CDA Deficiency as a Possible Culprit for Life-Threatening Toxicities After Cytarabine Plus 6-Mercaptopurine Therapy: Pharmacogenetic Investigations

Ciccolini, Joseph; Evrard, Alexandre; M’Batchi, Lithaty; Pourroy, Bertrand; Mercier, Cédric; Iliadis, Athanassios; Lacarelle, Bruno; Verschuur, Arnaud; Ouafik, L’Houcine; André, Nicolas

doi:10.2217/pgs.11.175

Cited by 16 publications

(8 citation statements)

References 19 publications

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“…Case reports in children suggest PM CDA status is predictive of Ara-C toxicity, but to date, no such relationship has been investigated in adults. 24 Here we establish for the first time the link between CDA phenotype and incidence of severe toxicities in adult patients with AML treated with Ara-C.…”

Section: Introductionmentioning

confidence: 75%

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

et al. 2018

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Key Points• Ara-C is the mainstay of treatment for patients with AML, and life-threatening toxicities are common.• We demonstrated that cytidine deaminase downregulation predicts severe/lethal toxicities with cytarabine.Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the CDA*2 allelic variant) were performed in 58 adult patients with AML treated with the standard 713 (Ara-C 1 anthracyclines)protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 6 0.7 U/mg vs 3.95 6 3.1 U/mg; Student t test P , .001). Subsequent receiver operating characteristic analysis identified a threshold in CDA activity (ie, 2 U/mg) associated with PM syndrome and increased risk of developing severe toxicities. Five percent of patients experienced lethal toxicities, all displaying CDA PM status (1.3 6 0.5 U/mg). In terms of efficacy, a trend toward higher response rates and longer progression-free survival and overall survival were observed in patients with low CDA activity. Taken together, the results of this study strongly suggest that CDA is a predictive marker of life-threatening toxicities in patients with AML receiving induction therapy with standard Ara-C.

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Section: Introductionmentioning

confidence: 75%

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

et al. 2018

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“…Interestingly, Bhatla et al (2009) have shown that Ara-C-related mortality was significantly elevated in carriers of the 79CC genotype in children with acute leukemia. Moreover, Ciccolini et al (2012) have related this SNP to life-threatening toxicities induced in a girl with lymphoma treated with Ara-C.…”

Section: Cytosine Arabinosidementioning

confidence: 99%

Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia

Gervasini¹,

Vagace²

2012

Front. Gene.

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The efficacy of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) patients has significantly increased in the last 20 years; as a result, the focus of research is slowly shifting from trying to increase survival rates to reduce chemotherapy-related toxicity. At the present time, the cornerstone of therapy for ALL is still formed by a reduced number of drugs with a highly toxic profile. In recent years, a number of genetic polymorphisms have been identified that can play a significant role in modifying the pharmacokinetics and pharmacodynamics of these drugs. The best example is that of the TPMT gene, whose genotyping is being incorporated to clinical practice in order to individualize doses of mercaptopurine. However, there are additional genes that are relevant for the metabolism, activity, and/or transport of other chemotherapy drugs that are widely use in ALL, such as methotrexate, cyclophosphamide, vincristine, L-asparaginase, etoposide, cytarabine, or cytotoxic antibiotics. These genes can also be affected by genetic alterations that could therefore have clinical consequences. In this review we will discuss recent data on this field, with special focus on those polymorphisms that could be used in clinical practice to tailor chemotherapy for ALL in order to reduce the occurrence of serious adverse effects.

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“…Increased activity and expression of CDA was shown in AML patients who are nonresponders to induction chemotherapy when compared with those who respond well to Ara-C [10,11]. On the other hand, low CDA activity and expression has shown associated with severe drug-related toxicities [12,13]. NT5C2 opposes DCK activity by dephosphorylating the monophosphorylated form of drug back to Ara-C.…”

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confidence: 99%

RNA Expression of Genes Involved in Cytarabine Metabolism and Transport Predicts Cytarabine Response in Acute Myeloid Leukemia

et al. 2015

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This study highlights the importance of evaluating expression of candidate Ara-C metabolizing genes in predicting ex vivo drug response as well as treatment outcome. RI could be a predictor of ex vivo Ara-C response irrespective of cytogenetic and molecular risk groups and a potential biomarker for AML treatment outcome and toxicity. Original submitted 22 December 2014; Revision submitted 9 April 2015.

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CDA Deficiency as a Possible Culprit for Life-Threatening Toxicities After Cytarabine Plus 6-Mercaptopurine Therapy: Pharmacogenetic Investigations

Cited by 16 publications

References 19 publications

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia

RNA Expression of Genes Involved in Cytarabine Metabolism and Transport Predicts Cytarabine Response in Acute Myeloid Leukemia

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