Clinico-biologic features and treatment outcome of adult pro-B-ALL patients enrolled in the GIMEMA 0496 study: absence of the ALL1/AF4 and of the BCR/ABL fusion genes correlates with a significantly better clinical outcome

Cimino, Giuseppe; Elia, Loredana; Mancini, Marco; Annino, Luciana; Anaclerico, Barbara; Fazi, Paola; Vitale, Antonella; Specchia, Giorgina; Raimondo, Francesco Di; Recchia, Anna Grazia; Cuneo, Antonio; Mecucci, Cristina; Pane, Fabrizio; Saglio, Giuseppe; Foà, Robin; Mandelli, Franco

doi:10.1182/blood-2002-12-3822

Cited by 33 publications

(26 citation statements)

References 40 publications

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“…We therefore focused our attention on ALL cells obtained before therapy in a welldefined cohort of 128 adult patients enrolled in a single treatment protocol (GIMEMA 0496;refs. 30,31). By correlating the expression of f12,600 probes with conventional phenotypic and molecular characteristics, we identified gene expression signatures associated with known phenotypic characteristics of adult ALL and also defined gene expression patterns associated with distinct mechanisms of leukemic transformation.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiles of B-lineage Adult Acute Lymphocytic Leukemia Reveal Genetic Patterns that Identify Lineage Derivation and Distinct Mechanisms of Transformation

Chiaretti

Gentleman

et al. 2005

Clinical Cancer Research

121

104

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Purpose: To characterize gene expression signatures in acute lymphocytic leukemia (ALL) cells associated with known genotypic abnormalities in adult patients. Experimental Design: Gene expression profiles from 128 adult patients with newly diagnosed ALL were characterized using high-density oligonucleotide microarrays. All patients were enrolled in the Italian GIMEMA multicenter clinical trial 0496 and samples had >90% leukemic cells.Uniform phenotypic, cytogenetic, and molecular data were also available for all cases. Results: T-lineage ALL was characterized by a homogeneous gene expression pattern, whereas several subgroups of B-lineage ALL were evident.Within B-lineage ALL, distinct signatures were associated with ALL1/AF4 and E2A/PBX1 gene rearrangements. Expression profiles associated with ALL1/AF4 and E2A/PBX1 are similar in adults and children. BCR/ABL + gene expression pattern was more heterogeneous and was most similar to ALL without known molecular rearrangements.We also identified a set of 83 genes that were highly expressed in leukemia blasts from patients without known molecular abnormalities who subsequently relapsed following therapy. Supervised analysis of kinase genes revealed a high-level FLT3 expression in a subset of cases without molecular rearrangements.Two other kinases (PRKCB1and DDR1) were highly expressed in cases without molecular rearrangements, as well as in BCR/ABL-positive ALL. Conclusions: Genomic signatures are associated with phenotypically and molecularly well defined subgroups of adult ALL. Genomic profiling also identifies genes associated with poor outcome in cases without molecular aberrations and specific genes that may be new therapeutic targets in adult ALL.After more than four decades of intensive research, the cellular origins of acute lymphocytic leukemia (ALL) have been well defined, and several distinct genetic mechanisms that lead to malignant transformation of these cells have been identified (1 -4). In f25% to 30% of adult patients, ALL cells express multiple genes associated with T-cell differentiation, and T-cell receptor genes show the presence of clonal rearrangements. In the remaining 70% to 75% of adult patients, ALL cells express markers of B-cell differentiation, and immunoglobulin genes reveal unique patterns of clonal rearrangement. These characteristics clearly define the derivation of these leukemias from distinct lymphoid precursor cells that have been committed to either T-lineage or B-lineage differentiation. Although chromosome translocations and molecular rearrangements are relatively infrequent in T-lineage ALL, these events occur commonly in B-lineage ALL and reflect distinct mechanisms of transformation. The relative frequencies of specific molecular rearrangements differ in children and adults with B-lineage ALL. In adult ALL, the BCR/ABL gene rearrangement occurs in about 25% of cases and the ALL1/AF4 gene rearrangement (also termed MLL/AF4) is present in 4% to 7% of cases (5). The BCR/ ABL gene rearrangement occurs much less freque...

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profiles of B-lineage Adult Acute Lymphocytic Leukemia Reveal Genetic Patterns that Identify Lineage Derivation and Distinct Mechanisms of Transformation

Chiaretti

Gentleman

et al. 2005

Clinical Cancer Research

121

104

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“…2,3,14 This prospective study shows that quantitative MRD assessment was a prognostic indictor in 45 adult patients affected by Ph þ ALL who underwent homogeneous treatment programs, the GIMEMA protocols 0496 and LAL2000. 10 Refractoriness to induction treatment is an obvious parameter of dismal prognosis in Ph þ ALL, but early relapses can also occur in patients who have a CHR to initial treatment. Therefore, we enrolled in our study only Ph þ ALL patients who had a CHR after induction treatment and who would benefit Here, we applied a rapid, accurate and sensitive real-time RT-PCR assay of the BCR/ABL transcripts that was developed by us within a European network of experienced centers, 12 to study the MRD kinetics during the early phases of treatment in those patients who showed CHR after induction treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Both GIMEMA protocols contemplated central handling of cell samples at diagnosis and at predetermined time intervals during the clinical follow-up. 10 According to this program, molecular analyses on all patients at presentation and during follow-up were performed at the CEINGE Biotecnologie Avanzate (University of Naples Federico II) and the Department of Biomedical Sciences (University of Turin), while cytogenetic analyses were performed at the Department of Cellular Biotechnologies and Hematology (University 'La Sapienza', Rome), the Center of Medical Biotechnology, Dipartimento di Scienze Biomediche e Terapie Avanzate (University of Ferrara) and the Dipartimento di Medicina Clinica e Sperimentale (Universiy of Perugia). The diagnosis of Ph þ and/or BCR/ABL þ ALL was based on standard cytogenetic and/or molecular analysis at diagnosis.…”

