*4.2.6 Infant ALL*

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

(HOX) genes [130–133]. Younger age is associated with worse outcome. Despite intensified therapy across various trials groups including COG and Interfant, the 5-year EFS remains poor (34–37%) in the KMT2A-rearranged infants [127, 128, 134]. The role of SCT in CR1 remains controversial. Japanese and COG P9407 studies have not shown any survival benefit with SCT compared to standard chemotherapy alone [134, 135]. The COG study AALL0631 failed to demonstrate any survival benefit with the upfront addition of lestaurtinib to the chemotherapy backbone, despite high levels of FLT3 expression [39, 136]. The COG pilot study AALL15P1, is evaluating the role of upfront addition of azacytidine in combination with standard chemotherapy (Interfant protocol) for epigenetic modification in KMT2A rearranged infant ALL [137].

#### *4.2.7 T ALL*

The outcomes for T ALL have been historically very poor, however with current therapeutic approaches, outcomes are now comparable to those of B ALL with 5-year EFS of 85% [138, 139]. MRD has emerged as the most important prognostic factor. Interestingly, kinetics of MRD clearance in T-ALL is slower than B-ALL, with late MRD negativity post-consolidation still translating into improved outcomes (7-year EFS, 80.6% ± 2.3%) [140]. The UKALL2003 and the AIEOP-BFM 2000 trials have shown decreased relapse risk and survival benefit with the use of dexamethasone [138, 140]. Currently, the COG AALL1231 randomized trial is evaluating the role of bortezomib during induction and delayed intensification in patients with newly diagnosed T-cell ALL in the age group of 1–30 years using an augmented BFM-like backbone. Interestingly, this trial is also testing dexamethasone vs. prednisolone during induction and the benefit of the addition of asparaginase during maintenance therapy. Increasingly, cooperative groups are moving away from the use of prophylactic cranial radiation or restricting its use to high risk disease or CNS 3 status in upfront therapy [10, 11, 138, 141, 142]. The COG AALL1231 randomized trial is currently testing the safety of omitting prophylactic cranial irradiation in the non-high risk and non-CNS3 cases. The recent pilot AALL00P2 study tested upfront incorporation of nelarabine in newly diagnosed T ALL and has shown improved 5-year EFS of 73% for all patients and 69% for those with slow early response [143]. The COG AALL0434 randomized study tested nelarabine in frontline therapy and demonstrated safety, however final results are awaited [144]. Allogenic SCT is currently reserved only for those with positive MRD post consolidation [145].

Relapse T-ALL still remains a therapeutic challenge as the salvage rates and OS are less than 25%. In the AALL01P2 study, out of 7 patients with relapsed T-ALL, only 2 achieved CR2 [146]. However, encouraging results from the AALL07P1 trial have shown CR2 of 68% by the addition of bortezomib to a 4-drug re-induction regimen [147]. The focus is on optimizing upfront therapy to prevent relapse in the high-risk patients, with increasing efforts directed at developing effective salvage therapies for relapsed disease. Genomic sequencing studies have identified mutations related to various signaling pathways like *JAK/ STAT*, *NOTCH*, *PI3K/Akt/mTOR* and *MAPK* with emerging pre-clinical evidence for targeted therapy [116, 148, 149]. Pre-clinical studies are also underway for the development of CD5 directed CAR T-cell therapy [117] as well as NK cell CARs against the T-ALL (personal communication from DiPersio and Rezvani).

#### *4.2.8 Early T-precursor (ETP) ALL*

ETP ALL has emerged as a new entity with increased heterogeneity at the molecular level. This subtype harbors *NOTCH1* mutation at a much lower

**41**

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

frequency than T-ALL. It has a transcriptional profile similar to normal hematopoietic and myeloid stem cells [150]. Comparative genomic hybridization studies have shown absence of biallelic deletion of the TCR gamma locus (ABGD) and inferior outcomes with early treatment failure in this sub-group. [151, 152]. Other pathways implicated are the *JAK/STAT*, *PI3K/Akt/mTOR*, *FLT3*, and *MAPK* [153, 154]. Ruxolitinib, a *JAK1/2* inhibitor has shown single-agent activity in pre-clinical studies [155]. There is emerging evidence that treatment on high risk regimens and MRD guided therapy leads to similar outcomes to those of

The role of monoclonal antibodies against human differentiation antigens was first demonstrated by Kohler and Milstein using hybridomas with a goal of treatment of hematological malignancies [158]. ALL is an excellent candidate for the incorporation of monoclonal antibody therapy due to a fairly constant lineage-specific antigen expression on the blasts and minimal expression of target antigen on normal tissues. Studies have demonstrated high remission rates with these agents, non-overlapping and manageable toxicity profiles leading to the FDA approval of these treatments for pediatric ALL. Monoclonal antibodies like blinatumomab and inotuzumab ozogamicin (InO) have shown excellent remission rates in pediatric ALL. The COG is currently evaluating antibodies like alemtuzumab, rituximab, blinatumomab, InO, and epratuzumab, both in r/r ALL as well as in newly diagnosed B-ALL in combination with standard chemotherapy, with a potential in future to be either incorporated with upfront therapy or replace certain components

