Successful Retransplantation of Bone Marrow Cells Following Failure of Initial Engraftment in 4 Patients with SCN
Authors: Nishimura Shiho , Mizoguchi Yoko , Karakawa Shuhei , Tomioka Keita , Miki Mizuka , Kawaguchi Hiroshi , Nakamura Kazuhiro , Kobayashi Masao 
Published: October 2019

Severe congenital neutropenia (SCN) is characterized by severe chronic neutropenia with a absolute neutrophil count of less than 0.5×109/L, maturation arrest of myeloid precursors at the promyelocyts/myelocyte stage, and the recurrent bacterial infections from early infancy. The induction of G-CSF therapy dramatically improved the prognosis of most patients with SCN. Analysis on patients on the Severe Chronic Neutropenia International Registry has demonstrated that the patients with SCN on long-term G-CSF treatment are at a risk of developing myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). Recently, hematopoietic stem cell transplantation (HSCT) has been applied for a curative treatment in SCN patients without malignant transformation. However, the optimal conditions of HSCT for SCN have not been established. The failure of engraftment has been reported in some of SCN patients receiving HSCT with reduced intensity conditioning (RIC) or using cord blood as a donor source. Here, we tried to undergo retransplantation of bone marrow cells for 4 SCN patients with ELANE mutation who referred to our hospital because of the engraftment failure of initial HSCT. The summary of initial HSCT is shown in Table. The source of stem cells and the conditioning regimen were heterogenous in four patients. In this study we used bone marrow cells as stem cell source for all patients to transfuse the sufficiently total nucleated cells. Bone marrow cells were obtained from an HLA-matched related, an HLA-matched unrelated, and two HLA-mismatched unrelated (7/8) donors, respectively. Conditioning regimen consisted of fludarabine (125 mg/m2), cyclophosphamide (140 mg/kg), anti-thymocyte globulin (ATG, 10-12 mg/kg), melpharan (90 mg/m2), and TLI (3.6 Gy). Short-term methotrexate and tacrolimus were administered for the prophylaxis of graft versus host disease (GVHD). Engraftment of neutrophils was observed within post-transplant 21 days in all patients. Three of 4 patients have achieved complete engraftment without any signs of GVHD during their course. One patient required additional donor-lymphocyte infusion to sustain the stable engraftment. All patients are alive for 1 to 5 years after HSCT with no signs of infections or transplantation-related morbidity. Furthermore, we observed successful BMT using similar conditioning regimen in other 4 SCN patients without prior transplantation. In our cohort, sufficient administration of ATG is thought to be critical for preventing both engraftment failure and acute GVHD. These results suggest that bone marrow transplantation using fludarabine-based conditioning regimen with a sufficient dose of ATG may be a feasible and effective treatment for SCN patients irrespective of initial engraftment failure. Indications for proceeding to HSCT have been under discussion in patients with SCN. Accumulation of cases and further analysis are necessary to assess the efficacy and safety of this regimen including late complication related to HSCT.

Table. HSCT characterictecs at the initial transplantation Case 1 2 3 4 Etiology ELANE G185R ELANE V72M ELANE 4501-4503 del ELANE V72M Age at the time of HSCT 10 months 2 years 3 years 9 months 15 months Stem cell source cord blood bone marrow cord blood bone marrow HLA disparity mismatched unrelated donor (5/6) matched unrelated donor (6/6) matched related donor (6/6) mismatched unrelated donor (6/8) Transfused NCC (108/kg) 0.7 1.9 0.49 1 Transfused CD34 cells (106/kg) 0.699 1.9 0.07 1.07 Conditioning regimen BU 16, CY 120, Flu 120 CY 140, Flu 125, L-PAM 90 TBI 3, ATG 2.5 CY 100, Flu 120 TBI 3, ALG 40 Flu 125, L-PAM 140 TBI 2, ATG 5 Posttransplant day of rejection 72 days 55 days after 4 times of DLI 14 days one year after mixed chimerism DLI (times) 0 4 3 0

Busulfan (BU, mg/kg), Cyclophophamide (CY, mg/kg), Fludarabine (Flu, mg/m2), Melpharan (L-PAM, mg/m2), Total body irradiation

(TBI, Gy), Anti-thymoglobulin (ATG, mg/kg), Anti-lymphoglobulin (ALG, mg/kg), donor lymphocyte infusion (DLI)

Disclosures

No relevant conflicts of interest to declare.