Elsevier

Cancer Genetics

Volume 243, May 2020, Pages 52-72
Cancer Genetics

Review Article
Evidence-based review of genomic aberrations in B-lymphoblastic leukemia/lymphoma: Report from the cancer genomics consortium working group for lymphoblastic leukemia

https://doi.org/10.1016/j.cancergen.2020.03.001Get rights and content

Highlights

  • This evidence-based review presents a detailed description of genomic aberrations in all categories of B-lymphoblastic leukemia including clinical outcomes, prognosis, and technical consideration for diagnosis.

Abstract

Clinical management and risk stratification of B-lymphoblastic leukemia/ lymphoma (B-ALL/LBL) depend largely on identification of chromosomal abnormalities obtained using conventional cytogenetics and Fluorescence In Situ Hybridization (FISH) testing. In the last few decades, testing algorithms have been implemented to support an optimal risk-oriented therapy, leading to a large improvement in overall survival. In addition, large scale genomic studies have identified multiple aberrations of prognostic significance that are not routinely tested by existing modalities. However, as chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) technologies are increasingly used in clinical management of hematologic malignancies, these abnormalities may be more readily detected. In this article, we have compiled a comprehensive, evidence-based review of the current B-ALL literature, focusing on known and published subtypes described to date. More specifically, we describe the role of various testing modalities in the diagnosis, prognosis, and therapeutic relevance. In addition, we propose a testing algorithm aimed at assisting laboratories in the most effective detection of the underlying genomic abnormalities.

Introduction

B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is a neoplasm of B-lineage precursor cells within the bone marrow or blood (B-ALL) or within nodal or extranodal sites (B-LBL) [1]. B-ALL represents the most common malignancy in the pediatric population and the second most common acute leukemia among adults. The US age-adjusted incidence rate of B-ALL is 1.38 per 100,000 individuals per year and nearly 6000 new cases and 1500 deaths were estimated in 2019 [2,3]. The median age at diagnosis is 15 years, with approximately 60% of patients diagnosed at less than 20 years of age, while only about 10% of patients are diagnosed at 65 years or older. Among the pediatric population, B-ALL represents 75–80% of acute leukemias; by contrast, only about 20% of all leukemias among adults are B-ALL [2,3]. Clinical manifestations include anemia, neutropenia, and/or thrombocytopenia, mostly due to bone marrow involvement by leukemic blasts that are typically positive for CD19, CD20, CD22, CD34, CD79a, HLA-DR, and TdT. Patients usually experience fatigue, infections, easy bruising or bleeding. Mild constitutional symptoms including achiness, fever, night sweats and weight loss may also be present. Aside from bone marrow involvement, B-ALL may manifest in the central nervous system (CNS) with features such as cranial neuropathies or meningeal symptoms in addition to testicular involvement in males [4]. Patient management incorporates numerous clinical metrics including patient age, WBC count, CNS status, persistence of minimal residual disease (MRD) at the end of induction therapy along with genomic abnormalities of the B-ALL clone [2].

Primary genomic classification plays a critical role in risk stratification, enrollment of patients onto treatment protocols and clinical trials and, in some cases, the detection of therapeutic targets. Given the vast amount of information regarding various B-ALL subtypes, a comprehensive compendium of each genomic abnormality can be a valuable resource for the laboratory director, geneticist, clinical provider and patient. According to the 2016 World Health Organization (WHO) update, B-ALL is classified in relation to nine recurrent genomic abnormalities [1]. In the most recent National Comprehensive Cancer Network (NCCN) guidelines, optimal risk classification and treatment planning require testing the bone marrow or peripheral blood for major recurring genetic abnormalities using conventional cytogenetics, FISH, reverse transcriptase PCR (RT-PCR) and chromosomal microarray analysis (CMA) to determine the B-ALL subtype [2]. Here, we present a detailed description of each B-ALL genomic entity reported to date, including the ones defined by the WHO. Furthermore, we discuss their incidence, associated age groups, testing modalities most commonly used for their identification and recurrent accompanying secondary abnormalities, as well as their prognosis and risk stratification value (Table 1). Because the detection of genomic abnormalities is crucial for the accurate management of patients with B-ALL, we present a proposed algorithm for genomic testing that takes into consideration the incidence of each abnormality, testing modalities best used for detection, and laboratory resources. This algorithm is aimed at providing a tool for laboratory directors to maximize the diagnostic yield of genomic abnormalities in B-ALL.

Section snippets

B-ALL with ETV6-RUNX1, t(12;21)(p13;q22)

The t(12;21)(p13.2;q22.2) resulting in the ETV6-RUNX1 fusion is the most common chromosomal rearrangement in pediatric B-ALL present in ~25% of patients diagnosed between the ages of 2 and 10 years. The t(12;21) is less prevalent in adult B-ALL with an estimated incidence of ~3% [5], [6], [7], [8], [9], [10], [11], [12]. It results in the in-frame fusion of the amino terminus of ETV6 (formally known as TEL) with all known functional domains of RUNX1 (formally known as AML1). While both ETV6 and

Discussion

B-ALL is the most common malignancy in the pediatric population and the second most common acute leukemia in adults. Diagnosis is established by demonstration of lymphoblasts in the bone marrow or peripheral blood, along with morphologic and immunophenotyping assessment using flow cytometry or immunohistochemistry [82]. Further classification requires accurate characterization of the primary genomic lesion of the B-ALL clone. The WHO currently recognizes 9 subtypes of B-ALL with recurrent

Declaration of Competing Interest

Tanner Hagelstrom is employed by Illumina Inc. All other authors declare no conflict of interest.

Acknowledgments

We acknowledge Jill Kappers (Mayo Clinic) for help with manuscript preparation.

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