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

X-linked hyper-IgM syndrome, abbreviated XHIM, is caused by mutations in the gene encoding CD40 ligand, a surface molecule on helper T cells that is essential for instructing B cells to switch antibody classes. Without a functional CD40 ligand, B cells remain frozen at the IgM stage, leaving patients unable to produce IgG, IgA, and IgE antibodies. The name of the disease reflects the paradoxical laboratory finding: IgM levels are normal or even elevated, while the rest of the antibody repertoire is missing. But the defect reaches further than humoral immunity. CD40 ligand signaling is also required for macrophage activation and for effective T cell communication with antigen-presenting cells, so patients suffer from a combined cellular and humoral immunodeficiency. The clinical consequences are devastating: recurrent and severe infections with bacteria, fungi, and above all opportunistic pathogens that healthy immune systems dispatch without notice.

Among these opportunistic threats, few are as characteristic or as consequential as Cryptosporidium parvum, a waterborne intestinal parasite that is merely an inconvenience for immunocompetent people but a relentless adversary in XHIM. The parasite colonizes the biliary tract, where it drives a progressive, scarring inflammation of the bile ducts known as sclerosing cholangitis. Over time the ducts are destroyed, bile flow is obstructed, and the liver fails. There is no reliably effective antimicrobial therapy for cryptosporidial cholangitis once it takes hold; the only definitive cure for the underlying immune defect is allogeneic hematopoietic stem cell transplantation, or HSCT, which replaces the patient’s defective hematopoietic system with donor stem cells capable of generating functional T cells and class-switched antibodies. The critical caveat, well recognized in the field, is that outcomes of HSCT deteriorate sharply once advanced liver disease has developed, creating a race against time that many patients lose.

The Bergamo patient illustrates exactly why that race matters. By age 19, his sclerosing cholangitis was progressive, and the team proceeded with HSCT from an unrelated donor matched at 8 of 10 HLA loci, a partially mismatched graft that carries heightened risks of rejection and graft-versus-host disease but was necessitated by the lack of a fully matched donor. Early after the infusion, he developed severe cholestasis and persistent fever. Diagnostic workup identified active Cryptosporidium parvum infection that responded poorly to antimicrobial agents. What ultimately turned the tide was not a new drug but the withdrawal of immunosuppression: as the team tapered the medications given to prevent graft rejection, the patient’s donor-derived T cells recovered, and with that immune reconstitution the cryptosporidial infection finally resolved. The observation underscores a central principle of transplant immunology in immunodeficiency: antimicrobial therapy can suppress pathogens, but only a reconstituted cellular immune system can truly clear them.

Engraftment, however, was not enough to save his native liver. The cholangiopathy, already advanced before transplantation, continued its downward course, and six months after the stem cell transplant the patient underwent liver transplantation. This sequential strategy, HSCT followed by solid organ transplantation, is exceptionally rare and exceptionally demanding. Each procedure imposes its own burden of immunosuppression, and the two must be balanced against each other: too little immunosuppression invites graft rejection and opportunistic infection, while too much suppresses the very T cell recovery that the bone marrow transplant was meant to achieve and that the patient’s survival against Cryptosporidium depended upon.

Superimposed on this balancing act was a second viral threat: cytomegalovirus, or CMV. CMV is among the most common and dangerous infections after transplantation, capable of causing pneumonia, hepatitis, colitis, and bone marrow suppression, and of amplifying the risk of rejection and secondary infections. Patients who are CMV-seropositive themselves, or who receive organs or stem cells from seropositive donors, are classified as high risk for reactivation once immunosuppression begins. For this patient, whose CMV risk profile was unfavorable and whose blood counts were severely depressed, the team selected letermovir, a relatively recent antiviral that inhibits the CMV terminase complex, an enzyme the virus needs to package its DNA into newly formed viral particles. Because the terminase complex has no human counterpart, letermovir is highly specific, sparing the mitochondrial and renal toxicity that complicates older CMV drugs such as ganciclovir and foscarnet, an advantage of particular importance in a patient already battling cytopenias and liver dysfunction.

The team administered letermovir prophylaxis for 100 days after transplantation, a duration consistent with the evidence base established in studies of CMV-seropositive recipients of hematopoietic stem cell transplants, where the drug has dramatically reduced clinically significant CMV infection during the early post-transplant period. During prophylaxis the patient remained protected. But when letermovir was discontinued, recurrent CMV reactivations emerged, a pattern well described in the literature as late CMV disease occurring after prophylaxis ends. Once again, the decisive intervention was not an escalation of antiviral therapy alone but the careful tapering of immunosuppression, which allowed further T cell immune reconstitution to take place. With each round of tapering, the patient’s donor-derived cellular immunity matured, and the CMV episodes resolved.

At three years of follow-up, the outcome is striking. The patient is clinically well, with full donor chimerism, meaning that every measurable hematopoietic cell in his blood now originates from the donor’s stem cells. His liver function is stable, a testament to the success of the sequential transplant strategy. Most remarkably, his immune recovery has been sufficient to allow discontinuation of the lifelong immunoglobulin replacement therapy that XHIM patients typically require, indicating that his donor-derived B cells, now receiving proper CD40 ligand signals from functional donor T cells, are producing their own antibodies of the correct classes. In effect, the two transplants together replaced both the cellular and the humoral arms of his immune system, and the liver transplant replaced the organ that the defective immune system had destroyed.

The authors draw several lessons from this course that extend beyond the single patient. First, the case reinforces the argument for early HSCT in XHIM, before Cryptosporidium-associated liver disease becomes irreversible, because the window in which stem cell transplantation can be performed safely closes as cholangiopathy advances. Second, it highlights the central role of immune reconstitution in controlling opportunistic infections, with both cryptosporidiosis and CMV reactivation resolving only as donor T cells recovered and immunosuppression was withdrawn. Third, it suggests that extended letermovir prophylaxis may have a useful role in high-risk liver transplant recipients, a population in whom the drug’s evidence base is still being defined, and that clinicians should anticipate late CMV reactivation when prophylaxis is stopped before immune recovery is complete. For a disease as rare as XHIM, individual cases carry disproportionate weight, and this one, documented with open access and full transparency, adds a valuable data point to the small but growing literature on managing combined immune and solid organ transplantation in the era of targeted antiviral prophylaxis.

Subject of Research: Sequential hematopoietic stem cell and liver transplantation with letermovir CMV prophylaxis in X-linked hyper-IgM syndrome

Article Title: Sequential transplantation of allogeneic hematopoietic stem cells and liver in x-linked hyper-IgM syndrome: the role of CMV prophylaxis with letermovir

Article References: Murgia, D., Algarotti, A., Micò, M. C., D’Antiga, L., Luca, M., Del Carro, F., Lussana, F., Rambaldi, A., & Grassi, A. (2026). Sequential transplantation of allogeneic hematopoietic stem cells and liver in x-linked hyper-IgM syndrome: the role of CMV prophylaxis with letermovir. Annals of Hematology. https://doi.org/10.1007/s00277-026-07261-0

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07261-0

Keywords: X-linked hyper-IgM syndrome, CD40 ligand deficiency, hematopoietic stem cell transplantation, liver transplantation, sclerosing cholangitis, Cryptosporidium parvum, cytomegalovirus, letermovir, immune reconstitution, donor chimerism, inborn errors of immunity, CMV prophylaxis