Blinatumomab is a bi-specific T-cell engager antibody with binding sites to CD19 on B cells and to CD3 on T cells. Binding activates cytotoxic T cells, which induce cell death in the leukemic cell via the perforin system [159]. This drug is administered as a continuous infusion over 28 days and has shown acceptable activity and safety in various trials and was first FDA approved in December, 2014 for use in r/r Ph negative ALL. Pioneering work by Topp et al. in a phase II, single-arm clinical trial showed that 80 % (16 of 20) of MRD positive patients became MRD negative post first cycle of blinatumomab [160]. Encouraging results from the BLAST trial, wherein 78% of the MRD positive patients became negative post one cycle of blinatumomab led to its FDA approval in MRD positive settings

In a phase I/II trial in 70 children <18 years of age with r/r ALL who were treated with single agent blinatumomab, 39% (27) achieved CR and MRD negativity in 52% [162, 163]. The AALL1331 phase III randomized trial is testing whether upfront addition of blinatumomab improves DFS in first relapse of ALL. In this trial all patients receive UK ALL R3 protocol for remission induction. Subsequently, the low risk group gets randomized to either control arm of R3 protocol or to receive three cycles of blinatumomab along with chemotherapy. The intermediate and the high-risk groups are randomized to either chemotherapy or two cycles of blinatumomab along with chemotherapy before proceeding to SCT. This trial is currently accruing patients and the results are

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

*4.2.9 Immune-targeting in relapsed/refractory B-ALL*

*4.2.10 Role of monoclonal antibodies in paediatric ALL*

standard T ALL [156, 157].

of standard of care chemotherapy.

*4.2.11 Blinatumomab*

as well [161].

awaited [164].

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

frequency than T-ALL. It has a transcriptional profile similar to normal hematopoietic and myeloid stem cells [150]. Comparative genomic hybridization studies have shown absence of biallelic deletion of the TCR gamma locus (ABGD) and inferior outcomes with early treatment failure in this sub-group. [151, 152]. Other pathways implicated are the *JAK/STAT*, *PI3K/Akt/mTOR*, *FLT3*, and *MAPK* [153, 154]. Ruxolitinib, a *JAK1/2* inhibitor has shown single-agent activity in pre-clinical studies [155]. There is emerging evidence that treatment on high risk regimens and MRD guided therapy leads to similar outcomes to those of standard T ALL [156, 157].

### *4.2.9 Immune-targeting in relapsed/refractory B-ALL*

### *4.2.10 Role of monoclonal antibodies in paediatric ALL*

The role of monoclonal antibodies against human differentiation antigens was first demonstrated by Kohler and Milstein using hybridomas with a goal of treatment of hematological malignancies [158]. ALL is an excellent candidate for the incorporation of monoclonal antibody therapy due to a fairly constant lineage-specific antigen expression on the blasts and minimal expression of target antigen on normal tissues. Studies have demonstrated high remission rates with these agents, non-overlapping and manageable toxicity profiles leading to the FDA approval of these treatments for pediatric ALL. Monoclonal antibodies like blinatumomab and inotuzumab ozogamicin (InO) have shown excellent remission rates in pediatric ALL. The COG is currently evaluating antibodies like alemtuzumab, rituximab, blinatumomab, InO, and epratuzumab, both in r/r ALL as well as in newly diagnosed B-ALL in combination with standard chemotherapy, with a potential in future to be either incorporated with upfront therapy or replace certain components of standard of care chemotherapy.

#### *4.2.11 Blinatumomab*

*Advances in Hematologic Malignancies*

KMT2A rearranged infant ALL [137].

