Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group

Abstract

Purpose 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. Methods 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. Results 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. Conclusion 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.

Minimal residual disease–guided therapy in childhood acute lymphoblastic leukemia

“…7,42 With 5-year survival rates exceeding 90% in many developed countries, 33 current efforts are focused on the early identification of patients with highly curable leukemia to avoid short-term morbidity and mortality and long-term treatmentrelated sequelae. 12,13 In this regard, attainment of negative MRD after exposure to only a few drugs for a short duration of time (ie, 2 weeks from treatment initiation), is a very useful indicator. 10,43 This approach is particularly helpful in patients with t(12;21)/ ETV6-RUNX1 or hyperdiploid (.50 chromosomes) ALL.…”

“…Pediatric oncologists treating children and adolescents with ALL have pioneered the use of MRD to monitor response to treatment, and all major pediatric oncology centers and cooperative groups worldwide now systematically use MRD levels to guide treatment decisions (Table 1). [8][9][10][11][12][13][14][15][16][17][18][19][20] Because precise measurements of MRD have important prognostic and therapeutic implications, it is essential to understand their clinical significance in the context of presenting clinical and biologic features, treatment regimen, and time interval at which MRD is measured.…”

A decrease in vitamin D levels is associated with methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia

“…The main sources of vitamin D are production in the skin through sunlight exposure, diet, and vitamin D supplements [7,11]. Vitamin D (D 2 Children with ALL may be at increased risk of vitamin D deficiency due to impaired sun exposure and impaired vitamin intake [12]. A retrospective study in 86 pediatric cancer patients with a median age of 7 years revealed vitamin D deficiency in 63% at diagnosis [13].…”

Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001

“…Five-year EFS was 87%, with EFS of 88% in MRD mediumrisk patients (high end-induction/low second time point MRD) who received intensification and maintenance therapy similar to DFCI 05-001 HR patients. 31 This result suggests that, among the patients classified as VHR based on MRD on DFCI 05-001, incorporation of a second MRD time point may have discriminated between those who could be successfully treated as HR patients (with low second time point MRD) vs those requiring more intensified therapy.…”

“…Others have shown that MRD measured at a second time point in therapy, 10 to 12 weeks after the start of treatment, is an important predictor of outcome. 7,14,31 The Italian Association of Pediatric Hematology Oncology-Berlin-Frankfurt-Munster ALL 2000 study used MRD assessment at 2 time points to stratify patients, with MRD assessment at days 33 and 78.…”