Molecular Response to Treatment Predicts Outcome in Isolated, but Not in Combined Bone Marrow Relapses of Childhood Acute Lymphoblastic Leukaemia: Interim Results of Trial ALL-REZ BFM 2002
Authors: Eckert Cornelia , Stackelberg Arend , Hagedorn Nikola , Barth Andrea , Seeger Karl , Henze Guenter 
Published: April 2020

Abstract
In the current trial ALL-REZ BFM 2002 for treatment of children with relapsed acute lymphoblastic leukemia (ALL) assessment of minimal residual disease (MRD) has been applied to quantify response to induction therapy at a submicroscopic level in children with intermediate-risk relapsed ALL aiming to stratify treatment, and improve survival. Time point of measurement of molecular response to therapy in bone marrow (BM) and the MRD cut-off used are based on a prospective blinded MRD-study performed during the previous trial ALL-REZ BFM 96. Further, in order to gain new experiences about a possible control of post-induction treatment, MRD reduction kinetics have been measured during treatment until stem cell transplantation (SCT) or end of maintenance therapy. MRD-quantification has been performed using quantitative real-time PCR with clone-specific T-cell receptor/Immunoglobulin gene rearrangements. Between 01/2002 and 08/2008, in 161 patients with intermediate risk (S2) including late isolated BM relapses and early or late combined BM relapses of B-cell precursor ALL, MRD after the second induction course (block F2) was used for post-induction treatment stratification. About half of intermediate risk patients with BM involvement showed a poor response to therapy (MRD ≥10−3 after F2) and were thereupon allocated to SCT. Probability of event-free survival of these patients is 48% (SE [standard error] ±8.5%) in the current ALL-REZ BFM 2002 trial compared to 18% (SE±6.5%) in the previous trial ALL-REZ BFM 96. MRD reduction kinetics until SCT were very heterogeneous in the poor response group. About 10% of this group presented as molecular non-responder with a persisting MRD-level of ≥10−2 after the 5th treatment block. In comparison to the previous trial, in the current trial the proportion of early relapses which includes only combined relapses among S2 patients was higher (20%) in the group with a molecular good response (MRD &lt;10−3 after F2) than in the group with MRD poor response (7%, p=0.018). Subsequent relapses in patients with MRD good response occurred mainly among combined relapses. Therefore, the probability of event-free survival of molecular good responders among isolated BM relapses was 86% (SE±6.6%), but among combined bone marrow relapses only 41% (SE±13.5%). Concerning the extramedullary compartment involved the ratio between central nervous system and testes changed from 1:1 in the ALL-REZ BFM 96 trial to 2.8:1 in the ALL-REZ BFM 2002 trial. In conclusion, the hypothesis that the prognosis of S2-patients with poor MRD-response can be improved by allogeneic SCT seems to be confirmed in the current trial. MRD is a reliable marker for quantification of response to therapy in the BM, but not in case of extramedullary involvement. In future trials, this observation might result in a modification of clinical decisions. Furthermore, we are analysing the dynamic of treatment-response including all quantitative MRD-values from diagnosis until SCT in order to establish a more comprehensive individual risk-score.