*4.2.7 T ALL*

(HOX) genes [130–133]. Younger age is associated with worse outcome. Despite intensified therapy across various trials groups including COG and Interfant, the 5-year EFS remains poor (34–37%) in the KMT2A-rearranged infants [127, 128, 134]. The role of SCT in CR1 remains controversial. Japanese and COG P9407 studies have not shown any survival benefit with SCT compared to standard chemotherapy alone [134, 135]. The COG study AALL0631 failed to demonstrate any survival benefit with the upfront addition of lestaurtinib to the chemotherapy backbone, despite high levels of FLT3 expression [39, 136]. The COG pilot study AALL15P1, is evaluating the role of upfront addition of azacytidine in combination with standard chemotherapy (Interfant protocol) for epigenetic modification in

The outcomes for T ALL have been historically very poor, however with current therapeutic approaches, outcomes are now comparable to those of B ALL with 5-year EFS of 85% [138, 139]. MRD has emerged as the most important prognostic factor. Interestingly, kinetics of MRD clearance in T-ALL is slower than B-ALL, with late MRD negativity post-consolidation still translating into improved outcomes (7-year EFS, 80.6% ± 2.3%) [140]. The UKALL2003 and the AIEOP-BFM 2000 trials have shown decreased relapse risk and survival benefit with the use of dexamethasone [138, 140]. Currently, the COG AALL1231 randomized trial is evaluating the role of bortezomib during induction and delayed intensification in patients with newly diagnosed T-cell ALL in the age group of 1–30 years using an augmented BFM-like backbone. Interestingly, this trial is also testing dexamethasone vs. prednisolone during induction and the benefit of the addition of asparaginase during maintenance therapy. Increasingly, cooperative groups are moving away from the use of prophylactic cranial radiation or restricting its use to high risk disease or CNS 3 status in upfront therapy [10, 11, 138, 141, 142]. The COG AALL1231 randomized trial is currently testing the safety of omitting prophylactic cranial irradiation in the non-high risk and non-CNS3 cases. The recent pilot AALL00P2 study tested upfront incorporation of nelarabine in newly diagnosed T ALL and has shown improved 5-year EFS of 73% for all patients and 69% for those with slow early response [143]. The COG AALL0434 randomized study tested nelarabine in frontline therapy and demonstrated safety, however final results are awaited [144]. Allogenic SCT is cur-

rently reserved only for those with positive MRD post consolidation [145].

Relapse T-ALL still remains a therapeutic challenge as the salvage rates and OS are less than 25%. In the AALL01P2 study, out of 7 patients with relapsed T-ALL, only 2 achieved CR2 [146]. However, encouraging results from the AALL07P1 trial have shown CR2 of 68% by the addition of bortezomib to a 4-drug re-induction regimen [147]. The focus is on optimizing upfront therapy to prevent relapse in the high-risk patients, with increasing efforts directed at developing effective salvage therapies for relapsed disease. Genomic sequencing studies have identified mutations related to various signaling pathways like *JAK/ STAT*, *NOTCH*, *PI3K/Akt/mTOR* and *MAPK* with emerging pre-clinical evidence for targeted therapy [116, 148, 149]. Pre-clinical studies are also underway for the development of CD5 directed CAR T-cell therapy [117] as well as NK cell CARs against the T-ALL (personal communication from DiPersio and Rezvani).

ETP ALL has emerged as a new entity with increased heterogeneity at the molecular level. This subtype harbors *NOTCH1* mutation at a much lower

**40**

*4.2.8 Early T-precursor (ETP) ALL*

Blinatumomab is a bi-specific T-cell engager antibody with binding sites to CD19 on B cells and to CD3 on T cells. Binding activates cytotoxic T cells, which induce cell death in the leukemic cell via the perforin system [159]. This drug is administered as a continuous infusion over 28 days and has shown acceptable activity and safety in various trials and was first FDA approved in December, 2014 for use in r/r Ph negative ALL. Pioneering work by Topp et al. in a phase II, single-arm clinical trial showed that 80 % (16 of 20) of MRD positive patients became MRD negative post first cycle of blinatumomab [160]. Encouraging results from the BLAST trial, wherein 78% of the MRD positive patients became negative post one cycle of blinatumomab led to its FDA approval in MRD positive settings as well [161].

In a phase I/II trial in 70 children <18 years of age with r/r ALL who were treated with single agent blinatumomab, 39% (27) achieved CR and MRD negativity in 52% [162, 163]. The AALL1331 phase III randomized trial is testing whether upfront addition of blinatumomab improves DFS in first relapse of ALL. In this trial all patients receive UK ALL R3 protocol for remission induction. Subsequently, the low risk group gets randomized to either control arm of R3 protocol or to receive three cycles of blinatumomab along with chemotherapy. The intermediate and the high-risk groups are randomized to either chemotherapy or two cycles of blinatumomab along with chemotherapy before proceeding to SCT. This trial is currently accruing patients and the results are awaited [164].

