Clinical and experimental efficacy of gemtuzumab ozogamicin in core binding factor acute myeloid leukemia

Leukemia-initiating cells of core binding factor (CBF) acute myeloid leukemia (AML) likely derive from early committed hematopoietic precursors expressing CD33. As such, targeting CD33 could ameliorate the chance of cure of CBF AML patients. We compared 12 CBF AML patients treated with Fludarabine, Cytarabine, Idarubicin and Gemtuzumab Ozogamicin (FLAI-GO regimen) with 25 CBF AML patients treated with the same schedule, but without GO. With the limit of small numbers, we observed a consistent trend toward better overall survival, disease free survival and event free survival in the FLAI-GO group. We also demonstrated the ability of GO to induce the disappearance in vitro of the AML1-ETO molecular transcript in a polymerase chain reaction-positive graft without decreasing the clonogenic potential of CD34+/CD38- cells. This represent the proof of principle for using GO in a purging strategy before autologous stem cell transplantation. Therefore, our data argue in favor of the reinstitution of GO in the therapy of CBF AML

Identification of new genomic lesions in childhood ALL without known genetic aberrations: A microarray study of gene expression and genotype data.

Despite the risk stratification based on the prognostic relevant translocations, approximately 20-25% of childhood ALL patients cannot be classified according to genetic hallmarks. Recent studies based on single nucleotide polymorphism (SNP) analyses showed that Loss of Heterozygosity (LOH), with or without loss of genetic material, is frequently related to childhood ALL and AML. Moreover, there is an increasing interest in integrating the gene expression profiles with chromosomal localizations to identify new genetic subgroups. We applied an integrated approach composed of DNA index estimation, PCR (and/or RT-PCR) and cytogenetics, to exclude patients with known molecular and cytogenetics aberrations. Aim of the study was to identify criptic abnormalities in childhood ALL patients by performing an integrative analysis of gene expression and copy number changes (CNC) data. The 30 patients included in our study met the following inclusion criteria: a) B-cell precursor childhood ALL b) DNA index 1; c) negativity at t(4;11), t(12;21), t(9;22), t(1;19) RT-PCR screening; d) cytogenetics revealing normal karyotype or not technically feasible. Patients genomic DNA has been analyzed by the Affymetrix GeneChip Mapping 100K SNP arrays to identify genomic regions of LOH and CNC. In parallel, biotin-labeled cRNA has been synthesized and hybridized on HG-U133Plus2 Probe Arrays in accordance with the MILE (mircroarray innovation in leukemia) protocols; all samples were part of the B-ALL class without known genetic aberrations.The presence of del(9)(p21) was found in 9/30 (30%) patients, with an homozygous commonly deleted region involving CDKN2A and CDKN2B genes in 7/30. Hemizygous losses on 9p13 were found in two cases. Four patients (13,3%) showed the hemizygous deletion of chromosome 12p13.2, with a commonly deleted region involving the ETV6 gene. In one ETV6 deleted patient FISH analysis identified a translocation involving the first ETV6 exon and an unknown partner gene. Four patients, including three ETV6 deleted, showed the presence of the intrachromosomal amplification of chromosome 21 (iAMP21) with a common region of amplification between 31.3-43.5 Mb and a common region of deletion in 2/4 patients between 43.5-47 Mb. Four patients showed large regions of LOH not associated with CNC. Three patients did not show CNC and random microdeletions were found in single cases. Remission samples were analyzed for 5 patients carrying different aberrations, showing small regions of LOH in both the diagnosis and remission samples in 4 cases. No CNC was found in the remission samples. We found a statistically significant reduction for the expression of the CDKN2A transcript located within the (9)(p21) region. We are applying a locally adaptive statistical procedure to identify genes whose expression signals are specifically modulated by CNC. The integration of genomic variation and gene expression profiling might may be useful to identify new hidden genetic lesions, and to learn how critical regulators of tumor are linked to genomic alterations in cancer cells

Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial.

Pre-clinical data suggest p53-dependent anthracycline-induced apoptosis and p53-independent taxane activity. However, dedicated clinical research has not defined a predictive role for TP53 gene mutations. The aim of the current study was to retrospectively explore the prognosis and predictive values of TP53 somatic mutations in the BIG 02-98 randomized phase III trial in which women with node-positive breast cancer were treated with adjuvant doxorubicin-based chemotherapy with or without docetaxel.Clinical Trial, Phase IIIJournal ArticleRandomized Controlled TrialResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe