Dasatinib is a potent BCR-ABL inhibitor effective in chronic myeloid leukemia and Ph ؉ acute lymphoblastic leukemia (ALL) resistant/intolerant to imatinib. In the GIMEMA LAL1205 protocol, patients with newly diagnosed Ph ؉ ALL older than 18 years (with no upper age limit) received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy. Postremission therapy was free. Fiftythree patients were evaluable (median age, 53.6 years). All patients achieved a complete hematologic remission (CHR), 49 (92.5%) at day 22. At this time point, 10 patients achieved a BCR-ABL reduction to < 10 ؊3 . At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. A significant difference in DFS was observed between patients who showed at day 22 a decrease in BCR-ABL levels to < 10 ؊3 compared with patients who never reached these levels during induction. In multivariate analysis, BCR-ABL levels of < 10 ؊3 at day 85 correlated with disease-free survival. No deaths or relapses occurred during induction. Twenty-three patients relapsed after completing induction. A T315I mutation was detected in 12 of 17 relapsed cases. Treatment was well tolerated; only 4 patients discontinued therapy during the last phase of the induction when already in CHR. In adult Ph ؉ ALL, induction treatment with dasatinib plus steroids is associated with a CHR in virtually all patients, irrespective of age, good compliance, no deaths, and a very rapid debulking of the neoplastic clone. IntroductionDespite an improved understanding of the biology of acute lymphoblastic leukemia (ALL), the overall prognosis of adult patients remains unsatisfactory. 1-3 The Philadelphia (Ph) chromosome is the most frequent genetic abnormality in adult ALL; its prevalence increases with age, accounting for 12% to 30% in patients 18 to 35 years of age, 40% to 45% in patients 36 to 50 years of age, 4,5 and Ͼ 50% in patients older than 60 years. 6 The Ph chromosome and BCR-ABL fusion gene have been associated with a highly unfavorable prognosis, independent of age, 7,8 and elderly patients were often treated only with supportive therapy.The tyrosine kinase inhibitor (TKI) imatinib has profoundly altered the management of patients with chronic myeloid leukemia and impacted on the natural course of the disease. 9,10 Imatinib has also been effectively used in Ph ϩ ALL, both in adults and children. [11][12][13] In a GIMEMA study, all 29 Ph ϩ ALL patients aged 60 years of age or older treated with imatinib plus prednisone without chemotherapy as first-line treatment obtained a complete hematologic remission (CHR). 14 The GMALL study group also showed that, in elderly patients with de novo Ph ϩ ALL, induction with imatinib resulted in a significantly higher CR rate and lower toxicity than with chemotherapy. 15 Dasatinib is a second-generation TKI with a 300-fold greater activity than imatinib in vitro. 16,17 Dasatinib has demonstrated a marked efficacy in patients with CML after relapse or resistance to imatinib...

Monoclonal antibody (MoAb)-based therapies have opened innovative treatment avenues that have impacted on the management of patients with both neoplastic and non-neoplastic hematological diseases. The aim of our study was to evaluate in a large series of cases of acute lymphoblastic leukemia (ALL) the expression of specific antigens, CD19, CD20, CD22, and CD33, for which MoAbs are available for clinical use. For each antigen, evaluation was based on the percentage of positive leukemic cells and the degree of antigen expression by mean fluorescence intensity (MFI) and antibody binding capacity (ABC) that were correlated with age, immunophenotype, and presence/absence of particular molecular markers. We can document that some of the analyzed antigens showed a degree of expression related to the B-cell maturation profile, and that the antigen expression intensity appeared to vary according to the presence of specific genetic markers. These findings suggest that the possible clinical use of a given MoAb in patients with ALL should take into account both the maturation profile of the leukemic cells and the presence of a given molecular transcript. Only clinical studies will conclusively demonstrate whether the differences in antigenic expression truly correlate with the different therapeutic efficacies of the various clinical grade MoAbs.

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The online version of this article has a Supplementary Appendix. BackgroundThe genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and MethodsOur aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. ResultsMutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. ConclusionsATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.