IntechOpen

Home > Books > Advances in Hematologic Malignancies

Open access peer-reviewed chapter

Pediatric Acute Lymphoblastic Leukemia: Recent Advances for a Promising Future

Written By

Sneha Tandon and Angela S. Punnett

Submitted: April 7th, 2019 Reviewed: May 27th, 2019 Published: October 23rd, 2019

DOI: 10.5772/intechopen.87092

IntechOpen
Advances in Hematologic Malignancies Edited by Gamal Abdul Hamid

From the Edited Volume

Advances in Hematologic Malignancies

Edited by Gamal Abdul Hamid

Book Details Order Print

Chapter metrics overview

1,015 Chapter Downloads

View Full Metrics
Advertisement

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and accounts for approximately 75% of all cases of childhood leukemia. Both diagnostic and therapeutic advances have been instrumental in improving the outcomes of once a dreaded disease. Currently, approximately 90% of the children treated according to risk-directed and response-adapted therapy will be long-term survivors. The use of pediatric protocols for the treatment of adolescent and young adults (AYA) has also resulted in significant improvements in their long-term survival. New therapies including tyrosine kinase inhibitors (TKIs), monoclonal antibodies and CAR T-cell therapy are changing the approach to therapy for relapsed or refractory disease. We are approaching a time where therapy for all patients will be personalized with the use of genome-based characterization of disease and incorporation of drugs against actionable targets, ultimately leading to improved clinical outcomes and decreased toxicity of therapy. Still, certain subgroups including patients with relapsed disease, infant ALL, and those with certain cytogenetic/molecular variants, remain challenging to treat. This chapter is an overview of the recent advances in the ALL disease biology, newly identified prognostic factors and an overview of emerging therapeutic options.

Keywords

  • acute lymphoblastic leukemia
  • minimal residual disease
  • CAR T-cell therapy
  • monoclonal antibody
  • advances

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].

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].

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 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, 8, 9, 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.

Figure 3.

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).

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 [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].

Advertisement

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, 17, 18]. It is an amalgam of leukemia biology, patient factors as well as therapy. With the current protocol-based, 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, 20, 21, 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 (10−6) [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.

Advertisement

3. Novel diagnostics in ALL

The recent WHO 2016 classification has incorporated morphological, immunophenotypic and the existing cytogenetic features with the new molecular features associated with the various subgroups of ALL [28]. Cytogenetic/molecular abnormalities have been identified in 60–80% of patients with ALL using traditional methods [29]; however, with the advent of genome-wide analysis, this number is expected to increase. Evolution of the diagnostics from morphology, immunohistochemistry, and banding techniques to genome-wide analysis and epigenomics has led to an increased appreciation of the biology of leukemia. Genome-wide studies have also provided insight into the variation in the response to chemotherapy drugs among patients, explaining both the differences in toxicities and response to therapy [30]. In the near future, it can be envisioned that ALL will be molecularly characterized and defined, thus enabling us to deliver tailored therapy.

Advertisement

4. Existing and novel genomics of ALL

Cytogenetic aberrations in ALL have emerged as one of the most important prognostic factors driving the biology of the disease and patient outcomes [29]. Existing and recently identified novel prognostic markers are illustrated in Figure 4 [31]. Children carrying either high hyperdiploidy (51–65 chromosomes) or ETV6-RUNX1 as their cytogenetic drivers have an excellent prognosis with survival of >90% at 5 years. Adverse prognostic factors include t(9; 22), MLL translocation, t(17; 19), complex karyotype, low hypodiploidy (31–39 chromosomes), near haploidy (24–30 chromosomes), and near triploidy (60–78 chromosomes) [13]. Germline TP53 mutations are seen in children with ALL and low hypodiploidy (chromosomes 31–39) and confer a poor prognosis [32]. New additions to the list of adverse prognostic factors include BCR-ABL-1 like mutations, iAMP21, CRFL2 overexpression, JAK mutations, and translocations involving immunoglobulin heavy chain (IGH), TCF-PBX1, IKZF1, PAX5, ERG and EBF1 mutations [31, 33, 34, 35, 36, 37]. Association of CDKN2A/2B deletions with Ph + ALL have emerged as a poor prognostic factor with guarded prognosis even with SCT [33]. FLT3 mutations have been found in KMT2A rearranged infant ALL and confer a poor prognosis [38, 39, 40]. Growing understanding of the biology of the disease allows better risk stratification and in some cases alterations to therapy to improve outcomes. For example, therapy intensification has resulted in improved outcomes in children harboring the iAMP21 mutation [41, 42].

Figure 4.

Sub-classification of childhood ALL. Blue wedges refer to B-progenitor ALL, yellow to recently identified subtypes of B-ALL, and red wedges to T-lineage ALL (reprinted from Ref. [31], copyright (2013) with permission from Elsevier).

In T-cell ALL, mutations commonly found are those involved in T-cell development. Mutations of the NOTCH-1 activating gene are seen in approximately 50–60% of all the T-ALL cases, while mutations involving the tumor suppressor gene FBXW7 are found in approximately 15% of cases [43]. The French group (FRALLE) has demonstrated favorable outcomes in those with NOTCH/FBXW7 mutations along with wild-type PTEN/RAS [44]. However, the prognostic significance of these in T-ALL is not well defined [45, 46]. Genome-wide association studies have recently identified a number of inherited genetic polymorphisms that are associated with an increased predisposition to develop ALL. These novel genes include ARID5B, GATA3, IKZF1, CDKN2A, CDKN2B, PIP4K2A and TP63 [47, 48, 49, 50, 51, 52, 53].

