Combined haploidentical and cord blood transplantation for refractory severe aplastic anaemia and hypoplastic myelodysplastic syndrome

Abstract

Umbilical cord blood (UCB) transplantation is a potentially curative treatment for patients with refractory severe aplastic anaemia (SAA), but has historically been associated with delayed engraftment and high graft failure and mortality rates. We conducted a prospective phase 2 trial to assess outcome of an allogeneic transplant regimen that co-infused a single UCB unit with CD34⁺ -selected cells from a haploidentical relative. Among 29 SAA patients [including 10 evolved to myelodysplastic syndrome (MDS)] who underwent the haplo cord transplantation (median age 20 years), 97% had neutrophil recovery (median 10 days), and 93% had platelet recovery (median 32 days). Early myeloid engraftment was from the haplo donor and was gradually replaced by durable engraftment from UCB in most patients. The cumulative incidences of grade II-IV acute and chronic graft-versus-host disease (GVHD) were 21% and 41%, respectively. With a median follow-up of 7·5 years, overall survival was 83% and GVHD/relapse-free survival was 69%. Patient- and transplant-related factors had no impact on engraftment and survival although transplants with haplo-versus-cord killer-cell immunoglobulin-like receptor (KIR) ligand incompatibility had delayed cord engraftment. Our study shows haplo cord transplantation is associated with excellent engraftment and long-term outcome, providing an alternative option for patients with refractory SAA and hypoplastic MDS who lack human leucocyte antigen (HLA)-matched donors.

Keywords: allogeneic stem-cell transplantation; haploidentical transplant; natural killer cell killer-cell immunoglobulin-like receptor ligand incompatibility; severe aplastic anaemia; umbilical cord blood.

Fig 1.

Cumulative incidence of neutrophil and platelet recovery. (A) neutrophil recovery; (B) platelet recovery.

Fig 2.

Chimaerism and cord engraftment. (A) Median per cent myeloid chimaerism; (B) cumulative incidence of cord engraftment [cord absolute neutrophil count (ANC) ≥ 500/μl] and full cord myeloid chimaerism; (C) median per cent T-cell chimaerism; (D) cumulative incidence of full cord T-cell chimaerism; (E) cumulative incidence of cord engraftment (cord ANC ≥ 500/μl) by haplo-vs-cord KIR ligand incompatibility (E) and by haplo-vs-cord KIR ligand incompatibility and cord human leucocyte antigen match to the recipient (F).

Fig 3.

Immune reconstitution of lymphocytes, T-cells, NK- cells, B-cells and immunoglobulin levels. (A) absolute lymphocyte count, (B) CD3 T-cells, (C) CD4 T-cells, (D) CD8 T-cells, (E) NK cells, (F) CD19 B-cells, (G) IgA levels, (H) IgG levels.

Fig 4.

Cumulative incidence of GVHD, overall survival, and GVHD/relapse-free survival (GRFS). (A) acute GVHD, (B) chronic GVHD, (C) overall survival, (D) GRFS. Dash lines in (C-D) indicated the 95% confidence interval for overall survival and GRFS.