PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4). RESULTS: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

Australian and New Zealand Children's Haematology Oncology Group Perth Children's Hospital Perth Australia

Berlin Frankfurt Miünster Group Germany Kiel Germany

Center of Bioinformatics Biostatistics and Bioimaging University of Milano Bicocca Monza Italy

Chilean National Pediatric Oncology Group Santiago Chile

CLIP Dept of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Cytogenetic Cytouorimetric Molecular Biology Laboratory Center of Pediatric Hematology Oncology Azienda Policlinico G Rodolico San Marco Catania Italy

Czech Working Group for Pediatric Hematology Prague Czech Republic

DCAL Institute of Pharmaceutical Biology Goethe University Frankfurt am Main Germany

Department of Immunology Erasmus University Medical Center Rotterdam the Netherlands

Department of Pediatric Hematology Oncology IRCCS Bambino Gesù Children's Hospital Sapienza University of Rome Rome Italy

Department of Pediatric Hematology University Robert Debre Hospital APHP Paris France

Department of Pediatrics and Adolescent Medicine Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Pediatrics UKSH Kiel Germany

Dutch Childhood Oncology Group Utrecht the Netherlands

European Organisation for Research and Treatment of Cancer Children Leukemia Group Brussels Belgium

German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia Hamburg Germany

Pediatrics School of Medicine and Surgery University of Milano Bicocca Fondazione MBBM San Gerardo Hospital Monza Italy

Polish Pediatric Leukemia Lymphoma Study Group Zabrze Medical University of Silesia Katowice Poland

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

St Anna Children's Hospital Medical University of Vienna Vienna Austria

Telethon Kids Cancer Centre Telethon Kids Institute University of Western Australia Perth Australia

Tettamanti Research Center Pediatrics School of Medicine and Surgery University of Milano Bicocca Monza Italy

The Chinese University of Hong Kong Shatin Hong Kong Special Administrative Region People's Republic of China

United Kingdom Children Cancer Study Group London United Kingdom

J Clin Oncol. 2023 Oct 20;41(30):4825. doi: 10.1200/JCO.23.01844. PubMed

Zobrazit více v PubMed

Pieters R Schrappe M De Lorenzo P, et al. : A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): An observational study and a multicentre randomised trial. Lancet 370:240-250, 2007 PubMed

Pieters R De Lorenzo P Ancliffe P, et al. : Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the interfant-06 protocol: Results from an international phase III randomized study. J Clin Oncol 37:2246-2256, 2019 PubMed

Van Dongen JJ Seriu T Panzer-Grümayer ER, et al. : Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352:1731-1738, 1998 PubMed

Faderl S Kantarjian HM Talpaz M, et al. : Clinical significance of minimal residual disease in leukemia. Int J Oncol 17:1277-1287, 2000 PubMed

Pieters R de Groot-Kruseman H Van der Velden V, et al. : Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: Study ALL10 from the Dutch Childhood Oncology Group. J Clin Oncol 34:2591-2601, 2016 PubMed

Conter V Bartram CR Valsecchi MG, et al. : Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: Results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115:3206-3214, 2010 PubMed

Schrappe M Bleckmann K Zimmermann M, et al. : 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). J Clin Oncol 36:244-253, 2018 PubMed

Schrappe M Valsecchi MG Bartram CR, et al. : Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: Results of the AIEOP-BFM-ALL 2000 study. Blood 118:2077-2084, 2011 PubMed

Li A Goldwasser MA Zhou J, et al. : Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias. Br J Haematol 131:185-192, 2005 PubMed

Van der Velden VHJ Corral L Valsecchi MG, et al. : Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 23:1073-1079, 2009 PubMed

Popov A Buldini B De Lorenzo P, et al. : Prognostic value of minimal residual disease measured by flow-cytometry in two cohorts of infants with acute lymphoblastic leukemia treated according to either MLL-baby or interfant protocols. Leukemia 34:3042-3046, 2020 PubMed

Burmeister T Marschalek R Schneider B, et al. : Monitoring minimal residual disease by quantification of genomic chromosomal breakpoint sequences in acute leukemias with MLL aberrations. Leukemia 20:451-457, 2006 PubMed

Meyer C Schneider B Reichel M, et al. : Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Proc Natl Acad Sci U S A 102:449-454, 2005 PubMed PMC

van der Velden VHJ Cazzaniga G Schrauder A, et al. : Analysis of minimal residual disease by Ig/TCR gene rearrangements: Guidelines for interpretation of real-time quantitative PCR data. Leukemia 21:604-611, 2007 PubMed

van der Velden VHJ, van Dongen JJM: MRD detection in acute lymphoblastic leukemia patients using IG/TR gene rearrangements as targets for real-time quantitative PCR. Methods Mol Biol 538, 115-150, 2009 PubMed

Cazzaniga G De Lorenzo P Alten J, et al. : Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies. Haematologica 103:107-115, 2018 PubMed PMC

Dworzak MN Buldini B Gaipa G, et al. : AIEOP-BFM consensus guidelines 2016 for flow cytometric immunophenotyping of pediatric acute lymphoblastic leukemia. Cytometry 94:82-93, 2018 PubMed

Fine JP, Gray RJ: A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496-509, 1999

Bland JM; Altman D: Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1:307-310, 1986 PubMed

van der Velden VHJ, Wijkhuijs JM, van Dongen JJM: Non-specific amplification of patient-specific Ig/TCR gene rearrangements depends on the time point during therapy: Implications for minimal residual disease monitoring. Leukemia 22:641-644, 2008 PubMed

Kotrova M van der Velden VHJ van Dongen JJM, et al. : Next-generation sequencing indicates false-positive MRD results and better predicts prognosis after SCT in patients with childhood ALL. Bone Marrow Transplant 52:962-968, 2017 PubMed

Enshaei A O’Connor D Bartram J, et al. : A validated novel continuous prognostic index to deliver stratified medicine in pediatric acute lymphoblastic leukemia. Blood 135:1438-1446, 2020 PubMed

Maloney KW Devidas M Wang C, et al. : Outcome in children with standard-risk B-cell acute lymphoblastic leukemia: Results of Children's Oncology Group Trial AALL0331. J Clin Oncol 38:602-612, 2020 PubMed PMC

Burke MJ Salzer WL Devidas M, et al. : Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: A report from the COG. Haematologica 104:986-992, 2019 PubMed PMC

Insights into IGH clonal evolution in BCP-ALL: frequency, mechanisms, associations, and diagnostic implications

Favorable outcome of NUTM1-rearranged infant and pediatric B cell precursor acute lymphoblastic leukemia in a collaborative international study

Zobrazit více v PubMed

EudraCT
2005-004599-19

ClinicalTrials.gov
NCT00550992