**1. Background**

ALL is the most common childhood malignancy and accounts for approximately 30% of all childhood cancers and 75% of all cases of childhood leukemia [1, 2]. Each year, 3600 new cases of childhood ALL are diagnosed in the United States. Precursor B-ALL accounts for approximately 80–85% of the cases, while 15–20% are of the T-cell type [3]. The peak age group for ALL is 2–8 years, which accounts for approximately 80% of the childhood ALL burden. The incidence decreases from 90 cases per million in the 2-8-year age group to 30 per million beyond 8 years of age [3, 4]. ALL is more common in children compared to older age groups as shown in **Figures 1** and **2** [5].

The treatment of childhood ALL has evolved over the past 50 years. Successful development of multi-agent chemotherapy regimens, improved disease risk stratification as well as enhanced supportive care have been instrumental in improving survival (**Figure 3**) [6]. The ALL chemotherapy backbone has included various phases—remission induction, central nervous system-directed therapy, interim maintenance and continuation therapy—with essentially the same chemotherapy

**Figure 1.** *Incidence of leukemia by age, SEER 1975–1999 [6].*

**Figure 2.** *Incidence of acute lymphoblastic leukemia by age and gender, SEER, 1975–1999 [6].*

drugs in use since the 1960s. Modifications in dosing, mode of administration and varying combinations have resulted in improvements in outcomes now reaching a plateau [7–10]. Certain subgroups continue to have a very poor outcome, including those patients with relapsed disease, infant ALL, and specific disease-related cytogenetic and molecular changes.

Childhood ALL differs from adult ALL in several ways. The overall survival (OS) of pediatric ALL has reached 90%, whereas adults still fare poorly at approximately 40% [10, 11]. Biologically, there is a higher frequency of poor prognostic subtypes like Philadelphia (Ph) positive and multi-lineage leukemia (MLL) rearranged leukemia in adults compared to children (7% vs. 1–2%) [12]. On the contrary, children have a higher frequency of favorable cytogenetics like hyperdiploidy and ETV6-RUNX1 as their leukemia drivers [12]. The majority of children with ALL are treated at specialized centres and as part of clinical trials, unlike adults. Additionally, pediatric protocols have a greater dose intensity and deliver therapy guided by degree of myelosuppression. Adults generally tolerate treatment less well, resulting in increased treatment related toxicity

**33**

*Pediatric Acute Lymphoblastic Leukemia: Recent Advances for a Promising Future*

[13]. The increased treatment related toxicity in adults could also be due to the increased use of stem cell transplant (SCT) in first remission, unlike the pediatric population where it is reserved only for high risk, poor responding or relapsed subgroups. Additionally, the use of pediatric-type protocols for the treatment of adolescent and young adults has resulted in significant improvements in their

*Overall survival of children with acute lymphoblastic leukemia who were treated in the Children's Cancer Group and Children's Oncology Group trials between 1968 and 2009 (reprinted from Ref. [6], Copyright* 

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)

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

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,

) [23]. In a recent study by

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

*(2015) with permission from Massachusetts Medical Society).*

of Ig/TCR with a sensitivity of 1 in 1 million cells (10<sup>−</sup><sup>6</sup>

with a higher probability of relapse and poorer outcomes.

*DOI: http://dx.doi.org/10.5772/intechopen.87092*

long-term survival [14, 15].

**Figure 3.**

*Pediatric Acute Lymphoblastic Leukemia: Recent Advances for a Promising Future DOI: http://dx.doi.org/10.5772/intechopen.87092*

**Figure 3.**

*Advances in Hematologic Malignancies*

*Incidence of leukemia by age, SEER 1975–1999 [6].*

**Figure 1.**

**Figure 2.**

drugs in use since the 1960s. Modifications in dosing, mode of administration and varying combinations have resulted in improvements in outcomes now reaching a plateau [7–10]. Certain subgroups continue to have a very poor outcome, including those patients with relapsed disease, infant ALL, and specific disease-related

*Incidence of acute lymphoblastic leukemia by age and gender, SEER, 1975–1999 [6].*

Childhood ALL differs from adult ALL in several ways. The overall survival

(OS) of pediatric ALL has reached 90%, whereas adults still fare poorly at approximately 40% [10, 11]. Biologically, there is a higher frequency of poor prognostic subtypes like Philadelphia (Ph) positive and multi-lineage leukemia (MLL) rearranged leukemia in adults compared to children (7% vs. 1–2%) [12]. On the contrary, children have a higher frequency of favorable cytogenetics like hyperdiploidy and ETV6-RUNX1 as their leukemia drivers [12]. The majority of children with ALL are treated at specialized centres and as part of clinical trials, unlike adults. Additionally, pediatric protocols have a greater dose intensity and deliver therapy guided by degree of myelosuppression. Adults generally tolerate treatment less well, resulting in increased treatment related toxicity

**32**

cytogenetic and molecular changes.

*Overall survival of children with acute lymphoblastic leukemia who were treated in the Children's Cancer Group and Children's Oncology Group trials between 1968 and 2009 (reprinted from Ref. [6], Copyright (2015) with permission from Massachusetts Medical Society).*

[13]. The increased treatment related toxicity in adults could also be due to the increased use of stem cell transplant (SCT) in first remission, unlike the pediatric population where it is reserved only for high risk, poor responding or relapsed subgroups. Additionally, the use of pediatric-type protocols for the treatment of adolescent and young adults has resulted in significant improvements in their long-term survival [14, 15].
