Impact of minimal residual disease on the outcome of hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia within the FORUM trial.

In the randomized cohort of the international phase-III FORUM trial, which showed the superiority of total-body irradiation (TBI) over chemotherapy-based conditioning prior to hematopoietic stem cell transplantation (HSCT) for pediatric acute lymphoblastic leukemia (ALL), type of conditioning and remission phase, but not pre-HSCT minimal residual disease (MRD), were associated with outcome. We report the impact of MRD within the extended FORUM cohort. Patients (N=1,014) aged 4-21 years old, transplanted from a matched donor who had ≥1 MRD measurement prior to and/or 100 days and/or one year after HSCT were eligible. A threshold of 0.01% defined MRD positivity versus negativity. Prior to HSCT, 21% of patients were MRDpos. Three-year event-free survival (EFS) was 0.73 and 0.59 (P<0.001), and 3-year cumulative incidence of relapse (CIR) was 0.20 and 0.33 (P<0.001) in MRDneg and MRDpos patients, respectively. The level of MRD positivity pre-HSCT (<0.1% vs. ≥0.1%) did not significantly affect outcome. Pre-HSCT MRDneg and TBI/etoposide conditioning were associated with a 2-fold lower risk of relapse, whereas MRDpos had a 2-fold higher risk of any failure and/or death. No detrimental effect of MRDpos pre-HSCT could be demonstrated in patients with T-cell ALL. MRDpos versus MRDneg patients at day 100 had an EFS of 0.47 versus 0.77 (P<0.001) and a CIR of 0.51 versus 0.17 (P<0.001), respectively, but post-HSCT MRDpos did not necessarily imply relapse. In conclusion, the MRD status pre-HSCT and at day 100 post-HSCT was a strong prognostic factor for children transplanted for ALL in the extended FORUM cohort.