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Minimal Residual Disease

Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol

Leukemia volume 23, pages 1073–1079 (2009)Cite this article

Abstract

Acute lymphoblastic leukemia (ALL) in infants younger than 1 year is a rare but relatively homogeneous disease (∼80% MLL gene rearranged, ∼70% CD10-negative) when compared with childhood and adult ALL. Several studies in children and adults with ALL have shown that minimal residual disease (MRD) status is a strong and independent prognostic factor. We therefore evaluated the prognostic significance of MRD in infant ALL. Ninety-nine infant patients treated according to the Interfant-99 protocol were included in this study. MRD was analyzed by real-time quantitative PCR analysis of rearranged immunoglobulin genes, T-cell receptor genes and MLL genes at various time points (TP) during therapy. Higher MRD levels at the end of induction (TP2) and consolidation (TP3) were significantly associated with lower disease-free survival. Combined MRD information at TP2 and TP3 allowed recognition of three patients groups that significantly differed in outcome. All MRD-high-risk patients (MRD levels ⩾10−4 at TP3; 26% of patients) relapsed. MRD-low-risk patients (MRD level <10−4 at both TP2 and TP3) constituted 44% of patients and showed a relapse-rate of only 13%, whereas remaining patients (MRD-medium-risk patients; 30% of patients) had a relapse rate of 31%. Comparison between the current Interfant-06 stratification at diagnosis and the here presented MRD-based stratification showed that both stratifications recognized different subgroups of patients. These data indicate that MRD diagnostics has added value for recognition of risk groups in infant ALL and that MRD diagnostics can be used for treatment intervention in infant ALL as well.

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Acknowledgements

We gratefully acknowledge Patricia Hoogeveen, Maaike de Bie, Susi Fischer, Eva Csinady, and Jessica Buijs-Gladdines for excellent technical assistance and Marieke Comans-Bitter for preparing the figures. We thank all clinicians of the collaborative group for taking and sending in patient samples. This study was supported by the Dutch Cancer Foundation (KWF Grant EUR2001-2441; MWJCJ, VHJvdV), Fondazione Città Della Speranza, Fondazione Cariparo, AIRC, Murst (ex 40%) (GB), ‘Österreichische Kinderkrebshilfe’, the Research Program ‘Genome Research for Health’ of the Austrian Ministry of Education, Science and Culture (GEN-AU Child, GZ 200.136/1-VI/1/2005), OENB 12213 (ERP-G), Wilhelm-Sander Foundation (MM), the Deutsche Krebshilfe (research grant 107819; RM), IBISCUS and AIRC (LLN), Fondazione Tettamanti, Fondazione Cariplo, AIRC and MIUR (GC). This study was performed on behalf of the Interfant-99 study group (coordinator: R Pieters), which is composed of AIEOP (G de Rossi, A Biondi; Italy), ANZCHOG (R Suppiah; Australia, New Zealand), Argentina (M Felice), BFM-A (G Mann; Austria), BFM-G (M Schrappe; Germany), COALL (G Janka-Schaub; Germany), CWPGH (J Stary; Czech Republic), DCOG (R Pieters; the Netherlands), DFCI consortium (L Silverman; USA), EORTC-CLCG (A Fester; France, Belgium, Portugal), FRALLE (F Mechinaud; France), Hong Kong (CK Li), NOPHO (L Hovi; Scandinavian countries), PINDA (M Campbell; Chile), PPLLSG (T Szczepañski; Poland), SJCRH (JE Rubnitz; USA), UKCCSG (I Hann, A Vora; United Kingdom).

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Author notes

  1. V H J Van der Velden, L Corral, M G Valsecchi and M W J C Jansen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    V H J Van der Velden, M W J C Jansen & J J M Van Dongen

  2. Pediatric Clinic, San Gerardo Hospital, University of Milan-Bicocca, Milan, Italy

    L Corral, P De Lorenzo, G Cazzaniga & A Biondi

  3. ‘M Tettamanti’ Research Center, Monza, Italy

    L Corral, P De Lorenzo, G Cazzaniga & A Biondi

  4. Department of Clinical Medicine and Prevention, Interfant Trial Data Center, University of Milan-Bicocca, Monza, Italy

    M G Valsecchi & P De Lorenzo

  5. Children's Cancer Research Institute, Vienna, Austria

    E R Panzer-Grümayer

  6. St Anna Children's Hospital, Vienna, Austria

    E R Panzer-Grümayer & G Mann

  7. Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    M Schrappe & A Schrauder

  8. Institute of Pharmaceutical Biology/ZAFES/DCAL, University of Frankfurt, Frankfurt/Main, Germany

    C Meyer & R Marschalek

  9. Center of Pediatric Hematology Oncology, Azienda Policlinico University of Catania, Catania, Italy

    L L Nigro

  10. Hospital for Children and Adolescents, University of Erlangen, Erlangen, Germany

    M Metzler

  11. Department of Pediatrics, University of Padova, Padova, Italy

    G Basso

  12. Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands

    M L Den Boer & R Pieters

  13. Dutch Childhood Oncology Group, The Hague, The Netherlands

    R Pieters

Authors
  1. V H J Van der Velden
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  2. L Corral
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  5. P De Lorenzo
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  6. G Cazzaniga
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  7. E R Panzer-Grümayer
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  10. C Meyer
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  13. M Metzler
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  14. G Basso
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  15. G Mann
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  16. M L Den Boer
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  17. A Biondi
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  18. R Pieters
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Correspondence to J J M Van Dongen.

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The data reported in this manuscript are original, have not been published previously and have not been submitted for publication elsewhere.

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Van der Velden, V., Corral, L., Valsecchi, M. 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). https://doi.org/10.1038/leu.2009.17

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