4.1 Novel genomics

Salient features of the novel prognostic factors are described below:

4.1.1 Ph-like ALL

BCR-ABL1-like ALL has recently been recognized by sequencing studies by the COG-St Jude consortium (TARGET) and the DCOG, and disease shows a similar gene expression profile to that of Ph + ALL in the absence of the BCR-ABL-1 gene translocation [54, 55, 56]. This accounts for 10% of pediatric and 15–20% of AYA ALL and confers an extremely poor prognosis with 5-year disease free survival (DFS) of 25% in AYA patients [34, 54]. The AALL0331 study showed decrease prevalence of Ph-like ALL in children with NCI standard risk (SR) compared to high risk (HR) ALL [57]. Ph-like ALL harbors two types of genomic alterations namely kinase activatingand cytokine receptor alterations[58]. The kinase alterations which can be inhibited by ABL inhibitors include ABL1, ABL2, colony stimulating factor 1 receptor (CSF1R), platelet-derived growth factor receptor alfa and beta (PDGFRA, PDGFRB) [34]. Cytokine receptor alterations include alterations that act via the JAK/STATpathway. This includes membrane-bound thymic stromal lymphopoietin receptor (TSLRP)/CRLF2. Other pathways involving CRLF2 include PI3Kand the mTORpathways [58]. CRLF2gene rearrangements have been associated with 50% of the cases of Ph-like ALL, of which another 50% also show positivity for JAKmutations [33, 56]. Additionally, IKZF1deletions (28%), EPOR, RASpathway (10%) are also seen in this group. Patients harboring the CRLF2alterations fare poorly with high risk of relapse [59]. Similarly, increased expression of IKZF1possibly translates into high post induction MRD as well as higher risk of relapse [60, 61].

4.1.2 IKZF1 deletions

The IKZF1deletion has recently emerged as a novel genomic marker in childhood ALL. This subtype is commonly seen in older children, those with higher WBC counts, Down syndrome (DS), BCR-ABL and Ph-like ALL [55, 59, 62, 63]. Increased association is also seen with CRLF2mutations [62]. IKZF1deletion is an independent poor prognostic genomic feature in multivariate analysis [64, 65, 66, 67, 68]. The AIEOP-BFM group showed IKZF1deletions confer a poor prognosis only in the high end-induction MRD group with co-existent CDKN2A, CDKN2B, PAX5, or PAR1mutations [69].

4.1.3 JAK-pathway mutations.

JAKmutations are commonly found in Ph-like ALL (20%) and are also associated with CRLF2mutations [33]. These are also seen in approximately 15% of children with DS ALL [34, 70, 71]. Identification of this mutation is essential as it has therapeutic implications with responses seen both in vitro and in vivoto TKIs [72]. The ongoing phase II trial AALL1521 is testing upfront addition of ruxolitinib to chemotherapy for CRFL2rearranged or JAK-pathway mutant children with ALL [73].

4.1.4 Immunoglobulin heavy chain gene (IGH) rearrangement, CRLF2 overexpression

IGH, a novel, adverse prognostic, cytogenetic driver is seen in less than 3% of pediatric and 10% of AYA ALL [74]. This rearrangement is characterized by the juxtaposition of a partner oncogene like CRLF2(25%) or CEBP(10%) with IGHthat drives the overexpression. CRLF2overexpression is seen in a very high proportion (>50%) of children with DS, but the prognostic significance is still unclear [59].

4.1.5 iAMP21

This novel prognostic marker is seen in about 1.5–2% of pediatric ALL and is characterized by ≥3 extra copies of RUNX1gene on a single abnormal chromosome 21q22 [75, 76]. Increased predisposition to develop iAMP21ALL is seen in carriers of the Robertsonian translocation involving chromosomes 15 and 21 [77]. This subtype presents in older children (median 10 years), is more common in females, and presents with WBC count of less than 50 × 109/L. Presence of this mutation confers a poor prognosis with standard therapy as well as high post remission-induction MRD [41, 78, 79]. However, the outcomes are better with MRD-guided and intensive chemotherapy, as shown in the UKALL2003 and the ALL-BFM 2000 studies, hence precluding the need for SCT in first remission [41, 42].

4.2 Treatment

4.2.1 Adolescents and young adults (AYA) with ALL

AYA constitutes a unique group of ALL with an age range of 15–39 years as defined by the NCI. Based on disease biology, there has always been a debate as to the best regimen to be used in this age group. Historically, ALL in the AYA population has been associated with a poor outcome and higher treatment related morbidity. However, the current focus of treating AYA as per pediatric protocols has resulted in improvement in their outcomes [14, 15] as shown in Table 1. Chemotherapy protocols similar to the BFM backbone with corticosteroids, vincristine and asparaginase in induction, post-remission asparaginase, and CNS prophylaxis during induction have shown improved survival in this cohort of patients. Also, SCT is offered only to the very-high risk population in first complete remission (CR1) [80].

Serial no.Study groupPatients numbers (n)Median age (y)Survival (%)
1.CCG [14]1971667, OS 7y
2.CALGB [15]1241946
3.FRALLE93 [15]771667 EFS
4.AIEOP [83, 84]1501580, OS 2y
5.DCOG [85]471271 EFS
6.NOPHO92 [86]361674, OS 5y
7.MRC ALL [87]6115–1771, OS 5y
8.UKALL2003 [24]22916–2472 EFS

Table 1.

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

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).

To support this further, the excellent results from the large study by the GRAALL group have shown significantly improved survival (66% vs. 44%, P < 0.001) for those treated with pediatric-inspired protocols compared to historical controls treated with adult protocols [81]. The largest study which has evaluated this hypothesis is the US intergroup trial C10403, in which 318 AYA patients were treated as per the standard arm of the COG AALL0232 protocol. Encouraging results from this study showed a 2-year event free survival (EFS) of 66% and overall survival (OS) of 78%, with manageable toxicity profile and subsequently the NCI recommended that pediatric-inspired protocols could be used effectively up to the age of 40 years [82].

