Haploidentical Transplantation with Post-Transplant Cyclophosphamide in Children with Malignant and Non-Malignant Diseases

Background: HLA haploidentical stem cell transplantation with T-replete grafts and post-transplant immunosuppression with high-dose cyclophosphamide after reduced intensity conditioning has evolved into an increasingly accepted method of alternative donor transplantations in adults. Reported transplantation related mortality, GVHD and relapse rates are at least comparable to those of HLA matched donor transplantations.

Purpose: To assess the feasibility of this approach in children as a first or second allogeneic transplantation after myeloablative or reduced toxicity conditioning.

Patients/methods: Ten consecutive transplantations in children with either malignant (n=6) or non-malignant diseases (n=4) at a single institution transplanted with unmanipulated bone marrow from parental HLA haploidentical donors were analyzed. In the malignant cohort (3 ALL, 2 AML, 1 MDS) four patients were in advanced disease status (2 NR, 2 CR3) and three had received a prior allogeneic transplantation (2 relapses, 1 rejection). Conditioning in these patients was either TBI-VP16 (n=3) or myeloablative treosulfan-based (n=3). Among the non-malignant patients (2 IL10R deficiency, 1 sickle cell disease, 1 XIAP), one had rejected a prior T-cell depleted HLA haploidentical transplantation. These patients were conditioned with alemtuzumab, treosulfan, fludarabine ± thiotepa. All patients in both groups received cyclophosphamide 14,5mg/kg on days -3 and -2. GVHD prophylaxis consisted of cyclophosphamide 50mg/kg on days +3 and +4, tacrolimus and MMF from day +5. In the absence of GvHD MMF was stopped on day +35, tacrolimus tapered from day +60 (malignant) or day+100 (non-malignant).

Results: After a median follow-up of 6 months (1-25), 9 of 10 patients are fully engrafted, alive and free of disease. One patient with AML not in remission at transplantation died from pulmonary hemorrhage on day +24. He was also treated for CMV viremia pre-existing before transplantation. One ADV reactivation requiring pre-emptive treatment and no invasive fungal infections were noted in the other patients. Engraftment was recorded at a median of 17 days (neutrophils) and 26 days (platelets). Only in one patient transient acute skin GVHD (overall grade II) was observed, while no patient developed chronic GVHD. Mean CD3 counts of 310/µl, 937/µl and 1868/µl, CD4 115/µl, 291/µl and 1010/µl, CD8 176/µl, 589/µl and 802/µl and CD19 102/µl, 360/µl and 641/µl were measured on days +100, +180 and +365 respectively.

Conclusion: HLA haploidentical transplantation with post-transplant cyclophosphamide appears to be a safe and promising approach with very low GVHD rates and excellent immune reconstitution in children with malignant as well as non-malignant diseases. This may be combined with myeloablative as well as reduced toxicity conditioning regimes and is a promising approach even as a second allogeneic procedure after relapse or rejection following a first allogeneic transplant.