HLA-haploidentical hematopoietic stem cells transplantation with regulatory and conventional T-cell adoptive immunotherapy in pediatric patients with very high-risk acute leukemia

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is still needed for many children with very high-risk acute leukemia. An HLA-haploidentical family donor is a suitable option for those without an HLA-matched donor. Here we present outcomes of a novel HLA-haploidentical HSCT (haplo-HSCT) strategy with adoptive immunotherapy with thymic-derived CD4⁺CD25⁺ FoxP3⁺ regulatory T cells (Tregs) and conventional T cells (Tcons) performed between January 2017 and July 2021 in 20 children with high-risk leukemia. Median age was 14.5 years (range, 4-21), 15 had acute lymphoblastic leukemia, 5 acute myeloid leukemia. The conditioning regimen included total body irradiation (TBI), thiotepa, fludarabine, cyclophosphamide. Grafts contained a megadose of CD34+ cells (mean 12.4 × 10⁶/Kg), Tregs (2 × 10⁶/Kg) and Tcons (0.5-1 × 10⁶/Kg). All patients achieved primary, sustained full-donor engraftment. Only one patient relapsed (5%). The incidence of non-relapse mortality was 15% (3/20 patients). Five/20 patients developed ≥ grade 2 acute Graft versus Host Disease (aGvHD). It resolved in 4 who are alive and disease-free; 1 patient developed chronic GvHD (cGvHD). The probability of GRFS was 60 ± 0.5% (95% CI: 2.1-4.2) (Fig. 6), CRFS was 79 ± 0.9% (95% CI: 3.2-4.9) as 16/20 patients are alive and leukemia-free. The median follow-up was 2.1 years (range 0.5 months-5.1 years). This innovative approach was associated with very promising outcomes of HSCT strategy in pediatric patients.

Fig. 1. Transplantation schema.

Patients received myeloablative hyperfractionated total body irradiation and chemotherapy starting 15 days before CD34+ hematopoietic stem cell infusion. They received the donor Treg inoculum on day −4, the Tcon infusion on day −1 and the CD34+ infusion on day 0.

Fig. 2. Graft-versus-Host Disease.

Cumulative incidence of aGvHD (dashed line) and cGvHD (solid line) after transplantation.

Fig. 3. T-cell recovery after transplantation.

CD3+, CD4+, CD8+ and γδ T cells.

Fig. 4. Pathogen-specific T cell response.

CD4+ and CD8+ pathogen-specific frequencies in patients post-transplant and healthy donors.

Fig. 5. Non-relapse mortality (NRM) and relapse.

Cumulative incidences of NRM (solid line) and relapse (dashed line) considering as competing risks after transplantation.

Fig. 6. CRFS.

Grade ≥ 2 aGvHD/relapse-free survival after trasplantation.

Fig. 7. GRFS.

Estensive Chronic GvHD/relapse-free survival after transplantation.