High incidence of CDA deficiency in patients with hematological malignancies: perspectives and therapeutic implications

Donnette, Mélanie; Ciccolini, Joseph; Pissier, C.; Costello, Régis; Duffaud, Florence; Salas, Sébastien; Farnault, Laure; Tichadou, Antoine; Arcani, Robin; Jarrot, Pierre-André; Ouafik, L’Houcine; Venton, Geoffroy; Fanciullino, Raphaëlle

doi:10.1016/j.annonc.2021.01.072

Cited by 5 publications

(7 citation statements)

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“…16 Our previous work has shown that CDA deficiency is more common in patients with blood cancers. 7 In this real-world study, we have confirmed that the incidence of CDA deficiency is high in patients with haematological diseases, especially in AML patients. CDA activity was lower in AML patients compared to MDS patients, for which we have no explanation so far.…”

Section: Discussionsupporting

confidence: 70%

“…Patients were classified as PM (51.9%), EM (42.3%) and UM (6.8%). Interestingly, CDA values were low and shifted to the left compared to non‐cancer patients ( n = 79) based on patients included in a previous study, 7 and followed a lognormal distribution (Figure 1). By using a level of 2 UA/mg as a cut‐off for stratifying azacytidine‐treated patients with or without CDA deficiency, as previously proposed by our team, 16 CDA‐deficient patients were found in 50% of patients who exhibited a lower than 2 UA/mg CDA activity.…”

Section: Resultsmentioning

confidence: 89%

“…5,6 Importantly, we have recently shown that CDA deficiency is much more common in patients with haematological malignancies than in those with solid tumours or those without cancer. 7 We and others 8,9 have already shown that dysregulation of CDA may influence clinical outcomes in patients treated with Aza. CDA is encoded by a gene known to be highly polymorphic and deficiency is primarily considered to be a germline pharmacogenetic syndrome rather than an acquired phenotype, despite…”

mentioning

confidence: 88%

“…The CDA gene is highly polymorphic and CDA deficiency has been extensively studied as a cause of life‐threatening toxicities with a variety of nucleoside analogues such as gemcitabine, capecitabine and cytarabine 5,6 . Importantly, we have recently shown that CDA deficiency is much more common in patients with haematological malignancies than in those with solid tumours or those without cancer 7 . We and others 8,9 have already shown that dysregulation of CDA may influence clinical outcomes in patients treated with Aza.…”

Section: Introductionmentioning

confidence: 95%

“…9 CDA expression was associated with changes in the pharmacokinetics of Aza. 7 In this real-world study, we investigated the enzymatic expression of CDA in adult MDS and AML patients treated with Aza. We also investigated the association between CDA expression levels at baseline and clinical outcomes (i.e.…”

mentioning

confidence: 99%

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Cytidine deaminase status as a marker of response to azacytidine treatment in MDS and AML patients

Donnette,

Hamimed,

Ciccolini

et al. 2023

Br J Haematol

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SummaryAzacitidine (Aza) is a mainstay of treatment for patients with acute myeloid leukaemia (AML) ineligible for induction chemotherapy and other high‐risk myelodysplastic syndromes (MDS). Only half of patients respond, and almost all will eventually relapse. There are no predictive markers of response to Aza. Aza is detoxified in the liver by cytidine deaminase (CDA). Here, we investigated the association between CDA phenotype, toxicity and efficacy of Aza in real‐world adult patients. Median overall survival (OS) was 15 months and 13 months in AML and high‐risk MDS patients respectively. In addition, our data suggest that delaying Aza treatment was not associated with lack of efficacy and should not be considered a signal to switch to an alternative treatment. Half of the patients had deficient CDA activity (i.e. <2 UA/mg), with a lower proportion of deficient patients in MDS patients (34%) compared to AML patients (67%). In MDS patients, CDA deficiency correlated with longer landmark OS (14 vs. 8 months; p = 0.03), but not in AML patients. Taken together, our data suggest that CDA is an independent covariate and may therefore be a marker for predicting clinical outcome in MDS patients treated with Aza.

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Section: Discussionsupporting

confidence: 70%

Section: Resultsmentioning

confidence: 89%

mentioning

confidence: 88%