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% 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 pre-clinical models include; CRLF2inhibition (Givinostat [100], Luminespib [101], Selumetinib [102], TSLPR CART cells [103]), JAK-2(CHZ868) [104], mTORpathway (Rapamycin) [105], PI3Kand mTORpathways (Gedatolisib) [106], and TNF-ainhibition (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]. 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].

4.2.4 Hypodiploid ALL

Hypodiploidy (<45 chromosomes) is present in less than 5% of ALL. Survival across various studies ranges between 50 and 60% on currently available therapy [111, 112, 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, PAG1and IKZF3, and low hypodiploidy with P53, IKZF2, RB1, histone modifiersand 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 high-risk subset of pediatric ALL.

4.2.5 Down syndrome ALL

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]. IKZF1gene deletion, seen in approximately 35% of DS ALL portends inferior outcome [121, 122]. About 50–60% of the children with DS ALL harbor CRLF2mutation, much higher than in children with ALL without DS (<10%). Approximately, 20% of children with DS ALL also carry JAK2mutations, with majority also harboring CRLF2mutation. However, their prognostic significance is unknown [121, 123, 124].

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, 131, 132, 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/mTORand MAPKwith 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 NOTCH1mutation at a much lower 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 JAK1/2inhibitor 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

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 post-transplant, 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).

4.2.14 Liposomal drug formulations

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 third relapse of B or T ALL.

Advertisement

5. Conclusions and future directions

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 disease in these group of patients.

