Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group.
Outcome of childhood acute lymphoblastic leukemia (ALL) improved greatly by intensifying chemotherapy for all patients. Minimal residual disease (MRD) levels during the first months predict outcome and may select patients for therapy reduction or intensification.



Patients 1 to 18 years old with ALL were stratified on the basis of MRD levels after the first and second course of chemotherapy. Thereafter, therapy was substantially reduced in patients with undetectable MRD (standard risk) and intensified in patients with intermediate (medium risk) and high (high risk) levels of MRD. Seven hundred seventy-eight consecutive patients were enrolled. The method of analysis was intention-to-treat. Outcome was compared with historical controls.



In MRD-based standard-risk patients, the 5-year event-free survival (EFS) rate was 93% (SE 2%), the 5-year survival rate was 99% (SE 1%), and the 5-year cumulative incidence of relapse rate was 6% (SE 2%). The safety upper limit of number of observation years was reached and therapy reduction was declared safe.MRD-based medium-risk patients had a significantly higher 5-year EFS rate (88%, SE 2%) with therapy intensification (including 30 weeks of asparaginase exposure and dexamethasone/vincristine pulses) compared with historical controls (76%, SE 6%). Intensive chemotherapy and stem cell transplantation in MRD-based high-risk patients resulted in a significantly better 5-year EFS rate (78%, SE 8% v 16%, SE 8% in controls). Overall outcome improved significantly (5-year EFS rate 87%, 5-year survival rate 92%, and 5-year cumulative incidence of relapse rate 8%) compared with preceding Dutch Childhood Oncology Group protocols.



Chemotherapy was substantially reduced safely in one-quarter of children with ALL who were selected on the basis of undetectable MRD levels, without jeopardizing the survival rate. Outcomes of patients with intermediate and high levels of MRD improved with therapy intensification.
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada. r.pieters@prinsesmaximacentrum.nl.
Rob
R
Pieters
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Hester
H
de Groot-Kruseman
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Vincent
V
Van der Velden
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Marta
M
Fiocco
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Henk
H
van den Berg
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Evelien
E
de Bont
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
R Maarten
RM
Egeler
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Peter
P
Hoogerbrugge
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Gertjan
G
Kaspers
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Ellen
E
Van der Schoot
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Valerie
V
De Haas
Rob Pieters, Peter Hoogerbrugge, and Gertjan Kaspers, Princess Máxima Center for Pediatric Oncology, Utrecht; Rob Pieters, Hester de Groot-Kruseman, Marta Fiocco, and Valerie De Haas, Dutch Childhood Oncology Group, The Hague; Vincent Van der Velden and Jacques Van Dongen, University Medical Center Rotterdam, Rotterdam; Marta Fiocco, Leiden University, Leiden; Henk van den Berg, Academic Medical Center; Gertjan Kaspers, Free University Hospital Amsterdam; Ellen Van der Schoot, Sanquin Research, Amsterdam; Evelien de Bont, University of Groningen, Groningen, the Netherlands; and R. Maarten Egeler, The Hospital for Sick Children, Toronto, Canada.
Jacques
J
Van Dongen
D000293:Adolescent; D000970:Antineoplastic Agents / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D018365:Neoplasm, Residual / Q000145:classification / Q000175:diagnosis* / Q000628:therapy; D009426:Netherlands; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D012008:Recurrence
D000970:Antineoplastic Agents