Unrelated donor α/β T cell– and B cell–depleted HSCT for the treatment of pediatric acute leukemia

Abstract

Unrelated donor (URD) hematopoietic stem cell transplant (HSCT) is associated with an increased risk of severe GVHD. TCRαβ/CD19 depletion may reduce this risk, while maintaining graft-versus-leukemia. Outcome data with TCRαβ/CD19 depletion generally describes haploidentical donors, with relatively few URDs. We hypothesized that TCRαβ/CD19-depletion would attenuate the risks of GVHD and relapse for URD HSCT. Sixty pediatric and young adult (YA) patients with hematologic malignancies who lacked a matched-related donor were enrolled at two large pediatric transplantation centers between 10/2014 and 09/2019. All patients with acute leukemia had minimal residual disease testing and DP typing was available for 77%. All patients received myeloablative TBI- or busulfan-based conditioning with no post-transplant immune suppression. Engraftment occurred in 98%. Four-year overall survival was 69% (95%CI 52-81%) and leukemia-free survival was 64% (95%CI 48-76%), with no difference between lymphoid and myeloid malignancies (p=0.6297 and p=0.5441, respectively). One patient (1.7%) experienced primary graft failure. Relapse occurred in 11 patients (3-year cumulative incidence 21%, 95%CI 11-34), and 8 patients (cumulative incidence 15%, 95%CI 6.7-26) experienced non-relapse mortality. Grade III-IV acute GVHD was seen in 8 patients (13%), and 14 patients (26%) developed chronic GVHD, of which 6 (11%) had extensive disease. Non-permissive DP mismatch was associated with higher likelihood of acute GVHD (OR 16.50, 95%CI 1.67-163.42, p=0.0166), but not with the development of chronic GVHD. URD TCRαβ/CD19-depleted peripheral HSCT is a safe and effective approach to transplantation for children/YAs with leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02323867.

Controversies and expectations for the prevention of GVHD: A biological and clinical perspective

“…As expected with αß TB cell depletion, the rates of viral reactivation were higher than matched transplant approaches. Those reporting viral reactivations reported consistent rates of 40-65% of patients experiencing reactivations, with 20-65% reactivating CMV, 0-44% EBV, up to 57% adenovirus, 21% HHV6, and 23% BK virus ( 129 – 134 , 136 – 142 ). A large retrospective review showed the incidence of CMV and EBV reactivation were 53% and 33% respectively after αß TB cell depletion and associated with aGVHD ( 147 ).…”

“…Overall, this has been observed with median rates of grade II-IV aGVHD of 18% (ranging from 11-28%), and cGVHD of 8% (range 0-30%), with 0-21% experiencing extensive cGVHD ( 129 – 144 ). Notably, most of these studies utilized ATG, which has reduced aGVHD (see above), and not surprisingly, in one study in which ATG was removed, the observed rates of aGVHD were increased ( 136 ). The relapse rates ranged from 18-30% for those utilizing αßTB depleted HCT for the treatment of hematologic malignancies, comparable overall to other approaches ( 129 , 135 – 137 , 141 , 143 , 144 ).…”

“…The relapse rates ranged from 18-30% for those utilizing αßTB depleted HCT for the treatment of hematologic malignancies, comparable overall to other approaches ( 129 , 135 – 137 , 141 , 143 , 144 ). These data are confounded by a difference in the conditioning regimen; most have included myeloablative total body irradiation for all hematologic malignancies, a difference from other regimens that could potentially diminish relapse through greater leukemia clearance ( 129 , 136 , 137 , 141 ). One study of αßTB depleted HCT included matched unrelated donors and removed ATG from this preparative regimen due to increased relapsed rates with subsequent associated higher rates of aGVHD, suggesting that this preparative regimen may be best used in the haplo-identical setting ( 136 ).…”

“…These data are confounded by a difference in the conditioning regimen; most have included myeloablative total body irradiation for all hematologic malignancies, a difference from other regimens that could potentially diminish relapse through greater leukemia clearance ( 129 , 136 , 137 , 141 ). One study of αßTB depleted HCT included matched unrelated donors and removed ATG from this preparative regimen due to increased relapsed rates with subsequent associated higher rates of aGVHD, suggesting that this preparative regimen may be best used in the haplo-identical setting ( 136 ). This approach has been used for the treatment of relapsed refractory acute myeloid leukemias, without ATG, substituting tocilizumab therapy (anti-IL6), and scheduled CD45ra immature T cell depleted infusions with or without hypomethylating therapy.…”

Prospective PTCTC trial of myeloablative haplo-BMT with posttransplant cyclophosphamide for pediatric acute leukemias

“…The pediatric BMT community has expressed general concern regarding the CuI of relapse using PTCy. The CuI of relapse reported in published studies using haploidentical donors, MUDs, cord, and matched sibling donors has ranged from 12% to 70% 15 , 44 , 45 , 46 , 51 , 56 , 57 , 58 , 59 , 60 with pre-BMT MRD positivity and a high DRI associated with a higher incidence of relapse. The CuI of relapse of 32% and 36% at 1 and 2 years, respectively, in our small, multicenter study, with lower but not statistically significant CuI of relapse in MRD negative and low-intermediate DRI patients, is directly comparable with that reported in the pediatric BMT published literature and does not support that haplo-BMT with PTCy is inferior.…”