The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10-4 and 70 with MRD≥5×10-4 had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis.

Associazione Italiana Ematologia Oncologia Pediatrica Azienda Sanitaria Provinciale Ragusa Italy

Associazione Italiana Ematologia Oncologia Pediatrica Centro Ricerca Tettamanti Pediatric Department University of Milano Bicocca Monza Italy

Associazione Italiana Ematologia Oncologia Pediatrica Pediatric Department University of Milano Bicocca Fondazione MBBM Monza Italy

Berlin Frankfurt Münster Group Germany Germany and Switzerland

Children's Cancer and Leukaemia Group UK

Cooperative study group for treatment of ALL Germany

Czech Pediatric Hematology Working Group Czech Republic

Dutch Childhood Oncology Group the Netherlands

European intergroup study of post induction treatment of Philadelphia chromosome positive acute lymphoblastic leukemia Trial Data Center School of Medicine and Surgery University of Milano Bicocca Monza Italy

French Acute Lymphoblastic Leukemia Study Groups Italy

Nordic Society of Paediatric Haematology and Oncology Sweden Denmark Norway Finland and Iceland

Haematologica. 2018 Jan;103(1):4-5. doi: 10.3324/haematol.2017.182667. PubMed

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