Risk-Directed Treatment Intensification Significantly Improves Outcomes in Children With ALL and Intrachromosomal Amplification of Chromosome 21
In a study reported in Journal of Clinical Oncology, Anthony V. Moorman, PhD, of Newcastle University, and colleagues compared outcomes in children and adolescents with B-cell precursor acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21) in a trial in which iAMP21 was identified retrospectively and not used to guide treatment vs a trial in which patients with iAMP21 were assigned to the most intensive treatment group. Five-year event-free survival, relapse rate, and overall survival were significantly better in patients receiving intensive therapy in the latter trial.
Study Details
The study involved patients with B-cell precursor ALL treated in the Medical Research Council (MRC) ALL97 trial and the UK ALL2003 trial. Presence of iAMP21 was identified retrospectively in MRC ALL97 and was not used to guide therapy. In UK ALL2003, presence of iAMP21 was determined prospectively and patients were assigned to the group receiving the most intensive treatment, including augmented Berlin-Frankfurt-Munster consolidation, escalating Capizzi maintenance, double delayed intensification, and an option for first-remission transplantation. Presence of iAMP21 was determined by fluorescence in situ hybridization using probes specific for RUNX1.
Improved Outcomes
Overall, iAMP21 was found in 2% of patients, including 28 (2%) of 1,630 tested in MRC ALL97 and 53 (2%) of 2,575 tested in UK ALL2003.
Median follow-up was 4.9 years in UK ALL2003 and 9.3 years in MRC ALL97. Five-year event-free survival (78% vs 29%, P < .001), relapse rate (16% vs 70%, P < .001), and overall survival (89% vs 67%, P < .01) were all significantly better in patients in the UK ALL2003 trial (most intensive therapy group). On multivariate analysis adjusting for sex, age, and white blood cell count, the hazard ratios (HRs) for the MRC ALL97 group vs the UK ALL2003 group were 4.87 (P < .001) for event-free survival, 8.50 (P < .001) for relapse, and 3.67 (P = .015) for overall survival. Overall, relapse occurred in 12% of the UK ALL2003 group vs 81% of the MRC ALL97 group (HR = 7.2, P < .001). Five of six relapses in the UK ALL2003 group were categorized as late, although there was no significant difference in average time to relapse between the UK ALL2003 group and the MRC ALL97 group (4.3 vs 3.4 years, P = .166).
The investigators concluded: “iAMP21 patients with ALL benefitted from receiving more intensive therapy in UK ALL2003. In UK ALL2011, they will continue to be treated as cytogenetic high risk, receive intensive chemotherapy…, and will only be recommended for transplantation if they do not achieve a complete remission by the end of induction therapy. This study illustrates how the discovery and characterization of disease-specific genetic aberrations can be used to tailor therapy more precisely.”
The study was supported by Leukemia & Lymphoma Research.
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