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Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma.

ABSTRACT: BACKGROUND:The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes. METHODS:Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs. RESULTS:Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p?=?5.60E-03; OR?=?6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p?=?6.50E-03; OR?=?11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10 years after treatment (p?=?7.38E-03, p?=?7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10 years after the diagnosis (p?=?4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p?=?1.71E-03), 5-10 years after the diagnosis. CONCLUSIONS:Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.

SUBMITTER: Sagi JC

PROVIDER: S-EPMC6029426 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma.

Sági Judit C JC Egyed Bálint B Kelemen Andrea A Kutszegi Nóra N Hegyi Márta M Gézsi András A Herlitschke Martina Ayaka MA Rzepiel Andrea A Fodor Lili E LE Ottóffy Gábor G Kovács Gábor T GT Erdélyi Dániel J DJ Szalai Csaba C Semsei Ágnes F ÁF

BMC cancer 20180703 1

<h4>Background</h4>The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left vent ...[more]

PMID: 29970035

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Project description:During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors' late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy's long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines' possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect's vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

Project description:BackgroundBlinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects.MethodsIn this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival.ResultsOf the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group.ConclusionsTreatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).

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Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma.

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Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma.

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