Pre-Emptive Immunotherapy for Clearance of Molecular Disease in Childhood Acute Lymphoblastic Leukemia after Transplantation

Abstract

Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for the cohort without IT and .69 ± .10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21 ± .05, 3-year CITRM, .10 ± .04; IT patients: 3-year CIR, .18 ± .09, 3-year CITRM .13 ± .07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.

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

“…Patients with a negative MRD early post‐transplant had a good EFS probability, which was even better for those who were still negative at the third trimester assessment, although one relapse was observed in this subgroup at more than 4 years after transplantation. However, as previously suggested (Balduzzi et al , ; Rettinger et al , ), low level MRD positivity after transplantation was not invariably associated with relapse. Indeed, children with MRD ≤ 1 × 10 −3 at the first and third trimester post‐transplant had an EFS of 30% and 44%, respectively.…”

Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia

“…In conclusion, we find that RQ‐PCR chimerism may be a useful tool for early prediction of relapse in children transplanted for AML and ALL, and thus an alternative to frequent sampling of bone marrow for MRD analysis. Using a very low cutoff of an increase of 0.05% recipient DNA could possibly identify children at high risk of relapse several months prior to overt relapse, leaving time for intensified follow‐up or therapeutic intervention in order to revert an impending relapse …”

“…Relapse is the primary cause of mortality after allogeneic HCT, with a CIR of 20%‐35% for childhood ALL and AML . Outcome following relapse post‐HCT remains dismal in spite of a possible second HCT .…”

“…Early detection and pre‐emptive treatment of impending relapse such as modifications of immunosuppression, donor lymphocyte infusion, or immune therapy may in some cases circumvent relapse . As the range of immunotherapies under investigation expands, early identification of imminent relapse becomes increasingly important …”

“…Increasing recipient chimerism has repeatedly been associated with increased risk of relapse in pediatric ALL and AML, although some studies have failed to reproduce these results . Moreover, therapeutic interventions based on changes in chimerism have been associated with increased OS and EFS . However, the use of chimerism analysis by STR‐PCR is limited by the relatively low sensitivity, since the presence of 1%‐5% recipient DNA in peripheral blood will often translate into overt relapse, thus limiting the window of opportunity for effective intervention.…”