Clinical Goals of Targeted Therapy in Childhood ALL
Prospective clinical trials in childhood ALL have established robust prognostic parameters but, more importantly, they succeeded to reduce disease recurrence and to limit acute and late side effects.
Prospective assessment of individual treatment response has demonstrated unequivocally that in vivo sensitivity may identify patients across all genetic subtypes with very distinct risk to relapse. Highly sensitive clonespecific PCR-based detection of minimal residual disease (MRD) in the recent trial AIEOP-BFM ALL 2000 identified approximately 40% of Bpc-ALL and 16% of T-ALL patients with fast clearance of disease. Their cumulative risk of relapse is only 5%. By contrast, patients with high levels of MRD after induction and consolidation (6% in Bpc-, and 21% in T-ALL) have a risk of nearly 40% to relapse at 5 years. In addition, frequent monitoring of MRD in high-risk patients identified specific patient subsets with highly refractory disease. MRD response to subsequent treatment by fixed drug combinations, by novel elements, or by allogeneic hematopoetic stem cell transplantation indicated distinct patterns of in vivo resistance.
Sensitive MRD-based response assessment may currently be the most suitable tool to achieve the goal of truly risk-adapted therapy in childhood. Genetic signatures of response to treatment have been identified which after thorough validation will eventually be utilized to adjust treatment early on. Such genetic markers are potentially the rational target for a novel therapeutic intervention.