Improved Grfs Observed in a Multicenter Prospective Study of Tcrαβ- and CD45RA-Depleted Haploidentical Transplant in Children with Acute Leukemia

Objective: To test the hypothesis that TCRαβ- and CD45RA-depleted haploidentical hematopoietic stem cell transplantation (HSCT) with a reduced-intensity conditioning regimen and short-course graft-versus-host disease (GVHD) prophylaxis in children with refractory/relapse/high-risk acute leukemia (AL) could reduce the incidence of acute/chronic GVHD without compromising the graft versus leukemia effect, resulting in improved GVHD-free/relapse-free survival (GRFS).

METHODS: The outcome of TCRαβ- and CD45RA-depleted haploidentical HSCT (TCD group) was compared with that of concurrent traditional haploidentical HSCT (control group) during the same time period. The proportion of cases in TCD group and control group was 1:2. The incidence of grade II-IV aGVHD, cGVHD, transplant-related mortality (TRM), CMV and EBV reactivation rate, leukemia relapse, overall survival (OS), event-free survival (EFS) were analyzed. GRFS was defined as patients survived without relapse, grade II-IV aGVHD, or moderate to severe cGVHD.

RESULTS: From November 2020 to May 2022, 28 patients were enrolled in the TCD group and 56 patients in the control group from three centers in China with median follow-up time of 8 months（range, 2.5-20）and 7.5 months（range, 0.5-20）, respectively. There were no statistically significant differences in age, gender, type of leukemia, pretransplant disease status, degree of HLA mismatch, and number of infused CD34+ cells between the two groups. The TCD group received a reduced-intensity conditioning with TBI 3Gy, -8D; cyclophosphamide 60mg/kg/D, -7D; fludarabine 40mg/m²/D, -7 to -4D; busulfan 3.2-4.8mg/kg/D, -5 to -4D; and melphalan 70mg/m²/D, -3 to -2D. GVHD prophylaxis lasted only 1 month with mycophenolate mofetil from -1D to +30D. The control group received a conventional T-cell replete haploidentical HSCT with myeloablative conditioning and GVHD prophylaxis. The median time of neutrophil and platelet engraftment was 10 days (range, 9-13) and 12 days (range, 9-56) respectively in the TCD group, which were both faster than the control group with 13 days (range, 8-20) and 18 days (range, 8-74) respectively (P < 0.05). The incidence of graft failure was higher in TCD group (5/28, 1 primary failure and 4 secondary failures) than in control group (2/56, all primary failures, P = 0.013). The incidence of grade II-IV aGVHD (22% vs 42.6%, P = 0.071) and cGVHD (10.0% vs 42.0%，P=0.010) were lower in the TCD group than the control group. None of the patients in the TCD group developed moderate or severe cGVHD or TRM. TCD group also have lower incidence of CMV or EBV reactivation and hemorrhagic cystitis compared to the control group (21.4% vs 49.1%, 18.5% vs 46.3%, and 10.7% vs 39.3%, all P<0.05). The relapse rates was comparable between the two groups (4/28 versus 6/56; P = 0.725). One patient died in the TCD group (who received a salvage haploidentical transplantation after graft failure, relapsed again half a year later, and then died of severe hemorrhagic cystitis after third HSCT). Seven (7/56) patients died of TRM in the control group. The 1-year OS (100% vs 85.8%±5.2%) and EFS (72.4%±9.0% vs 68.0%±8.3%) were similar between the two groups (P > 0.050), but the GRFS of TCD group was significantly better than the control group (63.3%±10.1% vs 35.3%±8.5%，P=0.036).

CONCLUSIONS: TCRαβ- and CD45RA-depleted HSCT engrafted faster with very low incidences of a/cGVHD，virus reactivation , and TRM. There was no apparent increased risk of relapse, resulting in an improved GRFS. Graft failure remains a problem but all patients could be successfully regrafted without additional TRM, in part because their general status remained relatively well after their initial reduced-intensity conditioning.

Leung:Miltenyi Biotech: Current Employment; BioMedicine: Current Employment.