References

  1. 1. Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute; 2013. Section 28
  2. 2. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute; 2013. Section 29
  3. 3. Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute; 2013. Section 28
  4. 4. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute; 2013. Section 29
  5. 5. Bleyer A, O’Leary M, Barr R, Ries LAG, editors. Cancer Epidemiology in Older Adolescents and Young Adults 15-29 Years of Age, Including SEER Incidence and Survival: 1975-2000. National Cancer Institute, NIH Pub.No. 06-5767, Bethesda, MD 2006
  6. 6. Hunger SP, Mullighan GC. Acute lymphoblastic leukemia in children. New England Journal of Medicine. 2015;373:1541-1552
  7. 7. Bostrom BC, Sensel MR, Sather HN, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: A report from the Children’s Cancer Group. Blood. 2003;101(10):3809-3817
  8. 8. Matloub Y, Bostrom BC, Hunger SP, et al. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukaemia: A report from the Children’s Oncology Group. Blood. 2011;118(2):243-251
  9. 9. Seibel NL, Steinherz PG, Sather HN, et al. Early post induction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukaemia: A report from the Children’s Oncology Group. Blood. 2008;111(5):2548-2555
  10. 10. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. The New England Journal of Medicine. 2009;360(26):2730-2741
  11. 11. Kelly MJ, Trikalinos TA, Dahabreh IJ, Gaianferante M, Parsons SK. Cranial radiation for pediatric acute lymphoblastic leukemia: A systematic review and meta-analysis. American Journal of Hematology. 2014;89(10):992-997
  12. 12. Irken G, Oren H, Gulen M, et al. Treatment outcome of adolescents with acute lymphoblastic leukemia. Annals of Hematology. 2002;81:641-645
  13. 13. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. The New England Journal of Medicine. 2006;354:166-178
  14. 14. Stock W, La M, Sanford B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood. 2008;112(5):1646-1654
  15. 15. Boissel N, Auclerc MF, Lhéritier V, et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. Journal of Clinical Oncology. 2003;21(5):774-780
  16. 16. van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352(9142):1731-1738
  17. 17. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: A Children’s Oncology Group study. Blood. 2008;111(12):5477-5485
  18. 18. Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual disease in high risk B-ALL: A report from Children’s Oncology Group study AALL0232. Blood. 2015;126(8):964-971
  19. 19. Möricke A, Zimmermann M, Valsecchi MG, et al. Dexamethasone vs prednisone in induction treatment of paediatric ALL: Results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016;127(17):2101-2112
  20. 20. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): A randomized controlled trial. The Lancet Oncology. 2013;14(3):199-209
  21. 21. Place AE, Stevenson KE, Vrooman LM, et al. Intravenous pegylated asparaginase versus intramuscular nativeEscherichia colil-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): A randomized, open-label phase 3 trial. The Lancet Oncology. 2015;16(16):1677-1690
  22. 22. Pieters R, de Groot-Kruseman H, Van der Velden V, et al. Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: Study ALL10 from the Dutch childhood oncology group. Journal of Clinical Oncology. 2016;34(22):2591-2601
  23. 23. Wood B, Wu D, Crossley B, et al. Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL. Blood. 2018;131:1350-1359
  24. 24. Vora A, Goulden N, Mitchell C, et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): A randomized controlled trial. The Lancet Oncology. 2014;15(8):809-818
  25. 25. Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: Results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010;115(16):3206-3214
  26. 26. Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: Results of trial ALL-REZ BFM 90. Journal of Clinical Oncology. 2010;28:2339-2347
  27. 27. Freyer DR, Devidas M, La M, Carroll WL, Gaynon PS, Hunger SP, et al. Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: A report from the Children’s Oncology Group. Blood. 2011;117:3010-3015
  28. 28. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405
  29. 29. Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. The New England Journal of Medicine. 2004;350:1535-1548
  30. 30. Visscher H, Ross CJ, Rassekh SR, Barhdadi A, et al. Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. Journal of Clinical Oncology. 2012;30(13):1422-1428
  31. 31. Mullighan CG. Genomic characterization of childhood acute lymphoblastic leukemia. Seminars in Hematology. 2013;50(4):314-324
  32. 32. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nature Genetics. 2013;45(3):242-252
  33. 33. Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by deletion of Ikaros. Nature. 2008;453(7191):110-114
  34. 34. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinase-activating lesions n Ph-like acute lymphoblastic leukaemia. New England Journal of Medicine. 2014;371(11):1005-1015
  35. 35. Harvey RC, Mullingham CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: Correlation with genome-wide DNA copy number alterations, clinical charatcteristics, and outcome. Blood. 2010;116(23):4874-4884
  36. 36. Clappier E, Auclerc MF, Rapion J, et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with favorable outcome despite frequent IKZF1 deletions. Leukemia. 2014;28(1):70-77
  37. 37. Zaliova M, Zimmermannova O, Dorge P, et al. ERG mutation is associated with CD2 and attenuates the negative impact of IKZF1 deletion in childhood acute lymphoblastic leukemia. Leukemia. 2014;28(1):182-185
  38. 38. Anderson AK, Ma J, Wang J, et al. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nature Genetics. 2015;47(4):330-337
  39. 39. Chillon MC, Gomez-Casares MT, Lopez-Jorge CE, et al. Prognostic significance of FLT-3 mutational status and expression levels in MLL-AF4+ and MLL-germline acute lymphoblastic leukemia. Leukemia. 2012;26(11):2360-2366
  40. 40. Stam RW, Schneider P, de Lorenzo P, Valsecchi MG, den Boer ML. Pieters prognostic significance of high-level FLT3 expression in MLL-rearranged infant acute lymphoblastic leukemia. Blood. 2007;110(7):2774-2775
  41. 41. Harrison CJ, Moorman AV, Schwab C, et al. An international study of intrachromosomal amplification of chromosome 21 (iAMP21): Cytogenetic characterization and outcome. Leukemia. 2014;28(5):1015-1021
