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Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Münster 2009 Trial

Publication: Journal of Clinical Oncology

Abstract

Purpose

The International Berlin-Frankfurt-Münster (BFM) study group conducted a study on pediatric acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) was assessed using flow cytometry (FCM), and the impact of early intensification and methotrexate (MTX) dose on survival was evaluated.

Patients and Methods

We included 6,187 patients younger than 19 years. MRD by FCM refined the risk group definition previously used in the ALL intercontinental-BFM 2002 study on the basis of age, WBC count, unfavorable genetic aberrations, and treatment response measured morphologically. Patients at intermediate risk (IR) and high risk (HR) were randomly assigned to protocol augmented protocol I phase B (IB) versus IB regimen. MTX doses of 2 versus 5 g/m2 every 2 weeks, four times, were evaluated in precursor B-cell-ALL (pcB-ALL) IR.

Results

The 5-year event-free survival (EFS ± SE) and overall survival (OS ± SE) rates were 75.2% ± 0.6% and 82.6% ± 0.5%, respectively. Their values in risk groups were standard risk (n = 624), 90.7% ± 1.4% and 94.7% ± 1.1%; IR (n = 4,111), 77.9% ± 0.7% and 85.7% ± 0.6%; and HR (n = 1,452), 60.8% ± 1.5% and 68.4% ± 1.4%, respectively. MRD by FCM was available in 82.6% of cases. The 5-year EFS rates in patients randomly assigned to protocol IB (n = 1,669) and augmented IB (n = 1,620) were 73.6% ± 1.2% and 72.8% ± 1.2%, respectively (P = .55), while those in patients receiving MTX doses of 2 g/m2 (n = 1,056) and MTX 5 g/m2 (n = 1,027) were 78.8% ± 1.4% and 78.9% ± 1.4%, respectively (P = .84).

Conclusion

The MRDs were successfully assessed using FCM. An MTX dose of 2 g/m2 was effective in preventing relapse in non-HR pcB-ALL. Augmented IB showed no advantages over the standard IB.

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Data Supplement

Authors retain all rights in any data supplements associated with their articles.

The ideas and opinions expressed in this Data Supplement do not necessarily reflect those of the American Society of Clinical Oncology (ASCO). The mention of any product, service, or therapy in this Data Supplement should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify approved uses, the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in this publication or to any errors or omissions. Readers should contact the corresponding author with any comments related to Data Supplement materials.

Study Protocols

The following protocol information is provided solely to describe how the authors conducted the research underlying this article. The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors, JCO requests only specific elements of the most recent version of the protocol. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of this protocol material or due to any errors or omissions. Readers seeking additional information about the protocol are encouraged to consult the corresponding author directly.

Please click the protocol link below to access the information.

Prior Presentation

The study was presented in closed sessions at the Annual Meeting of the International BFM Study Group: Kiel, Germany, May 17, 2013; Prague, Czech Republic, April 25, 2014; Budapest, Hungary, April 22, 2015; Athens, Greece, May 10, 2016; Jerusalem, Israel, May 10, 2017; Helsinki, Finland, May 18, 2018; and Prague, Czech Republic, May 19, 2019.

Support

Supported by the University Medical Center Ljubljana Research Grant No. 20170025, Slovenia; Foundation from Children with Leukemia, and Grant OTKA K-108885, Debrecen, Hungary; Hellenic Society of Pediatric Hematology-Oncology, HeSPHO, Greece; National Pediatric Cancer Program, PINDA, Chile; and Croatian Cooperative Association for Hematological Diseases, CROHEM. The funders had no role in the study design, collection, analyses, interpretation of data, writing of the manuscript, or decision to publish the results.

Clinical Trial Information

EudraCT 2010-019722-13

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 3499 - 3511
PubMed: 37141547

History

Published online: May 04, 2023
Published in print: July 01, 2023

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Data Sharing Statement

Deidentified data and the trial protocol are available to qualified researchers who submit an in-scope proposal. The data will be available from the authors of the publication to ensure that data are used in accordance with the informed consent. Data are provided for the sole use of the approved request (tertiary dissemination will not be permitted). To gain access, data requesters will need to sign a data sharing agreement.

