Ruxolitinib Rescue Saves Child From Severe Liver GVHD After Thalassemia Transplant

A four-and-a-half-year-old boy with transfusion-dependent beta-thalassemia major has made a complete recovery from severe, liver-dominant acute graft-versus-host disease after an allogeneic hematopoietic stem cell transplant, according to a case report published in Clinical Case Reports. The child, treated at the Hayat Stem Cell Transplantation Center in Syria, developed profound cholestatic liver dysfunction just over three weeks after receiving stem cells from a fully matched sibling donor. What makes the case remarkable is not only the severity of the complication but the fact that it occurred entirely without the skin rash that usually signals acute graft-versus-host disease, and that a strategy of early, aggressive therapeutic escalation, including the Janus kinase inhibitor ruxolitinib and the monoclonal antibody rituximab, brought the boy back to full health with one year of sustained remission and transfusion independence.

Beta-thalassemia major is one of the most common inherited hemoglobin disorders in the world, concentrated in the Mediterranean basin, the Middle East, and Southeast Asia. The disease stems from defective synthesis of the beta-globin chain of hemoglobin, which produces ineffective red blood cell formation, chronic anemia, and a lifelong dependence on regular transfusions to keep hemoglobin levels adequate for normal growth. Although chronic transfusion combined with iron chelation therapy has dramatically improved survival, the inevitable iron overload continues to damage the heart, liver, and endocrine organs over time. Allogeneic hematopoietic stem cell transplantation remains the only established curative option, replacing the patient’s defective blood-forming system with donor cells that produce normal adult hemoglobin.

The boy in this report was diagnosed at three months of age, when hemoglobin electrophoresis revealed 82 percent fetal hemoglobin and only 15 percent HbA1. He received monthly transfusions with iron chelation until age four, when he was evaluated for transplantation. Pre-transplant workup included viral, cardiac, pulmonary, dental, ENT, and psychological assessments, along with whole-body computed tomography that showed only increased hepatic density. A liver biopsy demonstrated Grade I parenchymal iron overload without portal fibrosis. Under the Pesaro classification, used to stratify thalassemia patients by transplant risk, he was categorized as Class I, the most favorable group. His fully matched sibling donor provided peripheral blood stem cells totaling 11 million CD34-positive cells per kilogram and 580 million CD3-positive cells per kilogram.

Conditioning followed the EBMT protocol, combining busulfan at 4.4 milligrams per kilogram daily for four days, cyclophosphamide at 50 milligrams per kilogram daily for four days, and anti-lymphocyte globulin for two days. Prophylaxis against graft-versus-host disease consisted of methotrexate with leucovorin rescue plus cyclosporine A. Engraftment came quickly, with platelets recovering on day 13 and neutrophils on day 15, and day-30 chimerism analysis showed 99.2 percent donor cells. Then, on day 23, the child developed fatigue, progressive jaundice, and a liver enlarged four centimeters below the costal margin, with no rash whatsoever. Laboratory testing revealed the signature of severe cholestatic injury: alanine aminotransferase of 250 units per liter, gamma-glutamyl transferase of 936, and bilirubin climbing to at least 20 milligrams per deciliter. Screening for viral hepatitis and cytomegalovirus was negative, and the team diagnosed Grade III acute hepatic-predominant graft-versus-host disease with concurrent Grade II gastrointestinal involvement.

The absence of skin findings forced the clinicians into a careful differential diagnosis, because early post-transplant liver failure has several dangerous mimics. Sinusoidal obstruction syndrome, also called veno-occlusive disease, typically presents with unexplained weight gain, fluid retention, ascites, abdominal distension, hepatomegaly, and thrombocytopenia under the pediatric EBMT criteria. This boy showed none of those features: his weight stayed locked between 15.3 and 15.5 kilograms throughout the episode, he had no ascites or distension, and his platelet count remained normal. Doppler ultrasonography showed normal hepatic echogenicity with only mild hepatic vein dilatation and a mild rise in portal venous pressure, findings the team interpreted cautiously within the overall clinical picture rather than as diagnostic proof in either direction.

Transplantation-associated thrombotic microangiopathy was the other major consideration. The international consensus definition rests on a combination of anemia, thrombocytopenia, elevated lactate dehydrogenase, schistocytes on the blood smear, hypertension, elevated soluble C5b-9, and proteinuria. In this patient, platelets stayed within normal limits, LDH was normal at 250 units per liter, no schistocytes were seen, blood pressure remained normal, urinalysis showed no proteinuria, and renal function was preserved with a creatinine of 0.6 milligrams per deciliter at admission. The combination of marked cholestatic dysfunction, hepatomegaly, concurrent gastrointestinal graft-versus-host disease, exclusion of viral causes, and, ultimately, a clear response to graft-versus-host-directed therapy made hepatic-predominant acute graft-versus-host disease the most defensible diagnosis, although the authors are careful to note it remained clinically supported rather than histologically confirmed, since no liver biopsy was performed during the acute episode.