  42. 42. Attarbaschi A, Panzer-Grumayer R, Mann G, Moricke A, Konig M, Mecklenbrauker A, et al. Minimal residual disease-based treatment is adequate for relapse-prone childhood acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21: The experience of the ALL-BFM 2000 trial. Klinische Pädiatrie. 2014;226(6-7):338-343
  43. 43. Gallo Llorente L, Luther H, Schneppenheim R, et al. Identification of novel NOTCH1 mutations: Increasing our knowledge of the NOTCH signaling pathway. Pediatric Blood & Cancer. 2014;61(5):788-796
  44. 44. Petit A, Trinquand A, Chevret S, et al. Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia. Blood. 2018;131:289-300
  45. 45. Armstrong SA, Look AT. Molecular genetics of acute lymphoblastic leukaemia. Journal of Clinical Oncology. 2005;23(26):6306-6315
  46. 46. Karrman K, Forestier E, Heyman M, et al. Clinical and cytogenetic features of a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: Rare T-cell receptor gene rearrangements are associated with poor outcome. Genes, Chromosomes & Cancer. 2009;48(9):795-805
  47. 47. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nature Genetics. 2009;41(9):1006-1010
  48. 48. Treviño LR, Yang W, French D, et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nature Genetics. 2009;41(9):1001-1005
  49. 49. Migliorini G, Fiege B, Hosking FJ, et al. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood. 2013;122(19):3298-3307
  50. 50. Hungate EA, Vora SR, Gamazon ER, et al. A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology. Nature Communications. 2016;7:10635
  51. 51. Sherborne AL, Hosking FJ, Prasad RB, et al. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nature Genetics. 2010;42(6):492-494
  52. 52. Xu H, Yang W, Perez-Andreu V, et al. Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. Journal of the National Cancer Institute. 2013;105(10):733-742
  53. 53. Ellinghaus E, Stanulla M, Richter G, et al. Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia. Leukemia. 2012;26(5):902-909
  54. 54. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: A genome-wide classification study. The Lancet Oncology. 2009;10(2):125-134
  55. 55. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. The New England Journal of Medicine. 2009;360(5):470-480
  56. 56. Reshmi SC, Harvey RC, Roberts KG, et al. Targetable kinase gene fusions in high-risk B-ALL: A study from the Children’s Oncology Group. Blood. 2017;129(25):3352-3361
  57. 57. Kathryn G, Roberts KG, Reshmi SC, Harvey RC, et al. Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: A report from the Children’s Oncology Group. Blood. 2018;132:815-824
  58. 58. Tasian SK, Doral MY, Borowitz MJ, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRFL2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833-842
  59. 59. Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood. 2010;115(26):5312-5321
  60. 60. Fang Q , Zhao X, Li Q , et al. IKZF1 alterations and expression of CRLF2 predict prognosis in adult Chinese patients with B-cell precursor acute lymphoblastic leukemia. Leukemia & Lymphoma. 2017;58(1):127-137
  61. 61. Dou H, Chen X, Huang Y, et al. Prognostic significance of P2RY8-CRLF2 and CRLF2 overexpression may vary across risk subgroups of childhood B-cell acute lymphoblastic leukemia. Genes, Chromosomes & Cancer. 2017;56(2):135-146
  62. 62. Schmäh J, Fedders B, Panzer-Grümayer R, et al. Molecular characterization of acute lymphoblastic leukemia with high CRLF2 gene expression in childhood. Pediatric Blood & Cancer. 2017;64:e26539
  63. 63. Schwab CJ, Chilton L, Morrison H, et al. Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: Association with cytogenetics and clinical features. Haematologica. 2013;98(7):1081-1088
  64. 64. Krentz S, Hof J, Mendioroz A, et al. Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia. 2013;27(2):295-304
  65. 65. Feng J, Tang Y. Prognostic significance of IKZF1 alteration status in pediatric B-lineage acute lymphoblastic leukemia: A meta-analysis. Leukemia & Lymphoma. 2013;54(4):889-891
  66. 66. Dörge P, Meissner B, Zimmermann M, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica. 2013;98(3):428-432
  67. 67. Olsson L, Castor A, Behrendtz M, et al. Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011. Leukemia. 2014;28(2):302-310
  68. 68. Boer JM, van der Veer A, Rizopoulos D, et al. Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: An international collaborative study. Leukemia. 2016;30(1):32-38
  69. 69. Stanulla M, Dagdan E, Zaliova M, et al. IKZF1plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric B-cell precursor acute lymphoblastic leukemia. Journal of Clinical Oncology. 2018;36(12):1240-1249
  70. 70. Loh ML, Zhang J, Harvey RC, et al. Tyrosine kinome sequencing of paediatric acute lymphoblastic leukaemia: A report from the Children’s Oncology Group TARGET project. Blood. 2013;121(3):485-488
  71. 71. Bercovich D, Ganmore I, Scott LM, et al. Muatations of JAK2 in acute lymphoblastic leukaemias associated with down’s syndrome. Lancet. 2008;372(9648):1484-1492
  72. 72. Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153-166
  73. 73. A Phase 2 Study of Ruxolitinib with Chemotherapy in Children with Acute Lymphoblastic Leukemia.ClinicalTrials.govIdentifier: NCT02723994
  74. 74. Russell LJ, Enshaei A, Jones L, et al. IGH translocations are prevalent in teenagers and young adults with acute lymphoblastic leukemia and are associated with a poor outcome. Journal of Clinical Oncology. 2014;32(14):1453-1462
  75. 75. Harrison CJ, Haas O, Harbott J, et al. Detection of prognostically relevant genetic abnormalities in childhood B-cell precursor acute lymphoblastic leukemia: Recommendations from the biology and diagnosis Committee of the International Berlin-Frankfurt-Munster study group. British Journal of Haematology. 2010;151(2):132-142
  76. 76. Reichard KK, Kang H, Robinson HM, et al. Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood. 2007;109(6):2327-2330
  77. 77. Li Y, Schwab C, Ryan SL, et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukemia. Nature. 2014;508(7494):98-102
  78. 78. Heerema NA, Carroll AJ, Devidas M, et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children’s oncology group studies: A report from the children’s oncology group. Journal of Clinical Oncology. 2013;31(27):3397-3402