Section: Patientsmentioning

confidence: 99%

Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia

et al. 2005

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Philadelphia chromosome- positive (Ph+) acute lymphoblastic leukemia ( ALL) has a dismal prognosis. We prospectively evaluated minimal residual disease (MRD) by measuring BCR/ ABL levels with a quantitative real-time PCR procedure after induction and after consolidation in 45 adults with Ph+ ALL who obtained complete hematological remission after a high-dose daunorubicin induction schedule. At diagnosis, the mean BCR-ABL/GUS ratio was 1.55+/-1.78. A total of 42 patients evaluable for outcome analysis were operationally divided into two MRD groups: good molecular responders (GMRs; n = 28) with 42 log reduction of residual disease after induction and 43 log reduction after consolidation therapy, and poor molecular responders (PMRs; n = 14) who, despite complete hematological remission, had a higher MRD at both time points. In GMR, the actuarial probability of relapse- free, disease-free and overall survival at two years was 38, 27 and 48%, respectively, as compared to 0, 0 and 0% in PMR ( P = 0.0035, 0.0076 and 0.0026, respectively). Salvage therapy induced a second sustained complete hematological remission in three GMR patients, but in no PMR patient. Our data indicate that, as already shown in children, adult Ph+ ALL patients have a heterogeneous sensitivity to treatment, and that early quantification of residual disease is a prognostic parameter in this disease

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“…In particular, one patient was treated following the GIMEMA 0288 regimen, 12 eight patients according to the GIMEMA 0496 regimen, 13 and six patients according to the GIMEMA ALL 2000 regimen. The latter study is currently open to enrolment and considers ALL1-AF4-positive ALL patients as having a negative prognosis; these patients thus undergo an intensified consolidation phase with high-dose Ara-C and mithoxantrone (HAM), followed by either allogeneic or autologous haemopoietic stem cell transplantation, depending on the availability of an HLA-identical donor.…”

Section: Treatmentmentioning

confidence: 99%

Retrospective comparison of qualitative and quantitative reverse transcriptase polymerase chain reaction in diagnosing and monitoring the ALL1-AF4 fusion transcript in patients with acute lymphoblastic leukaemia

et al. 2004

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We compared quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) to qualitative RT-PCR in determining response to therapy and predicting clinical outcome in 18 retrospectively selected patients with ALL positive for the ALL1-AF4 fusion and with frozen RNA samples collected at diagnosis and during follow-up (96 samples analysed). The ALL1-AF4 junction was detected by qualitative RT-PCR in 18 patients and by Q-RT-PCR in 17 patients (one patient harboured the rare e10-e6 ALL1-AF4 junction, which falls outside of the primer and probe location designed for the Q-RT-PCR). In three of the 12 patients negative to qualitative RT-PCR after induction therapy, a small number of ALL1-AF4 copies was detected by Q-RT-PCR. Thus nine patients were negative and eight positive. Seven of the eight positive patients suffered a relapse, including two of the three patients positive to Q-RT-PCR yet negative to qualitative RT-PCR. Moreover, we found two (5%) discordant results among the 39 follow-up tests of the nine patients who converted to a negative qualitative-quantitative PCR status. The results suggest that qualitative RT-PCR is more appropriate for the routine diagnosis of this genetic alteration. However, Q-RT-PCR is more accurate in assessing the molecular response after induction treatment and could be more useful in clinical decision-making in ALL1-AF4-positive ALL patients.

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Clinico-biologic features and treatment outcome of adult pro-B-ALL patients enrolled in the GIMEMA 0496 study: absence of the ALL1/AF4 and of the BCR/ABL fusion genes correlates with a significantly better clinical outcome

Cited by 33 publications

References 40 publications

Gene Expression Profiles of B-lineage Adult Acute Lymphocytic Leukemia Reveal Genetic Patterns that Identify Lineage Derivation and Distinct Mechanisms of Transformation

Gene Expression Profiles of B-lineage Adult Acute Lymphocytic Leukemia Reveal Genetic Patterns that Identify Lineage Derivation and Distinct Mechanisms of Transformation

Significant reduction of the hybrid BCR/ABL transcripts after induction and consolidation therapy is a powerful predictor of treatment response in adult Philadelphia-positive acute lymphoblastic leukemia

Retrospective comparison of qualitative and quantitative reverse transcriptase polymerase chain reaction in diagnosing and monitoring the ALL1-AF4 fusion transcript in patients with acute lymphoblastic leukaemia

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