Reduced-Intensity delayed intensification in standard-Risk pediatric acute lymphoblastic leukemia defined by undetectable minimal residual disease: Results of an international randomized trial (AIEOP-BFM ALL 2000)

Martin Schrappe, Kirsten Bleckmann, Martin Zimmermann, Andrea Biondi, Anja Möricke, Franco Locatelli, Gunnar Cario, Carmelo Rizzari, Andishe Attarbaschi, Maria Grazia Valsecchi, Claus R. Bartram, Elena Barisone, Felix Niggli, Charlotte Niemeyer, Anna Maria Testi, Georg Mann, Ottavio Ziino, Beat Schäfer, Renate Panzer-Grümayer, Rita BeierRosanna Parasole, Gudrun Göhring, Wolf Dieter Ludwig, Fiorina Casale, Paul Gerhardt Schlegel, Giuseppe Basso, Valentino Conter

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Abstract

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (6 SE) was 89.2 6 1.3% and 92.3 6 1.2% (P = .04); cumulative incidence of relapse, 8.7 6 1.2% and 6.4 6 1.1% (P = .09); and overall survival, 96.1 6 0.8% and 98.0 6 0.6% (P = .06). Patients with ETV6-RUNX1–positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 6 0.5% and 0.6 6 0.4% for P-III and P-II, respectively (P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.

Original languageEnglish
Pages (from-to)244-253
Number of pages10
JournalJournal of Clinical Oncology
Volume36
Issue number3
DOIs
Publication statusPublished - Nov 17 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schrappe, M., Bleckmann, K., Zimmermann, M., Biondi, A., Möricke, A., Locatelli, F., Cario, G., Rizzari, C., Attarbaschi, A., Valsecchi, M. G., Bartram, C. R., Barisone, E., Niggli, F., Niemeyer, C., Testi, A. M., Mann, G., Ziino, O., Schäfer, B., Panzer-Grümayer, R., ... Conter, V. (2017). Reduced-Intensity delayed intensification in standard-Risk pediatric acute lymphoblastic leukemia defined by undetectable minimal residual disease: Results of an international randomized trial (AIEOP-BFM ALL 2000). Journal of Clinical Oncology, 36(3), 244-253. https://doi.org/10.1200/JCO.2017.74.4946