  79. 79. Moorman AV, Robinson H, Schwab C, et al. Risk-directed treatment intensification significantly reduces the risk of relapse among children and adolescents with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21: A comparison of the MRC ALL97/99 and UKALL2003 trials. Journal of Clinical Oncology. 2013;31(27):3389-3396
  80. 80. Stock W, La M, Sanford B, et al. What determines the outcome for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Leukemia Group B studies. Blood. 2008;112(5):1646-1654
  81. 81. Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: The GRALL-2003 study. Journal of Clinical Oncology. 2009;27(6):911-918
  82. 82. Advani A, Sanford B, Luger S, et al. Frontline-treatment of acute lymphoblastic leukemia (ALL) In older adolescents and young adults (AYA) using a pediatric regimen is Feaible: Toxicity results of the prospective US intergroup trial C10403(Alliance). Blood. 2013;122:903
  83. 83. Testi AM, Valsecchi MG, Conter V, et al. Difference in outcome of adolescents with acute lymphoblastic leukemia (ALL) enrolled in pediatric (AIEOP) and adult (GIMEMA) protocols. [Abstract]. Blood. 2004;104:A-1954
  84. 84. de Bont JM, van der Holt B, Dekker AW, et al. Adolescents with acute lymphatic leukaemia achieve significantly better results when treated following Dutch paediatric oncology protocols than with adult protocols. Nederlands Tijdschrift voor Geneeskunde. 2005;149(8):400-406
  85. 85. Hallböök H, Gustafsson G, Smedmyr B, et al. Treatment outcome in young adults and children >10 years of age with acute lymphoblastic leukemia in Sweden: A comparison between a pediatric protocol and an adult protocol. Cancer. 2006;107(7):1551-1561
  86. 86. Ramanujachar R, Richards S, Hann I, et al. Adolescents with acute lymphoblastic leukaemia: Outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatric Blood & Cancer. 2007;48(3):254-261
  87. 87. Hough R, Rowntree C, Goulden N, et al. Efficacy and toxicity of a paediatric protocol in teenagers and young adults with Philadelphia chromosome negative acute lymphoblastic leukaemia: Results from UKALL 2003. British Journal of Haematology. 2016;172(3):439-451
  88. 88. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lympoblastic leukemia. Nature. 2007;446:758-764
  89. 89. Suryanarayan K, Hunger SP, Kohler S, Carroll AJ, Crist W, Link MP, et al. Consistent involvement of the bcr gener by 9;22 breakpoints in pediatric acute leukemias. Blood. 1991;77(2):324-330
  90. 90. Bernt KM, Hunger SP. Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia. Frontiers in Oncology. 2014;4:54
  91. 91. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: Addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014;123(6):843-850
  92. 92. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: A children’s oncology group study. Journal of Clinical Oncology. 2009;27(31):5175-5181
  93. 93. Schultz KR, Carroll A, Heerema NA, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s oncology group study AALL0031. Leukemia. 2014;28(7):1467-1471
  94. 94. Zwaan CM, Rizzari C, Mechinaud F, et al. Dasatinib in children and adolescents with relapsed or refractory leukemia: Results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. Journal of Clinical Oncology. 2013;31(19):2460-2468
  95. 95. Kim DY, Joo YD, Lim SN, et al. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia—Positive acute lymphoblastic leukemia. Blood. 2015;126(6):746-756
  96. 96. Ravandi F, Jorgensen JL, Thomas DA, et al. Detection of MRD may predict the outcome of patients with Philadelphia chromosome-positive ALL treated with tyrosine kinase inhibitors plus chemotherapy. Blood. 2013;122(7):1214-1221
  97. 97. Giebel S, Czyz A, Ottmann O, et al. Use of tyrosine kinase inhibitors to prevent relapse after allogenic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. A position statement of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2016;122(19):2941-2951
  98. 98. ClinicalTrials.gov. International Phase 3 Trial in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. (Ph+ALL) Testing Imatinib in Combination with Two Different Cytotoxic Chemotherapy Backbones. Identifier NCT03007147
  99. 99. Roberts KG, Pei D, Campana D, et al. Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. Journal of Clinical Oncology. 2014;32(27):3012-3020
  100. 100. Savino AM, Sarno J, Trentin L, et al. The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRF2-rearranged BCP-ALL. Leukemia. 2017;31:2365-2375
  101. 101. Kucine N, Marubayashi S, Bhagwat N, et al. Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias. Blood. 2015;126(22):2479-2483
  102. 102. Suryani S, Bracken LS, Harvey RC, et al. Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia. Molecular Cancer Therapeutics. 2015;14(2):364-374
  103. 103. Qin H, Cho M, Haso W, et al. Eradication of B-ALL using chimeric antigen receptor-expressing T cells targeting the TSLPR oncoprotein. Blood. 2015;126(5):629-639
  104. 104. Wu S-C, Li LS, Kopp N, et al. Activity of the type II JAK2 inhibitor CHZ868 in B-cell acute lymphoblastic leukemia. Cancer Cell. 2015;28(1):29-41
  105. 105. Maude SL, Tasian SK, Vincent T, et al. Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2012;120(17):3510-3518
  106. 106. Tasian SK, Teachey DT, Li Y, et al. Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2017;129(2):177-187
  107. 107. Richmond J, Robbins A, Evans K, et al. Acute sensitivity of Ph-like acute lymphoblastic leukemia to the SMAC-mimetic birinapant. Cancer Research. 2016;76(15):4579-4591
  108. 108. ClinicalTrials.gov. Ruxolitinib or dasatinib with chemotherapy in patients with Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL). Available from:https://clinicaltrials.gov/ct2/show/NCT02420717.Identifier:NCT02420717
  109. 109. ClinicalTrials.gov. A phase 2 study of ruxolitinib with chemotherapy in children with acute lymphoblastic leukemia. Available from:https://clinicaltrials.gov/ct2/show/NCT02723994.Identifier:NCT02723994
  110. 110. ClinicalTrials.gov. Combination chemotherapy in treating young patients with newly diagnosed high-risk B acute lymphoblastic leukemia and Ph-like TKI sensitive mutations. Available from:http://clinicaltrials.gov/ct2/show/NCT02883049.Identifier:NCT02883049
  111. 111. Harrison CJ, Moorman AV, Broadfield ZJ, et al., Childhood and Adult Leukaemia Working Parties. Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia. British Journal of Haematology. 2004;125(5):552-559
