*4.2.2 Philadelphia-chromosome positive ALL (Ph + ALL)*

This high-risk group of ALL constitutes about 20–30% of the adult ALL and 3% of pediatric ALL [88]. Approximately 90% of the pediatric Ph + ALL have the p190 translocation, which results from the translocation within the 'minor' breakpoint cluster region (mBCR) [89]. It is also characterized by a high frequency (66%) of deletions in B-cell development genes like IKZF1, PAX5, EBF1 and CDKN2A/B. [33, 88, 90]. Historically, outcomes were extremely poor with 5-year OS of 19%


*CCG, Children's Cancer Group; CALGB, Cancer and Leukemia Group; FRALLE, French Acute lymphoblastic Leukemia Study Group; AIEOP, Associazione Italiana di Ematologia e Oncologia Pediatrica; DCOG, Dutch Childhood Oncology Group; NOPHO, Nordic Society for Pediatric Hematology and Oncology; MRC ALL, Medical Research Council (United Kingdom).*

#### **Table 1.**

*Improved outcomes for AYA when treated according to pediatric-based protocols.*

without transplant and 35–45% with transplant in CR1. However, survival has drastically improved with the advent of TKIs as seen in the UKALLXII/ECOG2993 study, 4-year OS with imatinib compared to historical cohort, 38% vs. 22% [91]. The AALL0031 reported excellent 5-year EFS of 70% ± 12% in patients treated with continuous imatinib and intensive chemotherapy compared with 31–39% for historical controls [92, 93]. Second generation TKIs are highly potent, demonstrate faster and deeper remissions, as well as increased CNS activity with an acceptable toxicity profile. The COG AALL0622 trial, did not show any survival advantage of dasatinib over imatinib when added to upfront chemotherapy backbone, 5-year OS 81% vs. 86% for AALL0031 and AALL0622 respectively. In the same study, IKZF1 deletions were identified in 57% of cases and were associated with inferior outcomes [94].

Ph + ALL is no longer considered a subgroup for allogeneic SCT in CR1, and is reserved for poor responders or for relapsed disease. The AALL0031 study showed improved 3-year EFS equal to or better than sibling-related SCT (88% vs. 57%) for patients treated with imatinib and intensive systemic chemotherapy. Long-term follow-up data from the same study showed 5-year DFS of 70% in the imatinib plus chemotherapy group compared to SCT (65%-sibling donor, 59%-unrelated donor) [93]. The Korean Society of Adult Hematology working party showed similar 2-year molecular relapse-free survival in those not transplanted versus those transplanted (65% vs. 53%) [95]. In a study by Ravandi et al., achievement of negative MRD status was a significant prognostic factor regulating long-term survival. The 4-year OS rates were 66, 43 and 32% in patients with 3-month CMR, major molecular remission (MMR) and less than MMR, respectively [96]. Hence, adequate molecular response is the deciding factor for no SCT versus SCT.

With regards to the use of TKIs in the post-transplantation period, the consensus statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, recommends patients with undetectable MRD post allogenic SCT may be either treated prophylactically or, may be monitored and treated pre-emptively with TKI if they have detectable MRD post-transplant. TKIs may be continued for a period of 12 months of continuous MRD negativity for those undergoing SCT in CR1, and continued indefinitely for those undergoing SCT in ≥2nd CR status [97]. Currently AALL1631, an international collaborative trial between the COG and the EsPhALL groups, is testing combination chemotherapy with imatinib in Ph + ALL. This randomized trial will assess survival and toxicity outcomes with less intensive therapy for those who are MRD negative post induction compared to the current EsPhALL and COG AALL1122 protocols. The role of post-transplant imatinib in the high-risk group of Ph + ALL undergoing SCT is also being evaluated [98].

