leukemia (AML), FAB-M2, and concurrent Gilbert syndrome underwent haplo-HSCT on 12 May 2015 from brother, HLA compatibility, 6/10. Conditioning regimen: busulfan 8 mg/kg, fludarabine. Bone marrow was a source of stem cells:. GVHD prophylaxis: cyclophosphamide (30 mg/kg, days+3,+4), tacrolimus (from day+5), mycophenolate mofetil (45 mg/kg, days from +5 to +35). On day+90, tacrolimus was discontinued due to early bone marrow recurrence. On day+202, overlap-syndrome of grade 4 was developed, with skin, liver and lower gastrointestinal tract (GIT) lesions (grade 3, 4 and 3 respectively). The first-line therapy: methylprednisolone 2 mg/kg, causing partial response for skin. Etanercept (25 mg twice a day) and tacrolimus were added, followed by complete response for skin and GIT; bilirubin level was >250 μmol/L. The immunosuppressive therapy was discontinued on the day+237, due to pulmonary hemorrhage and transfer to intensive care unit. Increased bilirubin level (580 μmol/L) and intestinal bleeding were observed. This treatment was replaced by a Jak-2 inhibitor (ruxolitinib, 20 mg per day). The effect: decreased bilirubin level, without any dynamics for intestinal pathology. On day+249, fecal microbiota transplantation was performed, followed by resolution of GI symptoms. Mesenchymal stem cells were infused twice (D+257, D+266) with no response. Cholesterol levels raised over 40 mmol/L, having been treated bi-weekly plasmapheresis. From day+316 to day+426, the patient received 5 infusions of tocilizumab, he underwent 12 courses of extracorporeal photopheresis, sirolimus and low-dose interleukin-2, without any response (bilirubin 520 to 724 μmol/l). On day +350, liver biopsy was performed, and GVHD pathology was detected. Sirolimus and ruxolitinib were administered from day+460 to day+738. Ruxolitinib was replaced by a new-generation Jak-2 kinase inhibitor baricitinib (4 mg daily) on day+738. The following effect was observed: bilirubin level 220-420 mmol/L, hypercholesterolemia still persisted. On day+1120, baricitinib was discontinued. Further on, a decrease of bilirubin (213 μmol/L) and cholesterol levels (7.7 mmol/l) were documented. The therapy with sirolimus is going on, and significant improvement in the quality of life is noted.

Conclusion

Steroid-refractory severe chronic liver GVHD is a condition that might require prolonged immunosuppressive treatment with absence of complete response to current treatments. Despite high efficacy of JAK-2-inhibitors, they might be associated with serious adverse effects, like severe hypercholesterolemia. Gilbert syndrome may complicate the assessment of GVHD response and require liver biopsy to guide a therapy.

Keywords

Steroid-refractory graft-versus-host disease (SR-GVHD), overlap syndrome, Jak-2-inhibitors, Gilbert syndrome, fecal microbiota transplantation


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