Genome wide association studies for treatment‐related adverse effects of pediatric acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric hematological malignancy; notwithstanding the success of ALL therapy, severe adverse drugs effects represent a serious issue in pediatric oncology, because they could be both an additional life threatening condition for ALL patients per se and a reason to therapy delay or discontinuation with important fallouts on final outcome. Cancer treatment‐related toxicities have generated a significant need of finding predictive pharmacogenomic markers for the a priori identification of at risk patients. In the era of precision medicine, high throughput genomic screening such as genome wide association studies (GWAS) might provide useful markers to tailor therapy intensity on patients' genetic profile. Furthermore, these findings could be useful in basic research for better understanding the mechanistic and regulatory pathways of the biological functions associated with ALL treatment toxicities. The purpose of this review is to give an overview of high throughput genomic screening of the last 10 years that had investigated the landscape of ALL treatment‐associated toxicities. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics

CD38-Directed Vincristine Nanotherapy for Acute Lymphoblastic Leukemia

“…Acute lymphoblastic leukemia (ALL), which is the most common hematological malignancy in children, originates from the abnormal proliferation of immature lymphocytes in the bone marrow. − The intensive chemotherapy with multiple drugs has markedly improved the clinical remission and survival rates over the past decades. − The prognosis for patients who relapsed after the first-line therapy stays, nevertheless, poor due to lack of effective salvage regimens. , Moreover, many pediatric ALL survivors after intensive chemotherapy suffer severe lifelong side effects and an undermined quality of life − as a result of weak ALL selectivity. The intensive and poorly selective chemotherapy is also detrimental to patients’ immune system. − There is an urgent need to develop more selective and less toxic chemotherapy for ALL. − …”

How paediatric drug development and use could benefit from OMICs: A c4c expert group white paper

“…Targeted approaches like oligonucleotide microarrays or mass spectrometry‐based assays (MALDI‐TOF) to detect known single nucleotide polymorphisms (SNPs) and copy number variation are also very well established. Genome‐wide assocation study (GWAS) can yield not only disease susceptibility genes, but also clinically relevant PGx information, as was nicely shown in the example of childhood leukemia 12 . One of the first landmark papers regarding GWAS PGx demonstrated that flucloxacillin‐induced liver injury is associated with the HLA‐B*5701 allele 23 .…”

“…[98][99][100][101][102][103] As in adults, oncology is also pioneering in paediatric PGx and the example of treatment of childhood acute lymphoblastic leukemia demonstrates this enormous progress. 12 Here, the risk of toxic events in response to drug treatment can be significantly reduced by the consideration of PGx information on thiopurine haematoxicity and TPMT and NUDT15…”

“…Genome-wide assocation study (GWAS) can yield not only disease susceptibility genes, but also clinically relevant PGx information, as was nicely shown in the example of childhood leukemia. 12 One of the first landmark papers regarding GWAS PGx demonstrated that flucloxacillin-induced liver injury is associated with the HLA-B*5701 allele. 23 Other GWAS examples with relevance for children followed, such as the association of immediate penicillin hypersensitivity with HLA-DRB1*10:01, providing insights into the mechanisms of immediate reactions, 11 and the higher incidence of hypersensitivity (P = 7.5 Â 10, 5 odds ratio 1.64) and anti-asparaginase antibodies (P = 1.4 Â 10 5 , odds ratio 2.92) in children with asparaginase treatment for leukemia/lymphoma and HLA-DRB1*07:01.…”

Biomarkers for gastrointestinal adverse events related to thiopurine therapy

“…Thiopurine-induced gastrointestinal (GI) toxicity occurs in approximately 5%-20% of ALL and IBD patients; the main symptoms are nausea, vomiting, stomatitis, abdominal pain or cramping, gastritis, gastric ulcer, GI bleeding, and diarrhea[ 10 , 11 ]. Moreover, these immunosuppressors are associated with the risk of neurological complications, hepatotoxicity, pancreatitis, arthralgia, and skin rush[ 10 , 12 - 16 ].…”