Pre‐ and post‐transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia

Abstract

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre-HSCT and during the first and third trimesters after HSCT (post-HSCT1 and post-HSCT3). The overall event-free survival (EFS) was 50%. The cumulative incidence of relapse and non-relapse mortality was 41% and 9%. Any degree of detectable pre-HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10 and ≥1 × 10 , respectively, versus 73% in MRD-negative patients (P < 0·001). This effect was maintained in different disease remissions, but low-level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post-HSCT1 and post-HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre-emptive immuno-therapy.

Minimal residual disease status determined by multiparametric flow cytometry pretransplantation predicts the outcome of patients with ALL receiving unmanipulated haploidentical allografts

“…Moreover, we also identified pre‐MRD status as an independent predictor of LFS and OS whereby MRD negative patients showed clear superiority in achieving better LFS and OS compared to the MRD positive ones, either using 0% or 0.01% as cutoff values for positive and negative (Figure and Supporting Information Figure S1). In a recent study from Italy examining the outcomes of 119 transplanted pediatric patients with ALL, consisting of matched sibling donors (38%), matched unrelated donors (49%), and haploidentical donors (13%), positive pre‐MRD was shown to be a potent predictor of both CIR and event‐free survival . In UCBT settings, an analysis on behalf of the Eurocord, Cord Blood Committee and the Acute Leukemia working team of the European group for Blood and Marrow Transplantation showed that, for adult cases with Ph + ALL, 3‐year cumulative incidence of relapse was 45% in MRD + and 16% in MRD − patients ( P = 0.013).…”

Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience

“…Such factors cannot be reliably compared in three different retrospective studies, but some differences can be discussed. The HCT indication differed between the studies; in our cohort there were no PhALL cases and the HCT indication at the end of consolidation was MRD ≥10 À3 in the NOPHO versus 5 9 10 À4 in the BFM-Associazione Italiana di Ematologia e Oncologia Pediatrica (AEIOP) protocols in the two studies reported by Lovisa et al (2018) and Sutton et al (2015). Yet, these differences may not play a major role due to the relatively small difference in the MRD cut-off and the fact that PhALL patients are considered a low risk group within very high-risk patients (Pulsipher et al, 2014).…”

“…The association between MRD and relapse following HCT is well established in mixed remission cohorts (Knechtli et al , ; Sramkova et al , ; Bader et al , ; Balduzzi et al , ), but very sparse data exist regarding the influence of pre‐HCT MRD in putatively heterogenous CR1 cohorts. Two recent studies analysed the MRD dynamics pre‐ and post‐HCT in a total of 43 and 41 children, respectively, transplanted in CR1 according to national protocols (Sutton et al , ; Lovisa et al , ). In these cohorts, the fraction of MRD negative patients was markedly lower than in our cohort, 47% and 52% respectively.…”

“…In these cohorts, the fraction of MRD negative patients was markedly lower than in our cohort, 47% and 52% respectively. In the Italian study from three major HCT‐centres, patients with an MRD ≥10 −3 all relapsed, whereas those with MRD <10 −3 had a good EFS of 63% (Lovisa et al , ). In the Australian study, the MRD‐positive patients had a significantly inferior EFS of 38% vs. 80% in the MRD‐negative group.…”

“…However, the role of pre‐HCT MRD may vary according to HCT settings. Thus, in a recent retrospective analysis of pre‐HCT MRD, it was suggested that the association between relapse risk and low MRD pre‐HCT was present in the CR2, rather than in the CR1‐cohort (Lovisa et al , ). Furthermore, the impact of alloreactivity may influence the role of low MRD prior to HCT, as evidenced by the prospective Berlin‐Frankfurt‐Münster (BFM) trial ALL‐BFM‐SCT 2003 in which MRD pre‐HCT was not significantly associated with relapse risk (Bader et al , ).…”