#### *4.2.12 Inotuzumab ozogamicin (InO)*

InO is a monoclonal antibody against CD22 and conjugated to calicheamicin, a potent cytotoxic compound which binds to the DNA in the leukemic blasts, resulting in double-stranded DNA breaks and cell death via apoptosis [165]. It was FDA approved in August, 2017 for use in r/r ALL. In a phase II study in r/r ALL in the age group of 6–80 years, Kantarijian et al. demonstrated ORR of 57% with median OS of 6.7 months [166]. In phase III INO-VATE trial in relapsed adult B ALL, single agent InO showed superior outcome compared to standard chemotherapy with CR (81%) and 1-year OS (78%) [167] However, its use in pediatric population continues in development. A retrospective French study in children <18 years with r/r B-ALL showed promising results (CR 72%), with hepatic and hematologic toxicities [168]. Bhojwani et al. in r/r pediatric ALL showed high CR rate (67%) with MRD negativity, independent of cytogenetic subtype or prior lines of therapy [169]. The AALL1621 phase II randomized trial in the age group 1-21 years is evaluating the role of InO in children and young adults with r/r CD22+ B ALL [170].

#### *4.2.13 CAR T-cell therapy: the new driving force for relapsed ALL*

Relapsed or refractory ALL is one of the leading causes of childhood cancer mortality. Refractory ALL in particular has a dismal prognosis with significant chemotherapy resistance in the leukemic clone. The advent of CAR T-cell therapy has brought a paradigm shift in the management of children with highly resistant disease. Rosenberg et al. at the NCI pioneered the CAR T-cell therapy and demonstrated successful treatment of cancer using CAR T-cells. This attractive therapy harnesses the immune system of the host to eradicate the leukemic clone. Adoptive T-cell therapy involves engineering T-cell receptors (TCRs) to bind to specific antigens present on tumor cells. These modified TCRs, known as CARs, allow the immune system to specifically target and destroy tumor cells in an MHC independent manner, bypassing the immune escape mechanisms of downregulation of MHC class I antigens and altered antigen processing by tumor cells [171]. These modified T cells have the capacity to expand and proliferate in the host, produce cytokines to kill tumor cells, as well as cross blood-brain barrier as shown by Maude et al. [172].

Early results from ongoing trials have shown promising and durable responses. Current complete remission rate of 90% have been reported as per the CHP959 phase I study [172]. The ELIANA [173] and ENSIGN [174] trials in r/r B ALL showed high CR rates of 90%, significantly higher than salvage rates of 30% attained with chemotherapy [26, 175]. This led to the FDA approval of CD19 4-1BB CAR T-cell therapy in August 2017 for children and young adults up to the age of 25 years. Maude et al. showed durable remission and survival in children treated with CD19 CAR T cell therapy with EFS (50%) and OS (76%) at 12 months of follow-up [176]. Success from pediatric CAR T-cell therapy trials is driving research programs across ages and disease types worldwide. The advantage of this therapy is that it can be offered to patients who are ineligible for transplant or have relapsed posttransplant, with a potential to ultimately replace SCT.

Tumor lysis syndrome, cytokine release syndrome and neurotoxicity are known complications of this therapy [177]. Another off-target toxicity is the development of B-cell aplasia, a surrogate for CAR T-cell persistence, results in agammaglobulinemia, and requires long-term immunoglobulin replacement [172]. With the use of CD19 directed CART cells, there is a risk of CD19 negative relapse [177]. Trials are underway to study the efficacy of CD22 CART cells as well as the use of dual CARS (CD19 + CD22).

**43**

**Author details**

Toronto, ON, Canada

Sneha Tandon and Angela S. Punnett\*

provided the original work is properly cited.

disease in these group of patients.

Division of Hematology/Oncology, The Hospital for Sick Children, University of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: angela.punnett@sickkids.ca

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

The outcomes for pediatric ALL have significantly improved over the past five decades, and the focus is now on minimizing the toxicity and the late effects of chemotherapy. Liposomal doxorubicin has shown remarkably low non-hematological toxicity, although the infection rates may be significant due to severe myelosuppression [178, 179]. In an attempt to decrease the toxicity of therapy, TACL 2012-002 trial is testing the use of liposomal vincristine in children and AYA with relapsed ALL [180]. This study attempts to study the feasibility and safety of liposomal formulation of vincristine sulphate over standard vincristine in first, second or

Treatment of childhood ALL has evolved over the last 50 years with progress made both in the diagnostic and therapeutic arenas. A growing understanding of the biology of the disease has allowed better risk stratification and in some cases alterations to therapy to improve outcomes. Use of pediatric-type protocols in AYA ALL has improved outcomes. Break-through research leading to the development of CAR T-cell therapy, TKIs and monoclonal antibodies have brought a paradigm shift in the management of r/r B ALL. The medical community must now consider the significant cost of these therapies, with questions related to cost-effectiveness and resource allocation ripe for study. Long-term follow-up data for these revolutionary new cancer therapies are required. Outcomes for infant ALL and relapsed T ALL are still dismal and further research is needed to develop newer strategies to combat

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

**5. Conclusions and future directions**

*4.2.14 Liposomal drug formulations*

third relapse of B or T ALL.

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