Monitoring of Minimal Residual Disease After Allogeneic Stem Cell Transplantation In Relapsed Childhood ALL Allows The Identification Of Impending Relapse - Results Of The ALL BFM SCT 2003 Trial
Authors: Bader Peter , Kreyenberg Hermann , von Stackelberg Arend , Eckert Cornelia , Roland Meisel , Ulrike Pötschger , Stachel Daniel , Schrappe Martin , Schrauder Andre , Schulz Ansgar , Lang Peter , Mueller Ingo , Albert Michael H. , Klingebiel Thomas , Peters Christina 
Published: October 2019

Abstract

Purpose
Monitoring of minimal residual disease (MRD) after allogeneic stem cell transplantation (allo-SCT) by quantitative real-time PCR (qRT-PCR) of rearranged Ig- and TCR-genes may highlight patients with highest risk for relapse to whom pre-emptive treatment may be offered.

Patients and Methods
In the prospective phase 3 trial ALL-SCT-BFM-2003 (recruitment period 09/2003 to 09/2011; time point of analysis May 2013), MRD was assessed in bone marrow immediately on days +30, +60, +100, +200 and +365 post transplantation in 115 patients. Of these, 48 were male and 67 were female patients. All received a myeloablative conditioning regimen with TBI and VP 16. Patients received their transplant in CR2 (n=94), CR3 (n=21), CR4 (n=1) or NR (n=2). The transplantations were performed with bone marrow from matched sibling donors (MSD, n=23), matched unrelated donors (MUD, n=71) or with T-cell depleted stem cells from mismatched donors (MMD, n=21). Fifty-four patients were younger than 10 and 61 patients were older than 10 years at the time of transplant.
Standardized quantification of MRD was performed according to the guidelines of the Euro-MRD-Group and MRD results were not released to the clinicians.

Results
The total group of patients showed a pEFS of 0.52±0.10; cumulative incidence of relapse (CIR) and cumulative incidence of treatment related mortality (CI TRM) was 0.41±0.11 and 0.19±0.09, respectively. In 76 patients, MRD could also be assessed prior to transplant: patients who were MRD negative (n=41) had a three year pEFS of 0.62±0.04, patients with a MRD load of <10E-3 (n=28) of 0.49±0.14 and none of the patients who were MRD positive >1E-3 survived their disease. MRD values post transplant were analyzed as time-dependent covariates. When analyzed either for the different time points or for the highest MRD value post transplant, MRD results had always significant influence on survival. Taken the highest MRD value post transplant, probabilities of pEFS and CIR were 0.65±0.11 and 0.23±0.09 for MRD negative patients (n=72), 0.36±0.18 resp. 0.75 ±0.18 for patients with MRD <10-3 (n=36) compared to 0.00±0.0 and 1.0±0.0 in patients who developed MRD ≥10-3 leukemic cells (n=07) (pEFS, P<0.0001; CIR, P<0.0001). In multivariate cox regression analysis, MRD prior and post transplantation, as well as indication for SCT, significantly influenced the probability of survival. It is noteworthy, that all patients who developed a MRD load of >10E-3 at any time after transplant finally developed relapse and died. However, 49% of patients who became MRD positive <10E-3 did not necessarily develop frank relapse. Here, dynamic evolution needs to be considered as 9/15 patients with an MRD load of <10E-3 at day 200 survived. However, if MRD was not cleared by day 365 all patients finally relapsed.

Conclusion
Assessment of MRD post transplant allows the identification of patients with impending relapse. All patients who developed MRD >10E-3 at any time post transplant finally relapsed. Therefore, MRD may serve as an endpoint for further pre-emptive therapies.

Acknowledgment
This trial was supported by the “Deutsche Knochenmarkspender Datei” (DKMS).

Disclosures:
No relevant conflicts of interest to declare.