Genetic Alterations in Childhood Acute Lymphoblastic Leukemia: Interactions with Clinical Features and Treatment Response

Lee, Shawn H. R.; Li, Zhenhua; Tai, Si Ting; Oh, Bernice Ling Zhi; Yeoh, Allen Eng-Juh

doi:10.3390/cancers13164068

Cited by 20 publications

(15 citation statements)

References 157 publications

(275 reference statements)

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“…Previous studies showed that the ETV6 :: RUNX1 -like subtype had a relatively favorable outcome with very few reported relapses [ 130 , 179 ]. However, recent studies proved that it had poorer outcomes compared to ETV6 :: RUNX1 [ 180 ]. Additionally, among the 16 B-ALL subtypes, ETV6 :: RUNX1 -like patients had the worst five-year EFS rates along with KMT2A -rearranged and MEF2D-rearranged ALL patients.…”

Section: Genetic Biomarkersmentioning

confidence: 99%

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Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

Lejman

Chałupnik

Chilimoniuk

et al. 2022

IJMS

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Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies characterized by abnormal proliferation of immature lymphoid cells. It is the most commonly diagnosed childhood cancer with an almost 80% cure rate. Despite favorable survival rates in the pediatric population, a significant number of patients develop resistance to therapy, resulting in poor prognosis. ALL is a heterogeneous disease at the genetic level, but the intensive development of sequencing in the last decade has made it possible to broaden the study of genomic changes. New technologies allow us to detect molecular changes such as point mutations or to characterize epigenetic or proteomic profiles. This process made it possible to identify new subtypes of this disease characterized by constellations of genetic alterations, including chromosome changes, sequence mutations, and DNA copy number alterations. These genetic abnormalities are used as diagnostic, prognostic and predictive biomarkers that play an important role in earlier disease detection, more accurate risk stratification, and treatment. Identification of new ALL biomarkers, and thus a greater understanding of their molecular basis, will lead to better monitoring of the course of the disease. In this article, we provide an overview of the latest information on genomic alterations found in childhood ALL and discuss their impact on patients’ clinical outcomes.

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Section: Genetic Biomarkersmentioning

confidence: 99%

“…However due to the small number of patients with ETV6 :: RUNX1 -like ALL (9), more studies are required in this field [ 181 ]. It is possible that an ETV6 :: RUNX1 -like subtype may benefit from higher-intensity therapy [ 180 ].…”

Section: Genetic Biomarkersmentioning

confidence: 99%

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

Lejman

Chałupnik

Chilimoniuk

et al. 2022

IJMS

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“…Different study groups, such as the UKALL, NOPHO, AALL0031 and COG studies, consistently stratify near-haploid and low-hypodiploid B-ALL subtypes as high-risk based on the poor prognosis of the patients, which does not depend on treatment era or on the NCI risk group in which they are classified [ 24 , 26 , 71 ]. In view of the poor prognosis of patients with hypodiploid B-ALL, they have been classically treated with high-dose chemotherapy followed by allogeneic transplantation.…”

Section: Outcome and Treatment Strategies For B-all With Hypodiploidies <40 Chromosomesmentioning

confidence: 99%

Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much

Molina

Bataller

Thampi

et al. 2021

Cancers

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Hypodiploidy with less than 40 chromosomes is a rare genetic abnormality in B-cell acute lymphoblastic leukemia (B-ALL). This condition can be classified based on modal chromosome number as low-hypodiploidy (30–39 chromosomes) and near-haploidy (24–29 chromosomes), with unique cytogenetic and mutational landscapes. Hypodiploid B-ALL with <40 chromosomes has an extremely poor outcome, with 5-year overall survival rates below 50% and 20% in childhood and adult B-ALL, respectively. Accordingly, this genetic feature represents an adverse prognostic factor in B-ALL and is associated with early relapse and therapy refractoriness. Notably, half of all patients with hypodiploid B-ALL with < 40 chromosomes cases ultimately exhibit chromosome doubling of the hypodiploid clone, resulting in clones with 50–78 chromosomes. Doubled clones are often the major clones at diagnosis, leading to “masked hypodiploidy”, which is clinically challenging as patients can be erroneously classified as hyperdiploid B-ALL. Here, we summarize the main cytogenetic and molecular features of hypodiploid B-ALL subtypes, and provide a brief overview of the diagnostic methods, standard-of-care treatments and overall clinical outcome. Finally, we discuss molecular mechanisms that may underlie the origin and leukemogenic impact of hypodiploidy and may open new therapeutic avenues to improve survival rates in these patients.

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“…ALL is a genetically heterogeneous disease [13,34]. The National Cancer Institute (NCI) standard-risk (SR) criteria, presenting age of 1 to 10 years and WBC count < 50 × 10 9 /L), are simple yet surprisingly effective risk stratification criteria [35].…”

Section: The Importance Of the Nci Standard-risk (Sr) Criteriamentioning

confidence: 99%

“…The National Cancer Institute (NCI) standard-risk (SR) criteria, presenting age of 1 to 10 years and WBC count < 50 × 10 9 /L), are simple yet surprisingly effective risk stratification criteria [35]. Favorable genetic drivers, such as hyperdiploidy and ETV6-RUNX1, form the largest proportion of NCI SR patients [34]. In MS2003 [18], age remained prognostically significant for event-free survival (Figure 1).…”

Section: The Importance Of the Nci Standard-risk (Sr) Criteriamentioning

confidence: 99%

Curing the Curable: Managing Low-Risk Acute Lymphoblastic Leukemia in Resource Limited Countries

Lee

Yeoh

2021

JCM

Self Cite

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Although childhood acute lymphoblastic leukemia (ALL) is curable, global disparities in treatment outcomes remain. To reduce these global disparities in low-middle income countries (LMIC), a paradigm shift is needed: start with curing low-risk ALL. Low-risk ALL, which accounts for >50% of patients, can be cured with low-toxicity therapies already defined by collaborative studies. We reviewed the components of these low-toxicity regimens in recent clinical trials for low-risk ALL and suggest how they can be adopted in LMIC. In treating childhood ALL, the key is risk stratification, which can be resource stratified. NCI standard-risk criteria (age 1–10 years, WBC < 50,000/uL) is simple yet highly effective. Other favorable features such as ETV6-RUNX1, hyperdiploidy, early peripheral blood and bone marrow responses, and simplified flow MRD at the end of induction can be added depending on resources. With limited supportive care in LMIC, more critical than relapse is treatment-related morbidity and mortality. Less intensive induction allows early marrow recovery, reducing the need for intensive supportive care. Other key elements in low-toxicity protocol designs include: induction steroid type; high-dose versus low-dose escalating methotrexate; judicious use of anthracyclines; and steroid pulses during maintenance. In summary, the first effective step in curing ALL in LMIC is to focus on curing low-risk ALL with less intensive therapy and less toxicity.

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Genetic Alterations in Childhood Acute Lymphoblastic Leukemia: Interactions with Clinical Features and Treatment Response

Cited by 20 publications

References 157 publications

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

Near-Haploidy and Low-Hypodiploidy in B-Cell Acute Lymphoblastic Leukemia: When Less Is Too Much

Curing the Curable: Managing Low-Risk Acute Lymphoblastic Leukemia in Resource Limited Countries

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