  112. 112. Nachman JB, Heerema NA, Sather H, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 2007;110(4):1112-1115
  113. 113. McNeer J, Devidas M, Dai Y, Carroll AJ, et al. Hematopoietic stem-cell transplantation does not improve the poor outcome of children with hypodiploid acute lymphoblastic leukemia: A report from Children’s Oncology Group. Journal of Clinical Oncology. 2019;37:780-789
  114. 114. Safavi S, Paulsson K. Near-haploid and low-hypodiploid acute lymphoblastic leukemia: Two distinct subtypes with consistently poor prognosis. Blood. 2017;129(4):420-423
  115. 115. Mullighan CG, Jeha S, Pei D, et al. Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood. 2015;126(26):2896-2899
  116. 116. Tasian SK, Teachey DT, Rheingold SR. Targeting the PI3K/mTOR pathway in pediatric hematologic malignancies. Frontiers in Oncology. 2014;4:108
  117. 117. Mamokin M, Rouce RH, Tashiro H, Brenner MK. A T-cell-directed chimeric antigen receptor for the selective treatment if T-cell malignancies. Blood. 2015;126(8):983-992
  118. 118. Hasle H. Pattern of malignant disorders in individuals with Down’s syndrome. The Lancet Oncology. 2001;2(7):429-436
  119. 119. Whitlock JA. Down syndrome and acute lymphoblastic leukaemia. British Journal of Haematology. 2006;135(5):595-602
  120. 120. Zeller B, Gustafsson G, Forestier E, et al. Acute leukaemia in children with Down syndrome: A population-based Nordic study. British Journal of Haematology. 2005;128(6):797-804
  121. 121. Buitenkamp TD, Pieters R, Gallimore NE, et al. Outcome in children with Down syndrome and acute lymphoblastic leukaemia: Role of IKZF1 deletions and CRLF2 aberrations. Leukemia. 2012;26(10):2204-2211
  122. 122. Hanada I, Terui K, Ikeda F, et al. Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan. Genes Chromosome Cancer. 2014;53(11):902-910
  123. 123. Hertzberg L, Vendramini E, Ganmore I, et al. Down syndrome acute lymphoblastic leukemia, a highly heterogenous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: A report from the International BFM Study Group. Blood. 2010;115(5):1006-1017
  124. 124. Gaikwad A, Rye CL, Devidas M, et al. Prevalence and clinical correlates of JAK2 in acute lymphoblastic leukaemia. British Journal of Haematology. 2009;144(6):930-932
  125. 125. Heerema NA, Sather HN, Ge J, et al. Cytogenetic studies of infant acute lymphoblastic leukaemia: Poor prognosis of infants with t(4;11)-a report of the Childrens’ Cancer Group. Leukemia. 1999;13:679-686
  126. 126. Chessells JM, Harrison CJ, Watson SL, Vora AJ, Richards SM. Treatment of infants with lymphoblastic leukaemia: Results of the UK Infant Protocols 1987-1999. British Journal of Haematology. 2002;117:306-314
  127. 127. Hilden JM, Dinndorf PA, Meerbaum SO, et al., Children’s Oncology Group. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: Report on CCG 1953 from the Children’s Oncology Group. Blood. 2006;108(2):441-451
  128. 128. Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukemia (Interfant-99): An observational study and a multicentre randomized trial. Lancet. 2007;370(9583):240-250
  129. 129. Meyer C, Burmeister T, Groger D, et al. The MLL recombinome of acute leukemias in 2017. Leukemia. 2018;32(2):273-284
  130. 130. Taketani T, Taki T, Sugita K, et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004;103:1085-1088
  131. 131. Armstrong SA, Mabon ME, Silverman LB, et al. FLT3 mutations in childhood acute lymphoblastic leukaemia. Blood. 2003;103:3544-3546
  132. 132. Ross ME, Zhou Song G, et al. Classification of paediatric acute lymphoblastic leukaemia by gene expression profiling. Blood. 2003;102:2951-2959
  133. 133. Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukaemia by gene expression profiling. Cancer Cell. 2002;1:13-143
  134. 134. Dreyer ZE, Hilden JM, Jones TL, et al. Intensified chemotherapy without SCT in infant ALL: Results from COG P9407 (Cohort 3). Pediatric Blood & Cancer. 2015 Mar;62(3):419-426
  135. 135. Tomizawa D, Koh K, Sato T, et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: A final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia. 2007;21(11):2258-2263
  136. 136. Stam RW, Schneider P, de Lorenzo P, Valsecchi MG, den Boer ML, Pieters R. Prognostic significance of high-level FLT3 expression in MLL-rearranged infant acute lymphoblastic leukemia. Blood. 2007;110(7):2774-2775
  137. 137. ClinicalTrials.gov. A Groupwide Pilot study the Tolerability and Biological Activity of the Addition of Azacytidine (NSC#102816) to Chemotherapy in Infants with acute lymphoblastic leukemia (ALL) and KMT2A(MLL) Gene Rearrangement. Available from:https://clinicaltrials.gov.Identifier:NCT02828358
  138. 138. Patrick K, Wade R, Goulden N, et al. Improved outcomes for children and young people with T-acute lymphoblastic leukaemia: Results of the UKALL2003 Trial. Blood. 2014;124(21):3702
  139. 139. Place AE, Stevenson KE, Harris MH, et al. Outcome of childhood T-cell acute lymphoblastic leukemia (T-ALL): Results from DFCI protocol 05-001. ASCO Meeting Abstracts. 2014;32(suppl 15):10015
  140. 140. Schrappe M, Valsecchi MG, Bartram CR, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: Results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118(8):2077-2084
  141. 141. Winter SS, Devidas M, Chen S, et al. Capizzi-style methotrexate with pegasparginase (C-MTX) is superior to high-dose methotrexate (HDMTX) in T-lineage acute lymphoblastic leukemia(T-ALL): Results from Children’s Oncology Group (COG) AALL0434 [abstract]. Blood. 2015;126(23). Abstract 794
  142. 142. Sison EA, Silverman LB. CNS prophylaxis in pediatric acute lymphoblastic leukemia. Hematology. American Society of Hematology. Education Program. 2014;2014(1):198-201
  143. 143. Dunsmore KP, Devidas M, Linda SB, et al. Pilot study of nelarabine in combination with intensive chemotherapy in high-risk T-cell acute lymphoblastic leukemia: A report from the Children’s Oncology Group. Journal of Clinical Oncology. 2012;30(22):2753-2759
  144. 144. Winter SS, Dunsmore KP, Devidas M, et al. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children’s Oncology Group Study AALL0434. Pediatric Blood & Cancer. 2015;62(7):1176-1183
  145. 145. Raetz EA, Teachey DT. T-cell acute lymphoblastic leukemia. Hematology. 2016;2016:580-588
  146. 146. Raetz EA, Borowitz MJ, Devidas M, et al. Reinduction platform for children with first marrow relapse of acute lymphoblastic leukemia. A Children’s Oncology Group Study [corrected]. Journal of Clinical Oncology. 2008;26(24):3971-3978