Treatment began with prednisolone at 2 milligrams per kilogram daily, cyclosporine at 5 milligrams per kilogram daily, and azathioprine, supplemented by ursodeoxycholic acid, silymarin, cholestyramine, and intravenous acetylcysteine to support the injured liver. When this regimen produced only limited clinical and biochemical response, with jaundice and cholestasis persisting, the team escalated. Mycophenolate mofetil was added at 50 milligrams per kilogram daily, ruxolitinib at 5 milligrams daily, and rituximab at 375 milligrams per square meter weekly. Ruxolitinib, a selective inhibitor of JAK1 and JAK2, blocks the inflammatory signaling cascades that drive graft-versus-host disease and has become a standard option for steroid-refractory disease in adults, with growing pediatric evidence behind it. Within three weeks of escalation, the jaundice and hepatomegaly regressed markedly, liver enzymes improved substantially, and the gastrointestinal symptoms resolved.

The follow-up data over a full year underscore how complete the recovery was. Donor chimerism remained stable at 100 percent at three months, 99 percent at six months, 99.4 percent at nine months, and 99 percent at twelve months. Liver function normalized dramatically, with alanine aminotransferase falling from 250 to 35 units per liter, aspartate aminotransferase from 200 to 32, and gamma-glutamyl transferase from 936 to 45, while bilirubin returned to normal and albumin held steady at about 3.7 grams per deciliter. Hemoglobin electrophoresis at nine and twelve months showed sustained donor-type hemoglobin production, with HbA1 at 97 percent and HbA2 at 2.9 percent. The boy remained transfusion-independent throughout, immunosuppression was gradually tapered and discontinued, and he resumed normal daily activities with no evidence of thrombotic microangiopathy at any point.

The case adds to a still-limited pediatric experience with severe hepatic-predominant acute graft-versus-host disease, and the authors place their result in the context of the ruxolitinib literature. An early retrospective pediatric series by Khandelwal and colleagues reported an overall response rate of 45 percent at four weeks in children with steroid-refractory disease, while the prospective REACH4 study reported an overall response rate of 84.4 percent at day 28 and a durable response rate of 66.7 percent at day 56. The authors caution, however, that because multiple immunosuppressive agents were given concurrently, the contribution of any single drug, whether ruxolitinib or rituximab, cannot be disentangled from a single case. They also acknowledge that biomarkers such as soluble C5b-9 and haptoglobin were unavailable, so competing diagnoses cannot be excluded with absolute certainty.

Even with those limitations, the clinical lessons are concrete. Severe hepatic acute graft-versus-host disease can strike without any cutaneous manifestation and belongs in the differential of significant cholestatic liver dysfunction after transplantation. Progressive hepatic failure in the early post-transplant period demands systematic evaluation for sinusoidal obstruction syndrome and thrombotic microangiopathy, with longitudinal tracking of weight, fluid status, platelet count, LDH, renal function, blood pressure, peripheral smear, and urinary protein providing the discriminating evidence. And in settings where advanced diagnostics are scarce, the case suggests that early recognition paired with timely therapeutic escalation and close multidisciplinary monitoring can still deliver excellent outcomes, a message with real weight for the many transplant programs operating in resource-limited regions where thalassemia imposes its heaviest burden.

Subject of Research: Management of severe hepatic-predominant acute graft-versus-host disease after allogeneic stem cell transplantation in a child with beta-thalassemia major

Article Title: Successful Management of Severe Hepatic Acute Graft‐Versus‐Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in a Child With β‐Thalassemia Major: Clinical Lessons From Early Therapeutic Escalation

Article References: Alhiraki, H., Fares, A. A., & Kheder, M. (2026). Successful Management of Severe Hepatic Acute Graft‐Versus‐Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in a Child With β‐Thalassemia Major: Clinical Lessons From Early Therapeutic Escalation. Clinical Case Reports, 14(10), Article e73623. https://doi.org/10.1002/ccr3.73623

Image Credits: AI Generated

DOI: 10.1002/ccr3.73623

Keywords: graft-versus-host disease, beta-thalassemia major, hematopoietic stem cell transplantation, ruxolitinib, rituximab, cholestatic liver dysfunction, pediatric transplantation, sinusoidal obstruction syndrome, thrombotic microangiopathy, donor chimerism, immunosuppressive therapy, case report