Impact of conditioning regimen on outcomes of adolescents and young adults AML patients undergoing HCT in complete remission, with transplant conditioning intensity score of 3.5-4.0. a study from the acute leukemia working party of the european society for blood and marrow transplantation.

Abstract The optimal myeloablative conditioning regimen for adolescents and young adults (AYA) with acute myeloid leukaemia (AML) is currently unknown. In this retrospective analysis conducted on AML patients aged 18-40 years, in complete remission (CR), who received an allogeneic hemopoietic cell transplantation (HCT) and were reported to the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation database, we compared outcomes of different conditioning regimens. Patients transplanted from 2010 to 2022, from both HLA-matched related and unrelated donors, that had received one of four regimens: high-dose total body irradiation (TBI)-based (n=1031), thiotepa-busulfan (Bu)-fludarabine (Flu) (TBF) n=219), Bu-Flu (n=1100), and Bu-cyclophosphamide (Cy) (n=1973). All of them had a high transplant conditioning intensity score of 3.5-4.0.A total of 4323 patients with a median age of 30.9 years were included in the analysis. Noticeable differences among the four groups included: year of HCT, in vivo T-cell depletion, donor and patient cytomegalovirus serology, Karnofsky performance status score, cytogenetic risk, type of donor, disease status. Graft-versus-host disease (GvHD) prophylaxis was calcineurin inhibitor-based. Median follow-up for the entire population was 3.1 (95% CI 1.4-5.8) years. Outcomes were censored at 2-years. Two-year overall survival (OS) and progression-free survival (PFS) were as follows: 69.3% (95% CI 66.2-72.2) and 60.9% (95% CI 57.5-64) for TBI-based regimens; 81.2% (95% CI 73.9-86.6) and 71.6% (95% CI 63.5-78.2) for TBF; 74.4% (95% CI 71.3-77.3) and 65.1% (95% CI 61.6-68.3) for Bu-Flu; and 74.1% (95% CI 71.8-76.3) and 62.2% (95% CI 59.7-64.7) for Bu-Cy, respectively. Two-year cumulative incidence of disease relapse (RI) and non-relapse mortality (NRM) were: 29.5% (95% CI 26.5-32.5) and 9.7% (95% CI 7.8-11.7) for TBI; 22.8% (95% CI 16.3-29.9) and 5.7% (95% CI 2.7-10.1) for TBF; 27.3% (95% CI 24.2-30.5) and 7.7% (95% CI 6-9.6) for Bu-Flu; 29.4% (95% CI 27.1-31.7) and 8.4% (95% CI 7.1-9.9) for Bu-Cy, respectively. GvHD-free, relapse-free survival was: 45.9% (95% CI 42.6 – 49.2) for TBI, 58.8% (95% CI 50.5 – 66.1) for TBF, 48% (95% CI 44.5 – 51.4) for Bu-Flu, and 45.1% (95% CI 42.5 – 47.6) for Bu-Cy. The multivariate analysis confirmed prolonged OS and PFS for Bu-Flu (hazard ratio HR 0.73, CI 95% 0.57-0.92, p=0.008; HR 0.78, 95% CI 0.64-0.94, p=0.01), and TBF (HR 0.59, 95% CI 0.38-0.92, p=0.02; HR 0.67, 95% CI 0.47-0.94, p=0.02), respectively, as well as less RI for both Bu-Flu (HR 0.77, 95% CI 0.63-0.95, p=0.01), and TBF (HR 0.68, 95% CI 0.47-0.99, p=0.046). As expected, NRM was positively influenced by year of HCT by 5 years increment (HR 0.69, 95% CI 0.56-0.84, p0.001) and increasing patient age at HCT (HR 1.07, 95% CI 1.03-1.11, p=0.002). Poor risk cytogenetics was associated with worse OS (HR 2.25, 95% CI 1.87-2.72, p0.001), PFS (HR 1.94, 95% CI 1.65-2.27, p0.001) and higher RI (HR 2.11, 95% CI 1.77-2.51, p0.001). Patients in CR2 experienced worse OS (HR 1.46, 95% CI 1.24-1.72, p0.001), PFS (HR 1.37, 95% CI 1.19-1.58, p0.001), higher RI (HR 1.31, 95% CI 1.11-1.55, p0.001) and NRM (HR 1.53, 95% CI 1.16-2.02, p=0.003) compared with those in CR1. Patients grafted from unrelated donors showed less RI (HR 0.79, 95% CI 0.66-0.93, p=0.005) at the expense of higher NRM (HR 1.46, 95% CI 1.06-2.02, p=0.02), and grade III/IV acute GvHD (HR 1.69, 95% CI 1.24-2.31, p0.001). Patients conditioned with Bu-Flu experienced less grade II/IV (HR 0.62, 95% CI 0.48-0.80, p0.001) and grade III/IV acute GvHD (HR 0.63, 95% CI 0.41-0.96, p=0.03), and less extensive chronic GvHD (HR 1.66, 95% CI 1.19-2.31, p=0.002). The female to male combination was associated with risk of extensive chronic GvHD (HR 1.36, 95% CI 1.09-1.7, p=0.006), as well as in vivo T-cell depletion which was associated with less grade II/IV (HR 0.63, 95% CI 0.51-0.76, p0.001) and grade III/IV acute GvHD (HR 0.45, 95% CI 0.43-0.61, p0.001), overall (HR 0.51, 95% CI 0.43-0.60, p0.001) and extended chronic GvHD (HR 0.36, 95% CI 0.28-0.47, p0.001). In conclusion, AYA AML patients seem to benefit from high dose TBI-free regimens, in terms of survival and toxicity, with four major myeloablative regimens. TBF and Bu-Flu were associated with better clinical outcomes, partly reflecting the general improvement in supportive therapies and patient selection introduced in recent years. Prospective clinical trials are warranted.