AW-03. Graft failure after allogeneic stem cell transplantation in patients with hereditary storage diseases

Summary

Graft failure (GF), both primary (non-engraftment) and secondary one (rejection, mixed chimerism), represent a serious complication that significantly affects the results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in pediatric patients (pts) with hereditary storage diseases (HSD). Specification of GF risk factors and development of the GF prevention in pts with HSD is quite relevant. Our aim was to identify risk factors of GF after allo-HSCT in children with HSD.

Patients and methods

We retrospectively analyzed the data of 55 pediatric patients after allo-HSCTs performed at the RM Gorbacheva Research Institute from 2006 to 2023, with mucopolysaccharidosis type 1 (n=37), osteopetrosis (n=10), X-linked adrenoleukodystrophy (n=3), globoid cell leukodystrophy (n=3), metachromatic leukodystophy (n=1), Farber’s lipogranulomatosis (n=1). The median age at the time of allo-HSCT was 2.1 (0–15) years. The median time from diagnosis to allo-HSCT was 9.3 (1-52) months. Six allo-HSCTs were performed from a HLA-matched related donors, 44 – from an unrelated donors (35, fully HLA-matched; 9, HLA-mismatched 9/10; 5, from haploidentical donors. The graft source was bone marrow in 43 cases, and peripheral blood stem cells in 12 cases. Thirty-two pts received myeloablative conditioning, and 23 pts, non-myeloablative regimens. Graft-versus-host disease (GvHD) prophylaxis was based on antithymocyte immunoglobulin (ATG) in 18 pts, post-transplant cyclophosphamide (PTCy) was applied in 21 pts, and the combination of ATG and PTCy was used in 8 pts. Ex vivo graft manipulations were performed in 4 cases, i.e., CD34+ cell selection (n=3), and TCR alpha-beta and CD19 depletion (n=1).

Results

The follow-up period ranged from 1 to 144 (median 39.8) months. Forty-nine (89%) pts achieved neutrophil engraftment, with a median time of 19.5 (9-33) days. GF was diagnosed in 25 (45.5%) pts: in 6 (10.9%), primary GF; in 7 (14%), secondary GF with median time of 203 (67-1242) days; in 17 cases (35%), severe graft hypofunction was documented (with mixed chimerism in 15 cases). In 2 cases (4%), we traced persistence of mixed chimerism. The incidence of primary and secondary GF was significantly higher in the group of patients with osteopetrosis that in other HSDs: 50% (n=5) versus 18% (n=8), p=0.04, OR 4.63 (1.08-19.84). Incidence of severe graft hypofunction was significantly lower (21%, n=6) in the pts who received allo-HSCT later than 9.3 months after diagnosis when compared to the earlier HSCT terms (62%, n=13), p=0.008, OR 5.96 (1.69-21.03). The incidence of GF was significantly higher in the patients whose donors (known for 41 patients) were >29 years old (44%, n=18) compared to the cases with younger donors (9.7%, n=4), p=0.01, OR 6.19 (1.5-25.48). The compatibility of donors and recipients for HLA antigens and blood groups, as well as the stem cell source and graft cellularity, conditioning regimen, GvHD prophylaxis strategy did not show statistically significant associations with GF incidence. Meanwhile, the incidence of GF did not statistically influence the 5-year overall survival of patients with HSD (68% (n=25) versus 83.3% (n=30), p=0.183).

Conclusion

Graft failure (GF) most often occurs in pts with osteopetrosis in comparison with other HSD. Lower incidence of GF after allo-HSCT performed more then 9.3 months after diagnosis and hence age influence require clarification. Choosing of donors younger than 30 years reduces the incidence of GF in patients with HSD.

Keywords

Graft failure, non-engraftment, rejection, storage diseases.