Abstract
Introduction: HCT is an established curative treatment for children, adolescents, and young adults (CAYA) with high-risk/relapsed B-ALL. Inclusion of TBI in HCT conditioning has been shown to be superior to non-TBI approaches for B-ALL, but is associated with significant late effects. Based upon retrospective data showing low rates of relapse, we hypothesized that patients with negative pre-HCT MRD by next-generation-sequencing of IgH B-cell receptor rearrangements (NGS-MRD) could achieve 2-year EFS exceeding 75% with a non-TBI regimen, an outcome comparable to those receiving TBI-based regimens.
Methods: The Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) conducted a phase II prospective trial at 45 Centers in North America (ONC1701 EndRAD: NCT03509961) between 2018 and 2025 to evaluate outcomes of myeloablative non-TBI conditioning regimens for allogeneic HCT in B-ALL patients at lower risk for relapse defined by absence of NGS-MRD (Clonoseq) of B-cell receptor rearrangements (BCR) just prior to HCT. Eligibility criteria included age >/= 1 year to <31 years, first or second complete remission status (CR1/CR2), and no isolated or combined CNS disease at relapse. Prior blinatumomab, inotuzumab ozogamicin, or CAR-T treatments were allowed. All graft sources were permitted. Mismatched related/haploidentical grafts received post-transplant cyclophosphamide or TCRαβ/CD19 depletion according to institutional preference. All patients received myeloablative non-TBI conditioning. Graft-versus-host disease (GVHD) prophylaxis was according to graft source and institutional standards.
Results: Fifty-one patients (51% males) in CR1 (49%) or CR2 (51%) status received HCT. Median age (range) at initial diagnosis and HCT were 11.9 (1.2-28.1) and 13.5 (2.3-32.5) years, respectively. Of patients enrolled, 33% were White/Non-Hispanic, 37% Hispanic, 12% Black or African American, and 18% other. Prior to HCT, 28 patients (55%) received blinatumomab, 1 (2%) received inotuzumab, while 11 (21%) received CAR-T, 7 (14%) received 2 prior immunotherapies, and 4 (8%) had no prior immunotherapy.Forty-four patients (86%) received the preferred study non-TBI conditioning regimen (busulfan, fludarabine, thiotepa); 2 comparable allowed regimens were received: fludarabine, melphalan, and thiotepa by 3 patients (6%) and melphalan, fludarabine, clofarabine, and thiotepa by 4 patients (8%). Donors included HLA matched siblings (41%), mismatched related/haploidentical (33%), matched unrelated (18%), or unrelated cord blood (8%). Related and unrelated donor graft sources were 71% bone marrow and 21% peripheral blood stem cells. Transplant-related mortality in the first 100 days post-HCT was low at 2%. At a median follow up of 2.3 (range: 0.2-6.0) years, the 2-year OS and EFS (alive/relapse-free) were 82% (95% CI: 67.1%, 90.6%) and 76.3% (95% CI: 61.1%, 86.1%), respectively. Five patients (10%) who were pre-HCT NGS-MRD negative by BCR had detectable T-cell receptor sequences (BCR-/TCR+); all 5 are alive and relapse-free. Non-relapse mortality (NRM) was 12% (6 patients, 0.1-2.9 years from HCT to NRM) and occurred predominantly in older children (4 (67%) >/=14 yrs old). Relapses occurred in 6 children, with 4 (67%) undergoing HCT in CR2. Four of the six relapses occurred after matched sibling donor HCT. Acute GVHD occurred in 20 patients (39%, with 15 (75%) grade 1-2 and 5 (25%) grade 3-4). Chronic GVHD occurred in 13 patients (25%) (11 (85%) requiring systemic immunosuppressive treatment).
Conclusions: The primary endpoint of our study was met with the 2-year EFS exceeding 75% following non-TBI conditioning and allogeneic HCT in pre-HCT NGS-MRD negative B-ALL. OS in our cohort is comparable to published Center for International Blood & Marrow Transplant Research (CIBMTR) results in B-ALL where patients receive TBI-based conditioning. Our results show that pre-HCT NGS-MRD can be used to allow the choice of myeloablative non-TBI preparative regimens for CAYA undergoing allogeneic HCT that may result in decreased late effects. Additional analyses to be reported at the meeting will more fully investigate factors that impact post-HCT outcomes, including baseline cytogenetics/genomics and post-HCT bone marrow and peripheral blood NGS-MRD, along with planned comparisons to an observational cohort (n=146) enrolled on the trial including infants and older patients treated non-TBI approaches and older children treated with TBI-based regimens.
