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

Abstract

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=1014), 4–21 years old, transplanted from a matched donor who had ≥1 MRD measurement prior to and/or 100 days and/or 1 year after HSCT were eligible. A threshold of 0.01% defined MRD positivity versus negativity.

Prior to HSCT, 21% of patients were MRD_pos. 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 MRD_neg and MRD_pos patients, respectively. The level of MRD positivity pre-HSCT (<0.1% versus ≥0.1%), did not significantly affect outcome. Pre-HSCT MRD_neg and TBI/etoposide conditioning were associated with a 2-fold lower risk of relapse, whereas MRD_pos had a 2-fold higher risk of any failure and/or death. No detrimental effect of MRD_pos pre-HSCT could be demonstrated in patients with T-cell ALL. MRD_pos versus MRD_neg 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 MRD_pos 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.