microRNAome expression in chronic lymphocytic leukemia: comparison with normal B-cell subsets and correlations with prognostic and clinical parameters.

PURPOSE: Despite its indolent nature, chronic lymphocytic leukemia (CLL) remains an incurable disease. To establish the potential pathogenic role of miRNAs, the identification of deregulated miRNAs in CLL is crucial. EXPERIMENTAL DESIGN: We analyzed the expression of 723 mature miRNAs in 217 early-stage CLL cases and in various different normal B-cell subpopulations from tonsils and peripheral blood. RESULTS: Our analyses indicated that CLL cells exhibited a miRNA expression pattern that was most similar to the subsets of antigen-experienced and marginal zone-like B cells. These normal subpopulations were used as reference to identify differentially expressed miRNAs in comparison with CLL. Differences related to the expression of 25 miRNAs were found to be independent from IGHV mutation status or cytogenetic aberrations. These differences, confirmed in an independent validation set, led to a novel comprehensive description of miRNAs potentially involved in CLL. We also identified miRNAs whose expression was distinctive of cases with mutated versus unmutated IGHV genes or cases with 13q, 11q, and 17p deletions and trisomy 12. Finally, analysis of clinical data in relation to miRNA expression revealed that miR26a, miR532-3p, miR146-5p, and miR29c* were strongly associated with progression-free survival. CONCLUSION: This study provides novel information on miRNAs expressed by CLL and normal B-cell subtypes, with implication on the cell of origin of CLL. In addition, our findings indicate a number of deregulated miRNAs in CLL, which may play a pathogenic role and promote disease progression. Collectively, this information can be used for developing miRNA-based therapeutic strategies in CLL.

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival.

BACKGROUND: The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. DESIGN AND METHODS: The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. RESULTS: Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13-21.95 and odds ratio 4.57, 95% confidence interval 1.01-20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38-33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00-36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46-8.45). CONCLUSIONS: Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival.

Survival of elderly patients with acute myeloid leukemia.

BACKGROUND AND OBJECTIVES: The prognosis of elderly patients with acute myelogenous leukemia (AML) is usually dismal, while the true survival of older patients not included in clinical trials is not known. We retrospectively evaluated the impact on survival of an aggressive versus a non-aggressive approach in 1005 patients aged >60 years registered in the database of the GIMEMA cooperative group. DESIGN AND METHODS: Group A patients (n=621) received aggressive treatment, while group B patients (n=384) underwent non-aggressive therapy. The groups were different for risk factor distribution: the patients in group B had a higher median age, worse performance status (PS) and a higher proportion of previous myelodysplastic disease. RESULTS: The overall median survival was 7 and 5 months in groups A and B, respectively (p min of 0.0001). At multivariate analysis the following factors were associated with a significantly shorter survival: age >71 years (RR=1.27; 95% CI=1.07-1.50), PS=2-4 (RR=1.44; 95% CI=1.24-1.68), white cell count > 10,000 mL (RR=1.37; 95% CI=1.06-1.75), and heart dysfunction requiring treatment (RR=1.26; 95% CI=1.05-1.50). No difference in survival was associated with aggressive or non-aggressive treatment (RR=1.1; 95% CI=0.94-1.32). Patients aged min of 70 years, with no heart disease, but a white cell count > 10,000/mL showed a significantly better survival when treated aggressively (median survival 7 vs 3 months, p = 0.011). INTERPRETATION AND CONCLUSIONS: Despite an obvious selection of patients with a worse prognosis in group B, the difference in survival between the two groups was marginal. Multivariate analysis failed to demonstrate a significant survival benefit in aggressively treated patients. All these considerations indicate that elderly patients with AML are overall unlikely to benefit from aggressive treatment, so that this should be offered only to selected patients.