Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment in eradicating high-risk acute myeloid leukemia (AML). Here, we present data from a novel HLA-haploidentical HSCT protocol that addressed the 2 remaining major unmet medical needs: leukemia relapse and chronic graft-versus-host disease (cGVHD). Fifty AML patients were enrolled in the study. The conditioning regimen included total body irradiation for patients up to age 50 years and total marrow/lymphoid irradiation for patients age 51 to 65 years. Irradiation was followed by thiotepa, fludarabine, and cyclophosphamide. Patients received an infusion of 2 × 106/kg donor regulatory T cells on day -4 followed by 1 × 106/kg donor conventional T cells on day -1 and a mean of 10.7 × 106 ± 3.4 × 106/kgpurified CD34+ hematopoietic progenitor cells on day 0. No pharmacological GVHD prophylaxis was administered posttransplantation. Patients achieved full donor-type engraftment. Fifteen patients developed grade ≥2 acute GVHD (aGVHD). Twelve of the 15 patients with aGVHD were alive and no longer receiving immunosuppressive therapy. Moderate/severe cGVHD occurred in only 1 patient. Nonrelapse mortality occurred in 10 patients. Only 2 patients relapsed. Consequently, at a median follow-up of 29 months, the probability of moderate/severe cGVHD/relapse-free survival was 75% (95% confidence interval, 71%-78%). A novel HLA-haploidentical HSCT strategy that combines an age-adapted myeloablative conditioning regimen with regulatory and conventional T-cell adoptive immunotherapy resulted in an unprecedented cGVHD/relapse-free survival rate in 50 AML patients with a median age of 53 years. This trial was registered with the Umbria Region Institutional Review Board Public Registry as identification code 02/14 and public registry #2384/14 and at www.clinicaltrials.gov as #NCT03977103.

Graphical abstract

Figure 1.

Transplantation schema. Patients received an age-adapted myeloablative conditioning regimen based on TBI, either fractionated (9 fractions delivered twice per day for 4.5 days; total dose, 13.5 Gy) or single dose of 8 Gy with lung shielding, for those age up to 50 years or based on TMLI for those age 51 to 65 years. TMLI was administered by helical tomotherapy in 9 fractions delivered twice per day for 4.5 days. TMLI target volumes were skeletal bones for total marrow irradiation (total dose, 13.5 Gy) and major lymph node chains and spleen for total lymphoid irradiation (total dose, 11.5 Gy). TBI or TMLI were followed by thiotepa (5-10 mg/kg), fludarabine (150-200 mg/m²), and cyclophosphamide (30 mg/kg). After conditioning, all patients received an infusion of 2 × 10⁶/kg donor Tregs on day −4 followed by 1 × 10⁶/kg Tcons on day −1 and a megadose of positively purified CD34⁺ hematopoietic progenitor cells on day 0. No pharmacological GVHD prophylaxis was administered posttransplantation.

Figure 2.

Outcomes of the whole cohort of patients. (A) Cumulative incidences of grade ≥2 aGvHD (purple line) and moderate/severe cGVHD (green line). (B) Cumulative incidences of relapse (red line) and NRM (green line). (C) Moderate/severe cGVHD/relapse-free survival by Kaplan-Meier curve after a median follow-up of 29 months (range, 8 days to 6 years). (D) Moderate/severe cGVHD/relapse-free survival according to type of conditioning regimen (gray line, TBI-based conditioning regimen; orange line, TMLI-based conditioning regimen).

Figure 3.

Outcomes of patients according to genetic risk at diagnosis and disease status at transplantation. (A) Cumulative incidence of NRM according to genetic risk at diagnosis (green line, favorable/intermediate genetic risk; red line, adverse genetic risk at diagnosis). (B) Cumulative incidence of relapse according to genetic risk at diagnosis (orange line, favorable/intermediate genetic risk; gray line, adverse genetic risk at diagnosis). (C) Moderate/severe cGVHD/relapse-free survival (by Kaplan-Meier curve) according to genetic risk at diagnosis (purple line, favorable/intermediate genetic risk [RISK⁻]; blue line, adverse genetic risk at diagnosis [RISK⁺]). (D) Cumulative incidence of NRM according to disease status at transplantation (red line, MRD⁺/active disease; green line, MRD⁻). (E) Cumulative incidence of relapse according to disease status at transplantation (lavender line, MRD⁺/active disease; orange line, MRD⁻). (F) Moderate/severe cGVHD/relapse-free survival according to disease status at transplantation (green line, MRD⁺/active disease; blue line, MRD⁻).