  147. 147. Horton T, Lu X, O’Brien M, et al. AALL07P1: Bortezomib with reinduction chemotherapy for first relapse pediatric ALL. A Children’s Oncolgy group Study. Pediatric Blood & Cancer. 2014;61(S2):S137
  148. 148. Liu Y, Easton J, Shao Y, Maciaszek J, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nature Genetics. 2017;49(8):1211-1218
  149. 149. Roti G, Stegmaier K. New approaches to target T-ALL. Frontiers in Oncology. 2014;4:170
  150. 150. Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481(7380):157-163
  151. 151. Gutierrez A, Dahlberg SE, Neuberg DS, et al. Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia. Journal of Clinical Oncology. 2010;28(24):3816-3823
  152. 152. Yang YL, Hsiao CC, Chen HY, et al. Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T-cell acute lymphoblastic leukemia. Pediatric Blood & Cancer. 2012;58(6):846-851
  153. 153. Durinck K, Goossens S, Peirs S, et al. Novel biological insights in T-cell acute lymphoblastic leukemia. Experimental Hematology. 2015;8:625-639
  154. 154. Vincente C, Schwab C, Broux M, et al. Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia. Haematologica. 2015;100(10):1301-1310
  155. 155. Maude SL, Dolai S, Delgado-Martin C, et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood. 2015;125(11):1759-1767
  156. 156. Patrick K, Wade R, Goulden N, et al. Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukemia treated on a contemporary protocol, UKALL2003. British Journal of Haematology. 2014;166(3):421-424
  157. 157. Woods BL, Winter SS, Dunsmore KP, et al. T-lumphoblastic leukemia(T-ALL) shows excellent outcome, lack of significance of the early thymic precursor (ETP) immunophenotype, and validation of the prognostic value of end-induction minimal residual disease (MRD) in Children’s Oncology Group (COG) Study AALL0434[abstract]. Blood. 2014;124(21).Abstract 1
  158. 158. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495-497
  159. 159. Nagorsen D, Kufer P, Baeuerle PA, Bargou R. Blinatumomab: A historical perspective. Pharmacology & Therapeutics. 2012;136(3):334-342
  160. 160. Topp MS, Gökbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T-cell engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. Journal of Clinical Oncology. 2014;32(36):4134-4140
  161. 161. Gökbuget N, Zugmaier G, Klinger M, et al. Long-term relapse-free survival in a phase 2 study of blinatumomab for the treatment of patients with minimal residual disease in B-Lineage acute lymphoblastic leukemia. Haematologica. 2017;102(4):e132-e135
  162. 162. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Journal of Clinical Oncology. 2016;34(36):4381-4389
  163. 163. Schlegel P, Lang P, Zugmaier G, et al. Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. Haematologica. 2014;99(7):1212-1219
  164. 164. ClinicalTrials.gov. Risk-Stratified Randomized Phase III Testing of Blinatumomab (NSC# 765986) in First Relapse of Childhood B-Lymphoblastic Leukemia (B-ALL). Available from:https://clinicaltrials.gov.Identifier:NCT02101853
  165. 165. Thomas X. Inotuzumab ozogamicin in the treatment of B-cell acute lymphoblastic leukemia. Expert Opinion on Investigational Drugs. 2012;21(16):871-878
  166. 166. Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: A single-arm, phase 2 study. The Lancet Oncology. 2018;19(2):240-248
  167. 167. Kantarjian HM, Deangelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. New England Journal of Medicine. 2016;375(8):740-753
  168. 168. Calvo C, Brethon B, Hamy CA, Adjaoud D, et al. Inotuzumab ozogamicin compassionate use for the French pediatric patients with relapsed or refractory acute lymphoblastic leukemia. Blood. 2018;132:5203
  169. 169. Bhojwani D, Sposto R, Shah NN, Rodriquez V, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2018
  170. 170. ClinicalTrials.gov. A Phase 2 Study of Inotuzumab Ozogamicin (NSC#772518, IND#TBD) in Children and Young Adults with Relapsed or Refractory CD22+B-Acute Lymphoblastic Leukemia(B-ALL). Identifier: 02981628
  171. 171. Muhammad N, Mao Q , Xia H. CAR T-cells for cancer therapy. Biotechnology & Genetic Engineering Reviews. 2017;33(2):190-226
  172. 172. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remission in leukemia. The New England Journal of Medicine. 2014;371(16):1507-1517
  173. 173. Grupp SA, Laetsch TW, Buechner J. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood. 2016;128:221
  174. 174. Maude SL, Pulsipher MA, Boyer MW. Efficacy and safety of CTL019 in the first US phase II multicentre trial in pediatric relapsed/refractory acute leukemia: Results of an interim analysis. Blood. 2016;128:2801
  175. 175. Ko RH, Ji L, Barnette P, Bostrom B, Hutchinson R, Raetz E, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: A therapeutic advances in childhood leukemia consortium study. Journal of Clinical Oncology. 2010;28:648-654
  176. 176. Maude SL, Laetsch TW, Buechner S, Rives S, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine. 2018;378:439-448
  177. 177. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. The New England Journal of Medicine. 2013;368(16):1509-1518
  178. 178. Hunault-Berger M, Leguay T, Thomas X, Legrand O, Huguet F, Bonmati C, et al. A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia. GRALL-SA1 study. Haematologica. 2011;96(2):245-252
  179. 179. Quarello P, Berger M, Rivetti E, Galletto C, Masetti R, et al. FLAG-liposomal doxorubicin (Myocet) regimen for refractory or relapsed acute leukemia pediatric patients. Journal of Pediatric Hematology/Oncology. 2012;34(3):208-216
  180. 180. ClinicalTrials.gov. A Pilot Study of Vincristine Sulphate Liposome Injection in Combination with UKALL R3 Induction Chemotherapy for Children, Adolescents, and Young Adults with Relapse of Acute Lymphoblastic Leukemia. Identifier: NCT02879643

Written By

Sneha Tandon and Angela S. Punnett

Submitted: April 7th, 2019 Reviewed: May 27th, 2019 Published: October 23rd, 2019

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All
Chapter 4 miRNAs in Acute Lymphoblastic Leukemia: Diagnosis,...

By Yazmín Gómez-Gómez, Jorge Organista-Nava, Berenice...

969 downloads

Chapter 5 New Protein Markers of Chronic Lymphocytic and Acu...

By Martina Maďarová, Dominik Dobransky and Tomas Dobr...

852 downloads

Chapter 6 Chronic Lymphocytic Leukemia: Rapidly Changing Tre...

By Yazan Samhouri, Rupin Shah and Cyrus Khan

869 downloads