Successful Hematopoietic Stem Cell Transplantation with Haploidentical Donors and Non-Irradiation Conditioning in Patients with Fanconi Anemia

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, congenital abnormalities, and a predisposition to malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for bone marrow abnormalities in FA. However, patients with FA are highly sensitive to the toxicity of conventional conditioning regimens, which often include high doses of cyclophosphamide (CTX) and irradiation. This sensitivity necessitates the development of less toxic conditioning regimens, particularly for HSCTs involving haploidentical donors, where data are scarce. This article presents a comprehensive overview of a study conducted at Peking University People’s Hospital, which successfully performed haploidentical HSCTs in 15 FA patients using a non-irradiation conditioning regimen.

Background and Rationale

FA patients exhibit hypersensitivity to DNA-damaging agents, such as CTX and irradiation, which are commonly used in conditioning regimens for HSCT. Traditional conditioning regimens for acquired aplastic anemia, which include 200 mg/kg CTX, are too toxic for FA patients. Consequently, low-dose CTX regimens are preferred. Some centers have incorporated irradiation into the conditioning regimen, but this approach carries risks of secondary malignancies and adverse effects on growth and development. To mitigate these risks, researchers have explored alternative regimens, such as those incorporating fludarabine, an immunosuppressive agent with less genotoxic effects.

Haploidentical HSCT, which involves donors who are only partially matched with the recipient, has emerged as a viable option for patients lacking fully matched donors. However, the use of haploidentical donors in FA patients has been limited, with few studies reporting outcomes. This study aimed to evaluate the efficacy and safety of a non-irradiation conditioning regimen in haploidentical HSCT for FA patients.

Study Design and Patient Characteristics

From June 2013 to February 2020, 15 consecutive FA patients (8 boys and 7 girls; median age: 8 years) underwent haploidentical HSCT at Peking University People’s Hospital. All patients tested positive for chromosomal breakage, and the diagnosis was confirmed by gene mutation analysis in all but one patient. Bone marrow failure, consistent with aplastic anemia criteria, was observed in 12 patients, while three patients exhibited myelodysplasia with increased blasts or marrow dysplasia. The donors, all parents (2 mothers and 13 fathers), were negative for chromosomal breakage. The HLA genotype disparity varied, with 3/6 (A, B, and DRB1) in two patients, 4/6 in one patient, 4/8 (A, B, C, and DRB1) in six patients, 5/10 (A, B, C, DRB1, and DQ) in four patients, and 6/10 in two patients.

Conditioning and Prophylaxis Regimens

The preparative regimen consisted of 60 to 80 mg/kg CTX, 150 mg/m² fludarabine, and 10 mg/kg thymoglobulin (rabbit anti-lymphocyte globulin, ATG). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A, mycophenolate mofetil, and short-term methotrexate. All patients received broad-spectrum antifungal agents, oral trimethoprim-sulfamethoxazole, and acyclovir for infection prophylaxis. Donors were primed with granulocyte colony-stimulating factor (G-CSF) from day -3 to day 0. Bone marrow stem cells were collected on day -1, and peripheral stem cells were harvested on day 0. Patients received G-CSF from day 6 until the neutrophil count exceeded 1 × 10⁹ cells/L.

Engraftment and Hematopoietic Recovery

All patients achieved neutrophil engraftment within 15 days (median: 11 days). Platelet recovery occurred at a median of 18 days (range: 8 to 62 days). Complete donor chimerism (100%) was achieved in all patients by 4 weeks post-transplantation.

GVHD and Toxicity

Acute GVHD (aGVHD), diagnosed according to the Seattle criteria, was observed in 14 patients, with 6 experiencing grade III–IV aGVHD. Thirteen patients were successfully treated with prednisolone alone or in combination with basiliximab. One patient with grade IV aGVHD affecting the skin, liver, and gut required additional therapy. Chronic GVHD was observed in three of the 11 evaluable patients, affecting the skin in all cases and the bowel in one patient, who responded well to steroids.

The conditioning regimen was well tolerated. Transaminase levels increased slightly in 11 patients but normalized quickly. Six patients developed mucositis, which resolved rapidly. Nine patients developed cytomegalovirus antigenemia, which was treated with ganciclovir. Epstein-Barr virus was detected in three patients, with one requiring rituximab therapy. No cases of sinusoidal obstruction syndrome were observed.

Survival and Outcomes

Fourteen patients were alive at a median follow-up of 10.5 months (range: 1 to 82.5 months), with 12 patients achieving normal blood counts and 2 experiencing mild thrombocytopenia. One patient died from intracranial and lung infections on day 51. The estimated 1-year disease-free survival rate was 92.9%. No secondary tumors were reported, although long-term follow-up is necessary to monitor for potential late effects.

Discussion

HSCT has been used to treat FA for approximately four decades, with recent studies reporting overall survival (OS) rates exceeding 80% for matched sibling donors and similar outcomes for alternative donors. However, data on haploidentical donor transplants remain limited. A 2016 Brazilian study of 30 haploidentical HSCTs with total body irradiation (TBI) conditioning reported a 1-year OS of 72%. In contrast, the present study achieved a 1-year disease-free survival rate of 92.9% using a non-irradiation conditioning regimen.

Graft failure is a significant challenge in alternative donor transplants. Previous studies reported complete hematopoietic recovery in only 51% of patients, with a 30-day cumulative neutrophil recovery rate of 83% in unrelated donor cases. In this study, all 15 patients achieved complete engraftment, demonstrating the efficacy of the non-irradiation regimen.

The incidence of GVHD remains a concern in haploidentical HSCT. In this study, 14 patients developed aGVHD, with 6 experiencing grade III–IV aGVHD. The high incidence of aGVHD may be related to the conditioning regimen’s toxicity. Reducing the CTX dose from 80 mg/kg to 60 mg/kg decreased the incidence of grade III–IV aGVHD by approximately 50%. Future studies could explore incorporating post-transplantation CTX to further reduce GVHD incidence.

Conclusion

This study demonstrates that haploidentical HSCT with a non-irradiation conditioning regimen is a viable and effective treatment option for FA patients. The regimen was well tolerated, with high rates of engraftment and survival. However, the high incidence of GVHD warrants further investigation. Larger, long-term studies are needed to validate these findings and optimize the conditioning regimen for haploidentical HSCT in FA patients.

doi.org/10.1097/CM9.0000000000001471

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