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ACUTE LYMPHOBLASTIC LEUKEMIA

Randomized post-induction and delayed intensification therapy in high-risk pediatric acute lymphoblastic leukemia: long-term results of the international AIEOP-BFM ALL 2000 trial

Leukemia volume 34, pages 1694–1700 (2020)Cite this article

Subjects

Between July 1 (September 1 for AIEOP), 2000 and June 30 (July 31 for AIEOP), 2006, 4839 children with ALL, 1–17 years-old, were enrolled into the AIEOP-BFM ALL 2000 trial (Austria, Germany, Italy, Switzerland) [2, 7]. ALL was diagnosed according to cytomorphological/cytochemical criteria. Immunophenotypic/genetic analyses were performed centrally at the national reference laboratories. Immunophenotyping by flow-cytometry, analyses for BCR-ABL1 and KMT2A-AFF1 (formerly known as MLL-AF4) and MRD assessment were performed according to consensus guidelines as previously reported [2, 7]. Indications of HSCT in 1st CR have been previously published (Supplementary information) [2, 3, 7]. CR was defined as a bone marrow with active hematopoiesis and <5% leukemic blasts. Resistance was defined as failure to achieve CR after the 3rd HR course. Relapse was defined as recurrence of ≥25% blasts in bone marrow or localized leukemic infiltrations at any other site.

All patients were stratified into three risk groups: standard-risk, intermediate-risk, and HR group according to genetics and early therapy response [16]. In brief, patients with prednisone poor response on day 8 (PPR), no CR after completion of induction phase IA, BCR-ABL1 or KMT2A-AFF1 were allocated to the HRG. MRD detection was based on immunoglobulin and T-cell receptor gene rearrangements and performed centrally at two different time points (TP): TP1, completion of phase IA (day 33) and TP2, completion of consolidation phase IB (day 78). Patients with MRD levels ≥5 × 10E–4 at TP2 were considered HR. All patients were treated with informed consent of their legal guardian(s). The study was conducted according to the Declaration of Helsinki, approved by the respective ethics committees and registered at clinicaltrials.gov (NCT00430118 for BFM; NCT00613457 for AIEOP).

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Acknowledgements

We thank all participating institutions and physicians for their support of the study. For AIEOP: this work was supported by Comitato M. L. Verga and Fondazione Tettamanti (Monza), Fondazione Città della Speranza, Associazione Italiana per la Ricerca sul Cancro (AB IG 2017 (#20564)) and Transcall2 (AB ID 189). For BFM: this work was supported by Deutsche Krebshilfe e.V., Bonn, Germany (grant 50-2698 Schr1 and grant 50-2410 Ba7), Oncosuisse/Krebsforschung, Switzerland (grant OCS 1230-02-2002), and St. Anna Kinderkrebsforschung, Austria.

Author information

Author notes

  1. These authors contributed equally: Andishe Attarbaschi, Georg Mann, Martin Zimmermann

  2. These authors jointly supervised this work: Valentino Conter, Martin Schrappe

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, St. Anna Children’s Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

    Andishe Attarbaschi, Georg Mann, Renate Panzer-Grümayer & Christina Peters

  2. Department of Pediatric Hematology and Oncology, Children’s Hospital, Medical School Hannover, Hannover, Germany

    Martin Zimmermann & Christin Linderkamp

  3. Department of Children and Adolescent Medicine, Children’s Hospital, Goethe University, Frankfurt, Germany

    Peter Bader

  4. Pediatric Onco-Hematology, Regina Margherita Children’s Hospital, AOU Città della Salute e della Scienza, Turin, Italy

    Elena Barisone

  5. Italian Institute for Genomic Medicine, Turin, Italy

    Giuseppe Basso

  6. Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of Milano-Bicocca, MBBM Foundation/ASST Monza, Monza, Italy

    Andrea Biondi, Gianni Cazzaniga, Antonella Colombini, Carmelo Rizzari & Valentino Conter

  7. Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany

    Gunnar Cario, Anja Möricke & Martin Schrappe

  8. Department of Pediatric Hematology and Oncology, Children’s Hospital, Albert Ludwigs University, Freiburg, Germany

    Christian Flotho

  9. University Children’s Hospital Augsburg, Swabian Children’s Cancer Center, Augsburg, Germany

    Michaela Kuhlen

  10. Department of Pediatric Hematology and Oncology, Children’s Hospital, Eberhard Karls University, Tübingen, Germany

    Peter Lang

  11. Department of Pediatric and Adolescent Medicine, Children’s Hospital, University of Lübeck, Lübeck, Germany

    Melchior Lauten

  12. Department of Pediatric Hematology-Oncology, IRCCS “Bambino Gesù” Children’s Hospital, Rome, Italy

    Franco Locatelli

  13. Department of Pediatrics, Sapienza, University of Rome, Rome, Italy

    Franco Locatelli

  14. Center of Pediatric Hematology Oncology, Azienda Policlinico-OVE, Catania, Italy

    Luca Lo Nigro

  15. Department of Pediatric Oncology, University Children’s Hospital, Zürich, Switzerland

    Felix Niggli

  16. Department of Pediatric Hemato-Oncology, A.O.R.N. Santobono-Pausilipon, Naples, Italy

    Rosanna Parasole

  17. Department of Woman and Child Health, Clinic of Pediatric Haematology-Oncology, University of Padova, Padova, Italy

    Maria Caterina Putti

  18. Department of Pediatrics, Pediatric Hemato-Oncology Unit, Children’s Hospital, University Hospital “Carl Gustav Carus”, Dresden, Germany

    Meinolf Suttorp

  19. Center of Biostatistics for Clinical Epidemiology, Department of Health Science, University of Milano-Bicocca, Milano, Italy

    Maria Grazia Valsecchi

Authors
  1. Andishe Attarbaschi
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  2. Georg Mann
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  3. Martin Zimmermann
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  7. Andrea Biondi
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Consortia

on behalf of the AIEOP-BFM (Associazione Italiana di Ematologia e Oncologia Pediatrica & Berlin-Frankfurt-Münster) Study Group

Contributions

M. Schrappe, V.C., G.M., A.B., F.L. and F.N. were involved in designing and planning the study. A.A., G.M., M.Z., M. Schrappe and V.C. wrote the manuscript. M. Schrappe, A.A., G.M., M.Z., P.B., E.B., G.B., A.B., G. Cario, A.C., M.K., P.L., M.L., C.L, F.L., L.N., A.M., F.N., R.P., C.P., M.C.P, C.R. and M. Suttorp were principal or co-investigators in their study groups and institutions, coordinated the national trials in their countries, provided study materials and recruited patients. G.B., G. Cazzaniga, C.F. and R.P.-G. were in charge of MRD analysis. M.Z. and M.G.V. performed the statistical analyses. M. Schrappe, M.Z., A.M., M.G.V. and V.C. oversaw data checking, pooling and reporting during the study period and analysed the data. All authors have approved the final version of the manuscript.

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Correspondence to Andishe Attarbaschi.

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Attarbaschi, A., Mann, G., Zimmermann, M. et al. Randomized post-induction and delayed intensification therapy in high-risk pediatric acute lymphoblastic leukemia: long-term results of the international AIEOP-BFM ALL 2000 trial. Leukemia 34, 1694–1700 (2020). https://doi.org/10.1038/s41375-019-0670-y

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