Haploidentical STEM-Cell Transplantation for Children with ACUTE Leukemia and NON-Malignant Disorders, Using ΑΒ + T Cell /CD19 + B-Cell Depletion, a Single Center Experience
Authors: Dadi Gal , Toren Amos , Nagler Arnon 
Published: December 2023

Background:

αβ+ T cells/CD19+ B cells depleted haploidentical Hematopoietic stem cell transplantation (αβ+ TCR/ CD19+ depleted haplo-HSCT) is increasingly used in children with acute leukemia (AL) and many non-malignant disorders (NMD) such as severe combined immune deficiency (SCID), inborn errors of immunity (IEI), bone marrow failure (BMF, acquired/congenital) and familial Hemophagocytic lymphohistiocytosis (HLH), in need of a transplant and not having a matched related donor. Within this heterogenous group of patients, it is important to try to define introductory requirements for successful outcomes, and to identify risk factors for transplant related complications.

Methods: Data was collected retrospectively regarding children age &lt;21 years with AL or NMD who underwent αβ+ TCR/ CD19+ depleted haplo-HSCT at Sheba Medical Center between the years 2012-2021.

Results: Seventy-four children underwent αβ+ TCR/ CD19+ depleted haplo-HSCT, for AL and NMD.

Acute Leukemia subgroup

Thirty-eight children had AL of them 34 patients engrafted successfully.

The median time for neutrophil and platelet engraftment was 10 (range 9-17) and 13 (range 10-22) days, respectively.

We observed 5-years overall survival (OS) and event free survival of 51% and 42%, respectively for the whole cohort.

There were no cases of grade 3-4 acute graft versus host disease and only two patients had chronic graft versus host disease.

EFS was higher in patients with graft composition of γδ+ T cells greater than the median value (MV) of 9.5X10^6 cells/kg than in patients who recieved cell dose lower than MV (54% vs 26%, P=0.04).

Non-malignant Disorders

Thirty-six children had NMD. Twenty-six of them (72%) engrafted and ten did not (did not achieved neutrophil count above 500 cells/uL at day 30).

Engraftment kinetics was similar to AL subgroup. Secondary rejection was observed in two patients.

Conditioning regimen varied within this subgroup.

For patients with BMF, busulfan or treosulfan/fludarabine was administrated.

All patients with HLH conditioned with treosulfan/fludarabine/thiotepa regimen.

Patients with SCID, either did not recieved conditioning or received fludarabine/thiotepa/melphalan or treosulfan/fludarabin conditioning.

For patients with IEI the protocol was based on treosulfan/fludarabin/thiotepa.

Full donor chimerism was observed at day 30 in all patients who engrafted.

Five-year OS was 56% for the whole cohort. OS was higher for patients without active infection at the day of transplant compared to patients with active infection (91.7% vs 33%, respectively, p=6.4X10-4).

Mortality was high with thirteen patients dying from infection and one from veno-occlusive disease.

Cumulative incidence of aGVHD was 30% with the majority were no greater than grade 2 and for cGVHD was 19%.

Conclusions: αβ+/CD19+ haploidentical Hematopoietic stem cell transplantation can offer long-term survival for children with acute leukemia and NMD.

For children with AL, we observed a presumed protective role for higher content of γδ+ T cell in the graft which need to be evaluate prospectively in a larger cohort. There were no cases of severe GVHD and the rate of grade 1-2 GVHD was low.

For children with NMD αβ+ TCR/CD19+ depleted haplo-HSCT is feasible and effective. Children with active infections at day 0 had poorer outcomes whereas children without an active infection had excellent outcomes. Thus, patients who have a clear indication for transplant should be evaluated for transplant as early as possible.