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

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Abstract

<p id="d15916422e231"> <div class="list"> <a class="named-anchor" id="d15916422e233">  </a> <ul class="so-custom-list"> <li id="d15916422e234"> <div class="so-custom-list-content so-ol"> <p class="first" id="d15916422e235">Ara-C is the mainstay of treatment for patients with AML, and life-threatening toxicities are common. </p> </div> </li> <li id="d15916422e237"> <div class="so-custom-list-content so-ol"> <p class="first" id="d15916422e238">We demonstrated that cytidine deaminase downregulation predicts severe/lethal toxicities with cytarabine. </p> </div> </li> </ul> </div> </p><p class="first" id="d15916422e242">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 <i>CDA*2</i> allelic variant) were performed in 58 adult patients with AML treated with the standard 7+3 (Ara-C + anthracyclines) protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 ± 0.7 U/mg vs 3.95 ± 3.1 U/mg; Student <i>t</i> test <i>P</i> < .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 ± 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. </p><p id="d15916422e257"> <div class="fig panel" id="absf1"> <a class="named-anchor" id="absf1">  </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/b70103b5-2d4c-4329-b1cd-2b67cb52c6d6/PubMedCentral/image/advances014126absf1"/> </div> <div class="panel-content"/> </div> </p>

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Therapeutic advances in acute myeloid leukemia.

Alan K Burnett, Meir Wetzler, Bob Löwenberg (2011)

The choice of treatment approach and outcome in acute myeloid leukemia (AML) depends on the age of the patient. In younger patients, arbitrarily defined as being younger than 60 years, 70% to 80% enter complete disease remission with several anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or stem-cell transplantation in high-risk patients will restrict overall relapse to approximately 50%. A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1). These are increasingly being used to direct postinduction therapy, but they are also molecular targets for a new generation of small molecule inhibitors that are in early development; however, randomized data have yet to emerge. In older patients who comprise the majority, which will increase with demographic change, the initial clinical decision to be made is whether the patient should receive an intensive or nonintensive approach. If the same anthracycline/cytarabine-based approach is deployed, the remission rate will be around 50%, but the risk of subsequent relapse is approximately 85% at 3 years. This difference from younger patients is explained partly by the ability of patients to tolerate effective therapy, and also the aggregation of several poor risk factors compared with the young. There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy. Their survival is approximately 4 months, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.

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High-dose daunorubicin in older patients with acute myeloid leukemia.

Bob Löwenberg, Gert Ossenkoppele, Wim van Putten … (2009)

A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.) 2009 Massachusetts Medical Society

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Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications.

Torsten Haferlach, Hartmut Döhner, Guido Marcucci (2011)

Molecular analyses of leukemic blasts from patients with acute myeloid leukemia (AML) have revealed a striking heterogeneity with regard to the presence of acquired gene mutations and changes in gene and microRNA expression. Multiple submicroscopic genetic alterations with prognostic significance have been discovered. Application of gene- and microRNA profiling has identified genome-wide expression signatures that separate cytogenetic and molecular subsets of patients with AML into previously unrecognized biologic and/or prognostic subgroups. These and similar future findings are likely to have a major impact on the clinical management of AML because many of the identified genetic alterations not only represent independent prognosticators, but also may constitute targets for specific therapeutic intervention. In this report, we review genetic findings in AML and discuss their clinical implications.