1. ¹Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
2. ²Pediatric Clinic, San Gerardo Hospital, University of Milan-Bicocca, Milan, Italy
3. ³'M Tettamanti' Research Center, Monza, Italy
4. ⁴Department of Clinical Medicine and Prevention, Interfant Trial Data Center, University of Milan-Bicocca, Monza, Italy
5. ⁵Children's Cancer Research Institute, Vienna, Austria
6. ⁶St Anna Children's Hospital, Vienna, Austria
7. ⁷Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
8. ⁸Institute of Pharmaceutical Biology/ZAFES/DCAL, University of Frankfurt, Frankfurt/Main, Germany
9. ⁹Center of Pediatric Hematology Oncology, Azienda Policlinico University of Catania, Catania, Italy
10. ¹⁰Hospital for Children and Adolescents, University of Erlangen, Erlangen, Germany
11. ¹¹Department of Pediatrics, University of Padova, Padova, Italy
12. ¹²Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
13. ¹³Dutch Childhood Oncology Group, The Hague, The Netherlands

Correspondence: Professor JJM Van Dongen, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Dr Molewaterplein 50, GE Rotterdam 3015, The Netherlands. E-mail: j.j.m.vandongen@erasmusmc.nl

¹⁴These authors contributed equally to this work.

Received 5 December 2008; Accepted 12 December 2008; Published online 12 February 2009.

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.