#### *4.2.3 Philadelphia-like ALL (Ph-like ALL)*

Ph-like ALL constitutes a high-risk subtype of pediatric B ALL. Most studies demonstrate a poorer prognosis despite augmented traditional chemotherapy [54, 57, 70]. Interestingly, the Total XV study showed MRD directed therapy negated its poor prognosis [99]. Research is currently ongoing for a better understanding of the genomics of this group and we now know that this group harbors certain targetable genetic alterations. Potential targets and agents tested in preclinical models include; *CRLF2* inhibition (Givinostat [100], Luminespib [101], Selumetinib [102], TSLPR CART cells [103]), *JAK-2* (CHZ868) [104], *mTOR* pathway (Rapamycin) [105], *PI3K* and *mTOR* pathways (Gedatolisib) [106], and *TNF-a* inhibition (Birinapant) [107]. These targets are now being prospectively studies in clinical trials across various centres. The MDACC trial in children older than 10 years is testing ruxolitinib or dasatinib with chemotherapy [108].

**39**

*4.2.6 Infant ALL*

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

Also, the phase II COG AALL1521 study is testing ruxolitinib with conventional chemotherapy in the age group of 1–21 years [109]. Another phase II trial from the NCI (COG AALL1131) in 1–30-year olds is testing dasatinib in combination

Hypodiploidy (<45 chromosomes) is present in less than 5% of ALL. Survival

Children with Down syndrome (DS) have an increased predisposition compared to non-DS children to develop ALL with a cumulative risk of approximately 2.1% by age of 5 years and 2.7% by age of 30 [118, 119]. Children with DS constitute a very special group of pediatric ALL characterized by predominantly B immunophenotype and a marked absence of T immunophenotype. This group is neither associated with the favorable nor the unfavorable cytogenetic abnormalities as seen in common pediatric ALL [120]. *IKZF1* gene deletion, seen in approximately 35% of DS ALL portends inferior outcome [121, 122]. About 50–60% of the children with DS ALL harbor *CRLF2* mutation, much higher than in children with ALL without DS (<10%). Approximately, 20% of children with DS ALL also carry *JAK2* mutations, with majority also harboring *CRLF2* mutation. However, their

This rare group comprises 2–4% of pediatric ALL and is characterized by high leukocyte count at diagnosis, bulky extramedullary disease, frequent CNS involvement, and a poor prognosis [125, 126]. A relatively large proportion of these infants harbor the KMT2A gene on chromosome 11q23 in their malignant clone. [127, 128]. To date, approximately 94 different partner genes of KMT2A have been identified, with AF4 being the commonest [129]. These leukemia may contain FLT3 mutations (18%) and are characterized by overexpression of homeobox

across various studies ranges between 50 and 60% on currently available therapy [111–113]. Near haploid (24–30 chromosomes) and low-hypodiploidy (chromosome 31–39) fare poorly on current protocols with 5–8-year EFS of 25–40% for near-haploid and 30–50% for low-hypodiploid ALL [111, 112, 114]. Interestingly, MRD has emerged as an important prognostic marker; improved long-term survival is seen in those with MRD negativity post induction compared to MRD positive disease as shown by Mullighan et al. (85.1% vs. 44.4%) [115]. Recent studies show that children carrying pathogenic germline TP53 mutations have a significantly higher incidence of hypodiploidy (65% vs. 1%), inferior EFS, OS and a very high chance of developing second cancers [92]. Also, a significantly large proportion (91.2%) of low hypodiploidy ALL is associated with germline TP53 mutation suggesting a possible association of hypodiploid ALL with Li-Fraumeni syndrome. In a study by Holmfeldt et al., near-haploid ALL was found to be associated with *RAS*-signaling, *CREBBP*, *CDKN2A/B*, *PAG1* and *IKZF3*, and low hypodiploidy with *P53*, *IKZF2*, *RB1*, *histone modifiers* and *CDKN2A/B* [32, 116, 117]. The COG ALL03B1 showed no survival benefit from CR1 SCT. Interestingly, this was also true if children were MRD (>0.01%) positive pre-transplant [113]. Novel therapeutic approaches with emphasis on molecular targets could be the way forward in improving the outcomes of this

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

with chemotherapy [110].

high-risk subset of pediatric ALL.

prognostic significance is unknown [121, 123, 124].

*4.2.5 Down syndrome ALL*

*4.2.4 Hypodiploid ALL*

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

Also, the phase II COG AALL1521 study is testing ruxolitinib with conventional chemotherapy in the age group of 1–21 years [109]. Another phase II trial from the NCI (COG AALL1131) in 1–30-year olds is testing dasatinib in combination with chemotherapy [110].
