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Ferrata Storti Foundation
Pediatric acute lymphoblastic leukemia
Hiroto Inaba1,2 and Charles G. Mullighan2,3
1Department of Oncology; 2Hematological Malignancies Program and 3Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
Haematologica 2020 Volume 105(11):2524-2539
ABSTRACT
The last decade has witnessed great advances in our understanding of the genetic and biological basis of childhood acute lymphoblastic leukemia (ALL), the development of experimental models to probe mechanisms and evaluate new therapies, and the development of more efficacious treatment stratification. Genomic analyses have revolution- ized our understanding of the molecular taxonomy of ALL, and these advances have led the push to implement genome and transcriptome characterization in the clinical management of ALL to facilitate more accurate risk-stratification and, in some cases, targeted therapy. Although mutation- or pathway-directed targeted therapy (e.g., using tyrosine kinase inhibitors to treat Philadelphia chromosome [Ph]-positive and Ph- like B-cell-ALL) is currently available for only a minority of children with ALL, many of the newly identified molecular alterations have led to the exploration of approaches targeting deregulated cell pathways. The effi- cacy of cellular or humoral immunotherapy has been demonstrated with the success of chimeric antigen receptor T-cell therapy and the bispecific engager blinatumomab in treating advanced disease. This review describes key advances in our understanding of the biology of ALL and optimal approaches to risk-stratification and therapy, and it suggests key areas for basic and clinical research.
Introduction
Contemporary childhood ALL studies have shown improved 5-year overall sur- vival (OS) rates exceeding 90% (Table 1).1-9 However, OS for the St. Jude Total Therapy Study XVI (94.3%) was similar to that for the Total Therapy Study XV (93.5%) (Figure 1).9 Therefore, with the conventional approach, the chemotherapy intensity has been raised to the limit of tolerance, and further improvements in out- comes and reduction of adverse effects will require novel therapeutic approaches. Historically, genetic factors identified by conventional karyotyping have been used to diagnose ALL and to risk-stratify children with the disease. However, the alter- ations thus identified, including hyper- and hypodiploidy and several chromosomal rearrangements, did not establish the basis of ALL in a substantial minority of chil- dren; nor did they satisfactorily reveal the nature of the genetic alterations driving leukemogenesis. Genomic studies have now clarified the subclassification of ALL and have demonstrated a close interplay between inherited and somatic genetic alterations in the biology of ALL. Many of these alterations have important impli- cations for diagnosis and risk-stratification of ALL and for the use and development of novel and targeted approaches.
Heritable susceptibility to acute lymphoblastic leukemia
Several lines of evidence indicate that there is a genetic predisposition to acute lymphoblastic leukemia (ALL), at least in a subset of cases. This evidence includes the existence of: (i) rare constitutional syndromes with increased risk for ALL; (ii) familial cancer syndromes; (iii) non-coding DNA polymorphisms that subtly influ- ence the risk of ALL; and (iv) genes harboring germline non-silent variants pre- sumed to confer a risk of sporadic ALL. Constitutional syndromes such as Down syndrome and ataxia-telangiectasia are associated with increased risk of B-cell-ALL (with CRLF2 rearrangement) and T-cell-ALL, respectively. Familial cancer syn- dromes such as Li-Fraumeni syndrome, constitutional mismatch repair deficiency syndrome, or DNA repair syndromes (e.g., Nijmegen breakage) have an increased
Correspondence:
HIROTO INABA
hiroto.inaba@stjude.org
CHARLES G. MULLIGHAN
charles.mullighan@stjude.org
Received: June 19, 2020.
Accepted: August 3, 2020. Pre-published: September 10, 2020.
doi:10.3324/haematol.2020.247031 ©2020 Ferrata Storti Foundation
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CENTENARY REVIEW ARTICLE