Host genetic variants of ABCB1 and IL15 influence treatment outcome in paediatric acute lymphoblastic leukaemia

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Abstract

Background:

Host germline variations and their potential prognostic importance is an emerging area of interest in paediatric ALL.

Methods:

We investigated the associations between 20 germline variations and various clinical end points in 463 children with ALL.

Results:

After adjusting for known prognostic factors, variants in two genes were found to be independently associated with poorer EFS: ABCB1 T/T at either 2677 (rs2032582) or 3435 (rs1045642) position ( P=0.003) and IL15 67276493G/G (rs17015014; P=0.022). These variants showed a strong additive effect affecting outcome ( P<0.001), whereby patients with both risk genotypes had the worst EFS ( P=0.001), even after adjusting for MRD levels at the end of remission induction. The adverse effect of ABCB1 T/T genotypes was most pronounced in patients with favourable cytogenetics ( P=0.011) while the IL15 67276493G/G genotype mainly affected patients without common chromosomal abnormalities ( P=0.022). In both cytogenetic subgroups, increasing number of such risk genotypes still predicted worsening outcome ( P<0.001 and=0.009, respectively).

Conclusion:

These results point to the prognostic importance of host genetic variants, although the specific mechanisms remain unclarified. Inclusion of ABCB1 and IL15 variants may help improve risk assignment strategies in paediatric ALL.

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Most cited references 39

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Treating childhood acute lymphoblastic leukemia without cranial irradiation.

Ching-Hon Pui, Dario Campana, Deqing Pei … (2009)

Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.) 2009 Massachusetts Medical Society

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Genetic determinants of response to clopidogrel and cardiovascular events.

Tabassome Simon, Céline Verstuyft, Murielle Mary-Krause … (2009)

Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown. We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up. Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51). Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. (ClinicalTrials.gov number, NCT00673036.) 2009 Massachusetts Medical Society

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Biology, risk stratification, and therapy of pediatric acute leukemias: an update.

Ching-Hon Pui, William Carroll, Soheil Meshinchi … (2011)

We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research. A review of English literature on childhood acute leukemias from the past 5 years was performed. Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients. The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.

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Author and article information

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Print): 18 March 2014

Publication date (Electronic): 16 January 2014

Volume: 110

Issue: 6

Pages: 1673-1680

Affiliations

[1 ]Division of Haematology-Oncology, Department of Paediatrics, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore , Singapore, Singapore

[2 ]Department of Paediatrics, Faculty of Medicine, University of Malaya , Kuala Lumpur, Malaysia

[3 ]University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya , Kuala Lumpur, Malaysia

[4 ]Department of Paediatric Oncology/Haematology, VU University Medical Center , Amsterdam, The Netherlands

[5 ]Department of Paediarics, Sime Darby Medical Centre Subang Jaya , Subang Jaya, Malaysia

[6 ]Department of Paediatric Medicine, Haematology/Oncology Service, KK Women's and Children's Hospital , Singapore, Singapore

[7 ]Viva-University Children's Cancer Centre, University Children's Medical Institute, National University Hospital , Singapore, Singapore

[8 ]National University Cancer Institute Singapore, National University Health System , Singapore

Author notes

[* ]E-mail: allen_yeoh@ 123456nuhs.edu.sg

Article

Publisher Item ID: bjc20147

DOI: 10.1038/bjc.2014.7

PMC ID: 3960629

PubMed ID: 24434428

SO-VID: 5023de58-5fb7-46e4-97be-fb01038c680a

License:

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

History

Date received : 18 September 2013

Date revision received : 11 December 2013

Date accepted : 17 December 2013

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Host genetic variants of ABCB1 and IL15 influence treatment outcome in paediatric acute lymphoblastic leukaemia

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Abstract

Background:

Methods:

Results:

Conclusion:

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Karger: Oncology

Most cited references 39

Treating childhood acute lymphoblastic leukemia without cranial irradiation.

Genetic determinants of response to clopidogrel and cardiovascular events.

Biology, risk stratification, and therapy of pediatric acute leukemias: an update.

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