Authors

Affiliations

Department of Pediatric Hematology and Oncology, Hospital Roberto del Rio, Universidad de Chile, Chilean National Pediatric Oncology Group, PINDA, Santiago, Chile
Csongor Kiss, MD, PhD
Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Martin Zimmermann, PhD
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Cecilia Riccheri, MD, PhD
Argentine Group for the Treatment of Acute Leukemia, GATLA, Buenos Aires, Argentina
Jerzy Kowalczyk, MD, PhD https://orcid.org/0000-0003-3080-0845
Department of Pediatric, Hematology, Oncology, and Transplantology, Medical University of Lublin, Lublin, Poland
Maria S. Felice, MD, PhD
Hematology and Oncology Department, Hospital de Pediatría Prof. Dr Juan P. Garrahan, SAHOP, Buenos Aires, Argentina
Milos Kuzmanovic, MD, PhD
Mother and Child Health Care Institute of Serbia “Dr Vukan Cupic”, Faculty of Medicine, Belgrade, Serbia
Gabor Kovacs, MD, PhD
2nd Department of Pediatrics Semmelweis University, Budapest, Hungary
Pediatric and Adolescent Oncology Clinic, Children's Hospital MITERA, Athens, Greece
Alejandro Gonzalez, MD, PhD
Institute of Hematology and Immunology, Pediatric Clinic, Havana, Cuba
Deceased
School of Medicine Division of Pediatric Hematology and Oncology, University Hospital Center, University of Zagreb, Zagreb, Croatia
Luis Castillo, MD, PhD
Pediatric Hemato-Oncology Department, Hospital Pereira Rossell, Pérez Scremini Foundation, Montevideo, Uruguay
Alexandra Kolenova, MD, PhD https://orcid.org/0000-0003-4300-5533
Department of Pediatric Hematology and Oncology, National Institute of Children’s Diseases and Medical School, Comenius University, Bratislava, Slovakia
Janez Jazbec, MD, PhD
University Medical Center Ljubljana, Ljubljana, Slovenia
Pediatric Oncology and Hematology Research Institute of N.N.Blokhin National Cancer Research Center, Center, Moscow, Russia
Dobrin Konstantinov, MD, PhD
Pediatric Hematology & Oncology Department, University Hospital “Tsaritsa Johanna-ISUL”, Sofia, Bulgaria
Janos Kappelmayer, PhD
Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Tomasz Szczepanski, MD, PhD https://orcid.org/0000-0001-5336-261X
Department of Pediatric Hematology and Oncology, Zabrze, Medical University of Silesia, Katowice, Poland
Michael Dworzak, MD, PhD https://orcid.org/0000-0002-8175-1097
St Anna Children's Cancer Research Institute (CCRI), Vienna, Austria
Mother and Child's Health Department, Division of Pediatric Hematology, Oncology and Stem Cell Transplant, University of Padova, Padova, Veneto, Italy
Giuseppe Gaipa, PhD
Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Neda Marinov, MT
Chilean National Pediatric Oncology Group, PINDA, Hospital Roberto del Rio/Universidad de Chile, Santiago, Chile
Hospital del Salvador, Universidad de Chile, Santiago, Chile
Jorge Rossi, PhD
Immunology and Rheumatology Department, Hospital de Pediatría Prof. Dr Juan P. Garrahan, Buenos Aires, Argentina
Attila Nagy, PhD
Department of Interventional Epidemiology, Faculty of Public Health, University of Debrecen, Debrecen, Hungary
Imre Gaspar, MD, PhD
Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
Department of Pediatric Hematology and Oncology Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Martin Schrappe, MD, PhD https://orcid.org/0000-0003-0034-5845
Department of Pediatric and Adolescent Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany

Notes

Myriam Campbell, MD, PhD, General Pedro Pablo Dartnell 1526, Nuñoa, Santiago 7750399, Chile; e-mail: [email protected].
*
M.C. and C.K. contributed equally to this work and share first authorship. J.S. and M.S. contributed equally to this work and shared senior authorships.

Author Contributions

Conception and design: Myriam Campbell, Csongor Kiss, Martin Zimmermann, Cecilia Riccheri, Jerzy Kowalczyk, Maria S. Felice, Gabor Kovacs, Luis Castillo, Janez Jazbec, Janos Kappelmayer, Michael Dworzak, Jan Stary, Martin Schrappe
Financial support: Csongor Kiss
Administrative support: Martin Zimmermann
Provision of study materials or patients: Cecilia Riccheri, Jerzy Kowalczyk, Maria S. Felice, Milos Kuzmanovic, Gabor Kovacs, Helen Kosmidis, Alejandro Gonzalez, Ernest Bilic, Luis Castillo, Alexandra Kolenova, Janez Jazbec, Alexander Popa, Dobrin Konstantinov, Janos Kappelmayer, Tomasz Szczepanski, Michael Dworzak, Barbara Buldini, Giuseppe Gaipa, Neda Marinov, Jorge Rossi, Jan Stary
Collection and assembly of data: Myriam Campbell, Csongor Kiss, Cecilia Riccheri, Jerzy Kowalczyk, Maria S. Felice, Milos Kuzmanovic, Gabor Kovacs, Helen Kosmidis, Alejandro Gonzalez, Ernest Bilic, Luis Castillo, Alexandra Kolenova, Janez Jazbec, Alexander Popa, Dobrin Konstantinov, Janos Kappelmayer, Tomasz Szczepanski, Barbara Buldini, Giuseppe Gaipa, Neda Marinov, Jorge Rossi, Imre Gaspar, Martin Schrappe
Data analysis and interpretation: Myriam Campbell, Csongor Kiss, Martin Zimmermann, Maria S. Felice, Janez Jazbec, Michael Dworzak, Attila Nagy, Jan Stary, Martin Schrappe
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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Myriam Campbell, Csongor Kiss, Martin Zimmermann, Cecilia Riccheri, Jerzy Kowalczyk, Maria S. Felice, Milos Kuzmanovic, Gabor Kovacs, Helen Kosmidis, Alejandro Gonzalez, Ernest Bilic, Luis Castillo, Alexandra Kolenova, Janez Jazbec, Alexander Popa, Dobrin Konstantinov, Janos Kappelmayer, Tomasz Szczepanski, Michael Dworzak, Barbara Buldini, Giuseppe Gaipa, Neda Marinov, Jorge Rossi, Attila Nagy, Imre Gaspar, Jan Stary, Martin Schrappe
Journal of Clinical Oncology 2023 41:19, 3499-3511

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