Successful bone marrow transplantation in 20 patients with severe congenital neutropenia using an immunosuppressive conditioning regimen: Results of a single institute Free

Severe congenital neutropenia (SCN) is a rare heterogeneous genetic disorder characterized by recurrent bacterial infections from early infancy due to severe chronic neutropenia. The majority of patients with SCN have benefitted by treatment with granulocyte colony-stimulating factor (G-CSF). However, patients on long-term G-CSF therapy have a relative risk of developing myelodysplastic syndrome/acute myeloid leukemia. The only curable treatment for these patients is hematopoietic stem cell transplantation (HSCT). Recently, HSCT with reduced intensity conditioning regimens have been used for treating patients with SCN before malignant transformation. However, the optimal conditions of HSCT for patients with SCN have not been established. In this study, we conducted bone marrow cell transplantation (BMT) in 20 patients with SCN using an immunomyelosuppressive conditioning regimen to minimize early and late transplant-related morbidity (TRM) in Hiroshima University Hospital.

Twenty patients with SCN carrying an ELANE mutation underwent BMT from 2007 to 2024. The median age at BMT was 5.0 years (range: 2.1–21.9 years). Five of 20 patients had experienced engraftment failure of initial HSCT. All patients had received G-CSF treatment before HSCT. One patient did not respond to a high dose of G-CSF and developed acute myeloid leukemia. Bone marrow cells were obtained from 5 HLA-matched related, 4 HLA-matched unrelated, 1 HLA-mismatched related (7/8), and 10 HLA-mismatched unrelated (7/8) donors. The conditioning regimen consisted of fludarabine, cyclophosphamide, melphalan, and total body irradiation (3.6 Gy) with or without antithymocyte globulin. Short-term methotrexate and tacrolimus were administered for the prophylaxis of graft-versus-host disease (GVHD).

All patients showed successful engraftment by day 28 after BMT. However, mixed donor and recipient chimerism in bone marrow cells gradually developed in 7 of 20 patients. One patient finally failed to engraft donor cells without the efficacy of donor lymphocyte infusions (DLIs). This patient received a second BMT in another hospital 1.5 years after the initial BMT, resulting in successful complete donor chimerism. In 4 of 6 patients, complete donor chimerism was achieved by serial DLIs. The remaining 2 patients received DLIs and have maintained mixed donor chimerism. Notably, 4 patients with mixed donor chimerism received BMT from HLA-matched siblings. The incidence of mixed chimerism was high in patients transplanted from HLA-matched related donors. Thirteen of 20 patients accomplished and sustained persistently complete donor chimerism without DLIs, irrespective of the initial or second BMT.

Acute and/or chronic GVHD was observed in 14 of 20 patients. Eight patients had grade I acute GVHD and 5 had grade II or III acute GVHD. All patients with acute GVHD were successfully treated with the administration of tacrolimus, corticosteroid, and mycophenolate mofetil. Three patients developed chronic GVHD with mild limited skin lesions, and 2 of them received DLIs to achieve complete donor chimerism.

Epstein–Barr virus-related post-transplant lymphoproliferative disease was observed in 5 of 20 patients. The other TRMs were thrombotic microangiopathy (n=2), pulmonary hypertension (n=1) and nephrotic syndrome (n=1). These TRMs resolved with suitable treatments. All patients are alive for 1.5 to 17.9 years after HSCT with no signs of severe infections or TRM. Although 2 patients have shown mixed donor chimerism, any infectious episodes and development of malignancy have not been observed. In another cohort of patients with chronic granulomatous disease who underwent BMT using a similar conditioning regimen in our hospital, 3 male patients naturally fathered their children, which suggested fertility.

In summary, our results in a single institution show the excellent outcome of BMT in patients with SCN carrying an ELANE mutation. BMT using immunosuppressive conditioning regimen at a relatively young age may be feasible and effective, irrespective of the donor source and the incompatibility of HLA. The careful and/or appropriate management of TRM, including late engraftment failure (mixed chimerism), is important to maintain long-term complete chimerism.