**2. Minimal residual disease (MRD)-guided therapy**

Minimal residual disease measured post-induction has been shown to be most predictive of long-term outcomes across various studies [16–18]. It is an amalgam of leukemia biology, patient factors as well as therapy. With the current protocolbased, risk-directed therapy complemented by MRD based risk stratification, approximately 90% of the children aged 1–18 years are expected to be long-term survivors [19–22]. Various sensitive techniques have been utilized for evaluation of MRD including multi-color flow-cytometry (MFC), RT-PCR and next generation sequencing, which can detect 1 leukemic cell in 10,000–100,000 normal cells [16]. Analysis and tracking of Ig/TCR gene rearrangements by PCR is feasible in 90% of B and T-ALL and detection of fusion gene transcripts in approximately 30–40%. Other new techniques of MRD analysis include high-throughput sequencing (HTS) of Ig/TCR with a sensitivity of 1 in 1 million cells (10<sup>−</sup><sup>6</sup> ) [23]. In a recent study by Wood et al., HTS and MFC were comparable and HTS produced similar results as regards the prognostic significance of MRD [23]. Therapy modification based on MRD in the UKALL2003 and the Dutch ALL10 trial was associated with improved outcomes in childhood ALL [22, 24]. The AIEOP-BFM-ALL 2000 trial showed improved outcomes in both pediatric B and T ALL with MRD based therapy [25]. With the use of clinical and biological factors to stratify children with ALL into various risk groups, risk-directed therapy has led to the delivery of less intense as well as less toxic therapy to the low risk groups and more intensive therapy to those with a higher probability of relapse and poorer outcomes.

Despite high cure rates for pediatric ALL, up to 20% of the children will relapse. Re-induction for this group of patients yields remission in 79–90% of patients,

however long-term survival is only 40–50% [26, 27]. Moreover, the outcomes are worse in patients with primary refractory or relapse and refractory disease (r/r) as well as relapse post SCT; hence the unmet need for durable therapies for such children. The incorporation of newer therapies including monoclonal antibodies and Chimeric Antigen Receptor (CAR) T-cell therapy offer an alternative approach to the management of relapsed/refractory pediatric B ALL. The increasing use of upfront genome-based characterization of disease, and incorporation of drugs against identified actionable targets, will ultimately lead to improved clinical outcomes and deceased toxicity of therapy. This chapter will focus on the recent diagnostic and therapeutic advances which are changing the way children with ALL are treated.
