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399 Clinical Implications of Minimal Residual Disease Detection in Infants with KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 ProtocolClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis II
Hematology Disease Topics & Pathways:
Clinically relevant
Sunday, December 6, 2020: 1:15 PM

Janine Stutterheim, MD, PhD1, Inge M. van der Sluis, MD, PhD2, Paola De Lorenzo3*, Julia Alten, MD4*, Philip Ancliff, MD5*, Andishe Attarbaschi, MD6,7*, Benoit Brethon, MD8*, Andrea Biondi, MD9,10, Myriam Campbell, MD11*, Giovanni Cazzaniga, PhD12, Gabriele Escherich, MD13,14*, Alina Ferster, MD15, Rishi Sury Kotecha, MBBChir, PhD16,17*, Birgitte Lausen, MD18,19*, Chi Kong Li, MD20, Luca Lo Nigro, PhD, MD21, Franco Locatelli, MD, PhD22, Rolf Marschalek, PhD23*, Martin Schrappe, MD PhD24, Jan Stary, MD, PhD25*, Ajay Vora, MD26,27, Jan Zuna, PhD28, Vincent H.J. Van Der Velden, PhD29*, Tomasz Szczepanski, MD, PhD30,31, Maria Grazia Valsecchi, PhD32* and Rob Pieters, MD, PhD, MSc33

1Princess Maxima Center, Utrecht, Netherlands
2Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
3University of Milano-Bicocca, Monza, Italy
4Dept. of Pediatrics, UKSH, Kiel, DEU
5Department of Haematology, Great Ormond Street Hospital, London, UK, London, GBR
6St. Anna Children's Hospital, Vienna, Austria
7BFM-A – Berlin-Frankfurt-Münster Austria, Vienna, Austria
8FRALLE - French Acute Lymphoblastic Leukemia Study Group, Paris, France
9Dept. Pediatrics, University of Milano-Bicocca, Fondazione MBBM/San Gerardo Hospital, Monza, Italy
10AIEOP - Associazione Italiana Ematologia Oncologia Pediatrica, Monza, Italy
11Hospital Roberto del Rio Santiago, Chilean National Pediatric Oncology Group, PINDA., Santiago, Chile
12Tettamanti Research Center, Department of Pediatrics, University of Milano-Bicocca/Fondazione MBBM, Monza, Italy
13Department of Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany
14COALL - German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia, Hamburg, Germany
15Hematology Oncology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium
16Telethon Kids Institute, University of Western Australia, Perth, Australia
17ANZCHOG - Australia New Zealand Children Oncology Group, Perth, Australia
18NOPHO – Nordic Society of Pediatric Hematology/Oncology, Copenhagen, Denmark
19Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
20Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong
21Head of Cytogenetic-Cytofluorimetric-Molecular Biology Lab - Azienda Policlinico OVE - Center of Pediatric Hematology Oncology, Catania, Italy
22IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Sapienza, University of Rome, Rome, Italy
23DCAL, Institute of Pharmaceutical Biology, Goethe-University, Frankfurt am Main, Germany
24BFM-G - Berlin-Frankfurt-Münster Group Germany, Kiel, Germany
25CPH- Czech Working Group for Pediatric Hematology, Prague, Czech Republic
26Great Ormond Hospital, London, United Kingdom
27UKCCSG - United Kingdom Children Cancer Study Group, London, United Kingdom
28CLIP, Dept. of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
29Department of Immunology, Erasmus University Medical Center, Rotterdam, NLD
30Department of Pediatrics Hematology and Oncology in Zabrze, Medical University of Silesia, Zabrze, Poland
31PPLLSG - Polish Pediatric Leukemia/Lymphoma Study Group, Zabrze, Poland
32University of Milano Bicocca, Monza, Italy
33Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands

Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A gene rearrangements and a poor outcome. Therefore, infants are treated with specific protocols. In older children, minimal residual disease (MRD) is used for risk group stratification. In infant ALL, data on MRD are scarce. We evaluated the prognostic value of MRD in a large series of infants with KMT2A rearranged ALL, treated within Interfant-06 in order to establish how to use MRD in these patients. This protocol included a randomization between lymphoid-style consolidation (protocol IB) versus a myeloid-style consolidation (ADE/MAE).

Patients and methods

MRD was measured in 249 infants with KMT2A-rearranged ALL by DNA-based PCR of rearranged KMT2A, immunoglobulin and/or T-cell receptor genes, at end of induction (EOI) (n=210), end of consolidation (EOC) (n=173) and after MARMA (n=164). MRD results were classified as negative, intermediate (<5x10-4), and high (≥5x10-4).


In samples with both data on KMT2A MRD PCR and IG/TR MRD targets available (n=223), results were concordant in 94% (n=210/223) of samples.

EOI MRD levels predicted outcome with 6-year disease free survival (DFS [SE]) of 60.2% (7.9), 45.0% (5.6), 33.8 % (5.3), for infants with negative, intermediate and high EOI MRD levels, respectively (p=0.0039). Strikingly, when analyzing MRD results according to consolidation treatment given, MRD levels at EOI predicted treatment outcome for patients treated with lymphoid-style consolidation, but not for patients treated with myeloid style consolidation. In patients treated with lymphoid-style consolidation 6-year DFS (SE) was 78.2% (9.8), 47.2% (7.1), 23.2% (7.1) for negative, intermediate and high MRD levels, (figure 1a) respectively (p<0.0001), whilst in myeloid-style treated patients the corresponding figures were 45.0% (10.7), 41.3% (9.4) and 45.9% (8.2) (figure 1b)

This implies that patients with low EOI MRD benefit from protocol IB lymphoid consolidation (DFS 78.2% versus 45.0%, figure 1c), while patients with high MRD benefit from ADE/MAE myeloid consolidation (DFS 45.9% versus 23.2%, figure 1d)). In line with these findings, co-expression of myeloid markers was found in a higher percentage of patients with high EOI MRD (81%) versus those with low EOI MRD (50%) (p=0.0186).

EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2 %(5.8), 40.1% (6.2), 11.9% (8.7) for infants with negative, intermediate and high EOC MRD levels respectively (p<0.0001). Patients that had positive EOI MRD and became negative at EOC also had a good outcome (6-DFS (SE) 65.7% (7.8))


Induction therapy selects infant ALL patients for the type of subsequent therapy; infants with high EOI MRD benefit from AML-like consolidation, whereas patients with low MRD benefit from ALL-like consolidation. This hypothesis is further supported by the more pronounced expression of myeloid markers in patients with high EOI MRD levels. Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

Disclosures: Brethon: Amgen: Other: invitation to meetings, remunerations for oral presentations, advices for the record of Blinatumomab in pediatrics in France. Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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