Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) remains a curative treatment for severe hemoglobinopathies, including sickle cell disease and thalassemia syndromes1–3. The success of HSCT depends on multiple factors, including donor compatibility, conditioning regimen, graft source, and post-transplant immunosuppression4. Matched sibling donor transplantation, particularly with a fully HLA-matched donor, is associated with excellent long-term outcomes5,6.

Despite advances in transplantation, graft-versus-host disease (GVHD) remains an important cause of morbidity and mortality after HSCT7. Gastrointestinal GVHD may present with severe diarrhea, abdominal pain, gastrointestinal bleeding, and nutritional compromise and is associated with significant morbidity8,9. Steroid-refractory GVHD remains a major therapeutic challenge and may require second-line therapies such as ruxolitinib and mesenchymal stem cell (MSC) therapy10,11.

In this case report, we describe the clinical course of a pediatric patient with transfusion-dependent sickle beta-thalassemia who underwent matched sibling donor HSCT complicated by severe gastrointestinal GVHD and CMV reactivation, highlighting the challenges and evolving therapeutic strategies in post-transplant care.

Case Presentation

A 5-year-old boy presented with a 2-day history of fever that resolved spontaneously. Laboratory evaluation revealed severe anemia (hemoglobin, 5.2 g/dL), a platelet count of 1.93 × 10⁵/mm³, and leukopenia (total leukocyte count, 4,000/mm³). High-performance liquid chromatography confirmed sickle beta-thalassemia. The child subsequently became transfusion-dependent and required monthly packed red cell transfusions for approximately one year.

Given the severity of the disease, he was evaluated for HSCT. HLA typing identified a fully matched (12/12) sibling donor, his 14-year-old sister. Pre-transplant infectious screening for HIV, hepatitis B, CMV, EBV, and adenovirus was negative.

Pre-Transplant and Conditioning

The patient received two cycles of pre-transplant immunosuppressive therapy (PTIS) consisting of cyclophosphamide, fludarabine, and dexamethasone, followed by G-CSF support.

Myeloablative conditioning, initiated on Day −10 in July 2025, consisted of rabbit anti-thymocyte globulin (ATG), thiotepa, treosulfan, and fludarabine. The patient received a peripheral blood stem cell graft with a cell dose of 7 × 10⁶ cells/kg on Day 0. Cyclosporine and methotrexate were used for GVHD prophylaxis12.

Post-Transplant Course

Engraftment was achieved, with neutrophil recovery on Day +10, platelet recovery on Day +21, and red cell engraftment by Day +50. The initial post-transplant period was uneventful. Prophylaxis included acyclovir, fluconazole, and later trimethoprim-sulfamethoxazole. CMV monitoring was performed weekly.

Initially, the patient developed Grade I liver GVHD, manifested by transaminitis (SGOT, 120 IU/L; SGPT, 125 IU/L). Oral prednisolone was started, and cyclosporine was continued along with antimicrobial prophylaxis. The patient improved and was discharged.

However, he was subsequently readmitted on 22 November 2025 with Grade III–IV gastrointestinal GVHD. He presented with high-volume watery diarrhea (10–15 episodes/day), reddish-black stools, abdominal pain and cramps, vomiting, poor oral intake, and weight loss.

For severe gastrointestinal GVHD, intravenous methylprednisolone at 1 mg/kg/day was initiated. Additional immunosuppressive therapy included oral budesonide, intravenous cyclosporine, and oral ruxolitinib (Jakavi). Because of hypertension, cyclosporine was discontinued and oral tacrolimus was started on 1 December 2025. As therapeutic tacrolimus levels could not be adequately achieved, sirolimus was added on 16 January 2026, and tacrolimus was subsequently discontinued.

Mycophenolate mofetil was initially started but was discontinued on 19 December 2025 because of CMV reactivation. The CMV viral load was 41,941 copies. Intravenous ganciclovir was initiated, later changed to oral valganciclovir, and subsequently changed back to intravenous ganciclovir because of suspected reactivation. CMV PCR was monitored every 15 days, and the viral load became undetectable on 17 January 2026.

As part of the management of gastrointestinal GVHD, mesenchymal stem cell (MSC) therapy was administered at a dose of 20 million cells. Three doses were given at two-week intervals, resulting in significant clinical improvement.

The severity of GVHD also progressively improved, from Grade IV during the severe gastrointestinal phase to Grade I at the time of discharge (Figure 2).

The stool frequency and corresponding treatment interventions during the different phases of the illness are summarized in Table 1.

