5'-nucleotidase, cytosolic II genotype, and clinical outcome in patients with acute myeloid leukemia with intermediate-risk cytogenetics.

Acute myeloid leukemia (AML) is a complex disease, and its treatment needs to be adjusted to the risk, which is conferred by cytogenetics and molecular markers. Cytarabine is the main drug to treat AML, and it has been suggested that the genotype of cytarabine metabolizing enzymes may have a prognostic relevance in AML. Here we report the association between the 5'-nucleotidase, cytosolic II (NT5C2) rs10883841, cytidine deaminase (CDA) rs2072671 and rs532545 genotypes and the clinical outcome of 477 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients younger than 50 years old with the NT5C2 rs10883841 AA genotype had lower overall survival (OS) (p: .003; HR 2.16, 95% CI 1.29-3.61) and lower disease-free survival (DFS) (p: .002; HR 2.45, 95% CI 1.41-4.27), associated to a higher relapse incidence (p: .010; HR 2.23, 95% CI 1.21-4.12). Interestingly, subgroup analysis showed that the negative effect of the NT5C2 rs10883841 AA genotype was detected in all subgroups except in patients with nucleophosmin mutation without high ratio FLT-3 internal tandem duplication. CDA polymorphisms were associated with the complete remission rate after induction chemotherapy, without influencing OS. Further studies are warranted to determine whether this pharmacogenomic approach may be helpful to individualize AML treatment.

Phase II trial to assess the safety and efficacy of clofarabine in combination with low-dose cytarabine in elderly patients with acute myeloid leukemia.

Previous studies have shown that clofarabine plus low-dose cytarabine (LDAC) could induce roughly 60 % of complete remissions (CR) with acceptable toxicity and induction mortality in elderly acute myeloid leukemia (AML) patients not suitable for intensive chemotherapy. The Programa Español de Tratamientos en Hematología group conducted a trial for patients diagnosed with untreated AML aged 60 years and older, using the combination of clofarabine (20 mg/m(2) × 5 days) plus low-dose cytarabine (20 mg/m(2) × 14 days). The protocol was flexible regarding the use of antifungal and antibacterial prophylaxis, and outpatient induction therapy was allowed. Although the planned recruitment goal was 75 patients, only 11 patients were enrolled (median age, 74 years) after observing high toxicity and unacceptable mortality (46 and 73 % at 4 and 8 weeks, respectively). The response assessment showed three CR (27 %), three resistant diseases (27 %), and five induction deaths (46 %). Induction was administered in an outpatient modality in five patients, while antifungal and antibacterial prophylaxis was not given in seven and five patients, respectively. In our context, induction therapy with the combination of clofarabine (20 mg/m(2)) plus LDAC was associated with high toxicity and unacceptable mortality in elderly AML patients, leading to the early interruption of the trial. Tight patients' clinical monitoring, follow-up, and intensive supportive care seem crucial to achieve at least acceptable clinical outcomes in elderly AML patients receiving clofarabine plus LDAC. This trial is registered at www.clinicaltrials.gov as no. NCT01193400.

UGT1A1 genotype influences clinical outcome in patients with intermediate-risk acute myeloid leukemia treated with cytarabine-based chemotherapy.

The treatment of acute myeloid leukemia (AML) is adjusted according to cytogenetic risk factors and molecular markers. Cytarabine remains the main drug to treat AML, and several studies have explored the prognostic relevance of the genotype of cytarabine metabolizing enzymes in AML. Glucuronidation has been identified to be relevant in the cytarabine clearance, but there are still few data concerning the clinical impact of genetic polymorphisms known to condition the activity of UDP-glucuronosyl transferases in AML patients. Here we report the association between the UGT1A1 rs8175347 genotype and the clinical outcome of 455 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients with the UGT1A1*28 homozygous variant (associated to a lower UGT1A1 activity) had a lower overall survival (OS) (25.8% vs. 45.5%; p: 0.004). Multivariate analysis confirmed this association (p: 0.008; HR: 1.79; 95% CI: 1.16-2.76). Subgroup analysis showed the negative effect of the UGT1A1*28 homozygous genotype on OS in women (14.8% vs. 52.7%; p: 0.001) but not in men. This lower OS was associated with longer neutropenia after consolidation chemotherapy and with higher mortality without previous relapse, suggesting an association between a low glucuronidation activity and mortal toxic events.

Incidence and prognostic significance of nephrotoxicity in patients receiving eshap as salvage therapy for lymphoma.

Nephrotoxicity is a well-known side effect of platinum-based chemotherapy. We retrospectively assessed the incidence and prognostic impact of nephrotoxicity with ESHAP rescue chemotherapy in 74 lymphoma patients (61 aggressive lymphomas). A higher incidence of nephrotoxicity (estimated glomerular filtration rate <60mL/min) was found when ESHAP was administred on an outpatient vs. inpatient basis (14/39 vs. 4/35). Patients submitted to ASCT with renal failure had a lower overall survival (OS) than those with normal renal function (2-yr OS probability [95%CI]: 88% [77%-99%] vs. 50% [22%-78%]). Outpatient administration of ESHAP may not be optimal for all patients and the impact of ESHAP-induced renal failure on ASCT outcomes in lymphoma needs to be assessed in prospective studies.