T and B depleted haploidentical haematopoietic stem cells transplant (hapHSCT) for children with refractory haematological diseases

Abstract

For children with no suitable HLA-matched donors or cord blood but requiring haematopoietic stem cells transplant, the use of haploidentical donor is one of the possible options to consider. There are 3 approaches for hapHSCT, including: 1) non-manipulated bone marrow (BM) or peripheral blood stem cells (PBSC); 2) positive ex-vivo selected CD34 stem cells from BM or PBSC; & 3) BM or PBSC with negative ex-vivo depleted T & B cells. The non-manipulated BM & PBSC hapHSCT mainly used in-vivo ATG as T cells depletion. The engraftment rate has been reported to be satisfactory but it is associated with significant high acute and chronic GVHD rate (40 to 60%). The positive CD34 selected donor’s graft is associated with much less GVHD but delayed engraftment and high infectious risk due to prolonged immune reconstitution is a concern. The ex-vivo depleted CD3 T cells and CD19 B cells or ex-vivo depleted CD3 T cells with in-vivo CD20 B cells depletion approach has been used by several centres in recent years for children with refractory haematological illnesses. Due to the high stem cells dose from the haploid PBSC and selected depletion of T & B cells only, rapid engraftment; low GVHD rate and rapid immune reconstitution has been reported. We therefore adopted this CD3/CD19 ex-vivo depleted hapHSCT for our patients who failed after conventional HSCT. So far 5 children (4 with relapsed leukaemia & one with refractory aplastic anaemia) received CD3/CD19 depleted PBSC grafts from their parents in our unit. All patients engrafted and their neutrophil engraftment occurred within 14 days (range 11-14 days) and platelet engraftment occurred within 28 days (ranged 15-28 days). None developed Gr II-IV GVHD. Except one patient developed adenovirus associated haemorrhagic cystitis, none suffered from severe infection. However, all of these high risk patients relapsed subsequently and most relapse/rejection occurred within 6 months after the transplant. The relapse free survival of such 2nd transplant is lower than the expected 30-40% reported by Handgretinger R, et al. As comparison, we did not use KIR mismatch status as selection criteria and we also did not monitor the graft status weekly after transplant so no prophylactic DLI had been added back in our cohort. This may imply the importance of graft status monitoring especially during the early transplant period with this approach. Future effort should be directed at more specific T cells depletion so GVL effect can be retained.