Table 1 · Stool frequency and treatment according to clinical phase

Stool frequency initially remained high during the refractory phase and subsequently decreased following MSC therapy. The overall trend in stool frequency across the different treatment phases is shown in Figure 3.

During the hospital stay, the child developed one episode of sepsis on 29 January 2026, characterized by high-grade fever up to 101 °F, vomiting, increased stool output, and poor oral intake. Antibiotics were escalated, and intravenous methylprednisolone was continued with dose escalation. The patient subsequently stabilized.

Because of associated cytopenias, romiplostim was administered in three doses, resulting in improvement in the platelet count15.

Clinically, the child initially had reddish-black, high-volume stools with severe abdominal pain. Over time, the stool color changed from reddish-black to greenish, then greenish-yellow, and finally yellowish, with a marked reduction in frequency and volume. Abdominal pain also improved significantly.

At discharge, the child was hemodynamically stable and afebrile, passing small-volume yellowish, mushy stools, tolerating oral feeds, and without vomiting. However, hypoalbuminemia and electrolyte abnormalities persisted and were under active management.

Discussion

This case highlights several important aspects of the management of pediatric sickle beta-thalassemia undergoing HSCT, including transplant indications, conditioning strategies, post-transplant complications, and evolving therapeutic approaches.

The patient had severe anemia and transfusion dependence, which are recognized indications for HSCT in severe hemoglobinopathies1,3. The availability of a fully HLA-matched sibling donor contributed to the favorable transplant course, as matched sibling transplantation is associated with excellent long-term outcomes in sickle cell disease5,6.

The use of pre-transplant immunosuppressive therapy (PTIS) in this case was intended to facilitate engraftment in a previously transfused patient. The conditioning regimen containing treosulfan, fludarabine, and thiotepa reflects the use of treosulfan-based conditioning approaches in HSCT12.

The patient achieved timely hematopoietic recovery, with neutrophil recovery by Day +10 and platelet recovery by Day +21. Peripheral blood stem cell grafts can provide rapid hematopoietic recovery following allogeneic transplantation13.

Initially, the patient developed Grade I liver GVHD, which responded to corticosteroids. However, progression to severe Grade III–IV gastrointestinal GVHD illustrates the unpredictable course of acute GVHD7,8. Gastrointestinal involvement can result in substantial fluid and nutritional losses and is associated with significant morbidity and adverse outcomes9.

Management of steroid-refractory GVHD

Management of steroid-refractory GVHD remains challenging. In this case, a multimodal approach was employed, including:

• Calcineurin inhibitors (cyclosporine, followed by tacrolimus)
• mTOR inhibitor (sirolimus)
• Janus kinase (JAK) inhibitor (ruxolitinib)
• Mesenchymal stem cell (MSC) therapy

Ruxolitinib has demonstrated efficacy in steroid-refractory GVHD and is an important second-line therapeutic option10. MSC therapy has immunomodulatory properties and has been investigated as a treatment for refractory GVHD11.

In this patient, despite corticosteroids and sequential immunosuppression, gastrointestinal symptoms persisted, necessitating escalation to ruxolitinib and subsequently MSC therapy. Following MSC administration, there was a marked reduction in stool frequency, improvement in abdominal pain, better oral intake, and gradual clinical stabilization.

CMV reactivation and supportive care

CMV reactivation is a well-recognized complication in patients receiving intensive immunosuppression after HSCT14. CMV infection may further complicate GVHD management and is associated with increased morbidity and mortality. Close PCR surveillance and prompt antiviral therapy are therefore essential14. In this case, treatment with ganciclovir was followed by clearance of CMV on serial PCR monitoring.

The patient also experienced sepsis and cytopenias during the post-transplant course, both recognized complications in heavily immunosuppressed HSCT recipients. These complications required prompt antimicrobial and supportive management. Romiplostim was used for thrombocytopenia and was followed by improvement in the platelet count15.

Despite these complications, the patient demonstrated gradual clinical improvement, with reduction in diarrhea, improvement in abdominal pain and oral intake, clearance of CMV, and stable graft function at discharge. This outcome emphasizes the importance of early recognition, individualized immunosuppression, intensive supportive care, and multidisciplinary management in complex post-transplant GVHD.

Conclusion

This case demonstrates successful clinical stabilization of severe gastrointestinal GVHD complicated by CMV reactivation following matched sibling HSCT for sickle beta-thalassemia. Early recognition, sequential modification of immunosuppression, antiviral therapy, ruxolitinib, and MSC therapy were important components of management.

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