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ACUTE LYMPHOBLASTIC LEUKEMIA

Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease

Leukemia volume 36, pages 2793–2801 (2022)Cite this article

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Abstract

Recently, we defined “CML-like” subtype of BCR::ABL1-positive acute lymphoblastic leukemia (ALL), resembling lymphoid blast crisis of chronic myeloid leukemia (CML). Here we retrospectively analyzed prognostic relevance of minimal residual disease (MRD) and other features in 147 children with BCR::ABL1-positive ALL (diagnosed I/2000–IV/2021, treated according to EsPhALL (n = 133) or other (n = 14) protocols), using DNA-based monitoring of BCR::ABL1 genomic breakpoint and clonal immunoglobulin/T-cell receptor gene rearrangements. Although overall prognosis of CML-like (n = 48) and typical ALL (n = 99) was similar (5-year-EFS 60% and 49%, respectively; 5-year-OS 75% and 73%, respectively), typical ALL presented more relapses while CML-like patients more often died in the first remission. Prognostic role of MRD was significant in the typical ALL (p = 0.0005 in multivariate analysis for EFS). In contrast, in CML-like patients MRD was not significant (p values > 0.2) and inapplicable for therapy adjustment. Moreover, in the typical ALL, risk-prediction could be further improved by considering initial hyperleukocytosis. Early distinguishing typical BCR::ABL1-positive ALL and CML-like patients is essential to enable optimal treatment approach in upcoming protocols. For the typical ALL, tyrosine-kinase inhibitors and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, no relevant prognostic feature applicable for therapy tailoring was found so far.

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Fig. 1: Schematic illustration of key differences between “Typical ALL” and “CML-like” disease.
Fig. 2: Overall comparison of MRD levels by IG/TR and BCR::ABL1 DNA-based monitoring.
Fig. 3: Outcome of patients according to the subtype.
Fig. 4: Outcome according to MRD levels at TP1 and TP2.
Fig. 5: MRD clearance at TP1 according to subtype and target.
Fig. 6: Outcome of patients according to leukocytosis at diagnosis.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was supported by grants from the Czech Health Research Council (NU21-03-00128) and Charles University (UNCE 204012), by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic), by the project National Institute for Cancer Research (Program EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next Generation EU, by Deutsche Krebshilfe (70112958), by the Italian Association for Cancer Research (AIRC) to AB (IG2017—20564) and G. Cazzaniga (IG2015—17593), and by the Comitato Maria Letizia Verga.

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Author notes

  1. These authors contributed equally: Marketa Zaliova, Giovanni Cazzaniga, Gunnar Cario.

Authors and Affiliations

  1. CLIP (Childhood Leukaemia Investigation Prague), Prague, Czech Republic

    Jan Zuna, Lenka Hovorkova, Justina Krotka, Lucie Winkowska, Eva Fronkova, Jan Stuchly, Jan Trka & Marketa Zaliova

  2. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic

    Jan Zuna, Lenka Hovorkova, Justina Krotka, Lucie Winkowska, Eva Fronkova, Jan Stuchly, Jan Stary, Jan Trka & Marketa Zaliova

  3. University Hospital Motol, Prague, Czech Republic

    Jan Zuna, Justina Krotka, Eva Fronkova, Jan Stary, Jan Trka & Marketa Zaliova

  4. Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    Amelie Koehrmann, Julia Alten, Martin Schrappe & Gunnar Cario

  5. Tettamanti Research Center, Pediatrics, University of Milano-Bicocca/Fondazione Tettamanti, Monza, Italy

    Michela Bardini, Lisa Brizzolara & Giovanni Cazzaniga

  6. Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany

    Rolf Koehler

  7. Charité-Universitätsmedizin Berlin, Berlin, Germany

    Cornelia Eckert

  8. Centre for Medical Genetics and Reproductive Medicine GENNET, Prague, Czech Republic

    Marie Trkova

  9. Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany

    Martin Zimmermann

  10. EsPhALL Trial Data Center, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy

    Paola De Lorenzo & Maria Grazia Valsecchi

  11. Pediatric Hemato-Oncolgy, Fondazione MBBM/ASST-Monza, University of Milano-Bicocca, Monza, Italy

    Valentino Conter & Andrea Biondi

  12. Medical Genetics, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy

    Giovanni Cazzaniga

Authors
  1. Jan Zuna
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Contributions

JZ, G.Cario, GCazzaniga, and MZ designed the study; LH, JK, AK, MB, LW, EF, JA, RK, CE, LB, MT, and JStu analyzed samples and provided data; MZ, PDL, MGV, VC, JSta, MS, AB, and JT provided diagnostic and clinical data; all authors participated on data integration, interpretation, and presentation; JZ and MZ wrote the draft; and all authors revised the draft and contributed to the final paper.

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Correspondence to Jan Zuna.

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Zuna, J., Hovorkova, L., Krotka, J. et al. Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease. Leukemia 36, 2793–2801 (2022). https://doi.org/10.1038/s41375-022-01668-0

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