Bone Marrow Transplantation (2020) 55:1410–1420 https://doi.org/10.1038/s41409-020-0801-0 ARTICLE Monitoring minimal residual/relapsing disease after allogeneic haematopoietic stem cell transplantation in adult patients with acute lymphoblastic leukaemia Klaus Wethmar 1 ● Svenja Matern 1 ● Eva Eßeling 1 ● Linus Angenendt 1 ● Heike Pfeifer 2 ● Monika Brüggemann 3 ● Patrick Stelmach 1 ● Simon Call 1 ● Jörn C. Albring 1 ● Jan-Henrik Mikesch 1 ● Christian Reicherts 1 ● Christoph Groth 1 ● Christoph Schliemann 1 ● Wolfgang E. Berdel 1 ● Georg Lenz 1 ● Matthias Stelljes 1 Received: 30 August 2019 / Revised: 14 December 2019 / Accepted: 16 January 2020 / Published online: 30 January 2020 © The Author(s), under exclusive licence to Springer Nature Limited 2020 Abstract Relapse after allogeneic haematopoietic stem cell transplantation (SCT) is a major cause of death in patients with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed the contributions of lineage-sorted donor cell chimerism (sDCC) and quantitative PCR (qPCR) targeting disease-specific genetic rearrangements to detect minimal residual/relapsing disease (MRD) and predict impending relapse in 94 adult ALL patients after SCT. With a median follow-up of surviving patients (n = 61) of 3.3 years, qPCR and/or sDCC measurements turned positive in 38 patients (40%). Of these, 22 patients relapsed and 16 remained in complete remission. At 3 years, qPCR and/or sDCC positive patients showed an increased incidence of relapse (50% vs. 4%, p < 0.0001), decreased relapse-free survival (RFS, 40% vs. 85%, p < 0.0001), and decreased overall survival (OS, 47% vs. 87%, p 0.004). Both, qPCR and sDCC pre-detected 11 of 21 relapses occurring within the first two years after SCT and, overall, complemented for each other method in four of the relapsing and four of the non-relapsing cases. Patients receiving pre-emptive MRD-driven interventions (n = 11) or not (n = 10) showed comparable median times until relapse, RFS, and OS. In our single centre cohort, qPCR and sDCC were similarly effective and complementary helpful to indicate haematological relapse of ALL after SCT. Introduction Adult patients with Philadelphia chromosome/BCR-ABL1 negative B-cell precursor ALL (Ph neg. ALL) receiving an allogeneic SCT in first complete remission (CR1) show a 2- year overall survival (OS) of 60–76% [1]. After relapse, survival rates are poor, with a median OS of 4.4 months following chemotherapy [2] and 7.7 months following antibody-based salvage regimens [3, 4]. Sensitive and spe- cific detection of minimal residual/relapsing disease after allogeneic SCT may allow prevention of overt relapses by early interventions, including withdrawal/reduction of immunosuppressive therapy, donor lymphocyte infusion (DLI), targeted inhibition of tyrosine kinases, and antibody- based therapies [3–8]. In ALL patients MRD is commonly monitored by quantitative polymerase chain reactions targeting clonal rearrangements of the immunoglobulin (Ig) and T-cell receptor genes (TR), or targeting other disease-specific genetic aberrations, including rearrangements/deletions of BCR-ABL1, KMT2A, or IKZF1 [5, 9, 10]. After SCT, the analysis of donor cell chimerism based on the amplification of short tandem repeat markers offers another route to pre- detect impending relapse [11–14]. While the determination of DCC in unsorted blood or bone marrow (BM) is com- promised by a relatively low sensitivity [14–17], the ana- lysis of lineage-sorted DCC, especially within the CD34 positive BM subset, was suggested to enable early detection * Matthias Stelljes stelljes@ukmuenster.de 1 Department of Medicine A/Haematology and Oncology, University of Muenster, Muenster, Germany 2 Department of Haematology and Oncology, Johann Wolfgang Goethe University, Frankfurt, Germany 3 Department of Haematology, University Hospital Schleswig- Holstein, Campus Kiel, Kiel, Germany Supplementary information The online version of this article (https:// doi.org/10.1038/s41409-020-0801-0) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: