Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis

Gleißner, Beate; Gökbuget, Nicola; Bartram, Claus R.; Janssen, Bart; Rieder, Harald; Janssen, Johannes W.G.; Fonatsch, Christa; Heyll, A.; Voliotis, D.; Beck, Joachim; Lipp, Thomas; Munzert, Gerd; Mäurer, J.; Hoelzer, Dieter; Thiel, Eckhard

doi:10.1182/blood.v99.5.1536

Cited by 293 publications

(241 citation statements)

References 39 publications

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“…The majority of adult patients with ALL are not cured, 3 in part, due to an increased frequency of unfavorable genetic alterations (most notably the Philadelphia chromosome encoding BCR-ABL1). [3][4][5] Furthermore, up to 25% of the children and over half of the adults experience relapse, which carries a dismal prognosis. [5][6][7] Improvements in these outcomes by refining schedules or escalating doses of existing chemotherapeutic agents is limited by toxicity.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 99%

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

2009

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Until recently, our understanding of the genetic factors contributing to the pathogenesis of acute lymphoblastic leukemia (ALL) has relied on the detection of gross chromosomal alterations and mutational analysis of individual genes. Although these approaches have identified many important abnormalities, they have been unable to identify the full repertoire of genetic alterations in ALL. The advent of highresolution, microarray-based techniques to identify DNA copy number alterations and loss-of-heterozygosity in a genomewide fashion has enabled the identification of multiple novel genetic alterations targeting key cellular pathways, including lymphoid differentiation, cell cycle, tumor suppression, apoptosis and drug responsiveness. Recent studies have extended these approaches to examine the biologic basis of high-risk ALL and treatment relapse. As these techniques continue to evolve and are integrated with genome-wide epigenetic and transcriptomic data, we will obtain a comprehensive understanding of the genetic and epigenetic alterations in ALL, and ultimately will be able to translate these findings into the development of novel therapeutic approaches directed against rational therapeutic targets. Here, we review recent data obtained from genome-wide profiling studies in ALL, and discuss potential avenues for future investigation.

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Section: Acute Lymphoblastic Leukemiamentioning

confidence: 99%

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

2009

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“…The outcome of patients with Ph-positive ALL (Ph þ ALL) following conventional chemotherapy is dismal, showing o20% long-term survival. [1][2][3][4] Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has offered a curative option in Ph þ ALL, [3][4][5] relatively high rates of relapse and non-relapse mortality (NRM) impair the treatment success even after allo-HSCT. The International Bone Marrow Transplant Registry reported a leukemia-free survival rate of 38% following human leukocyte antigen (HLA)-identical allo-HSCT for Ph þ ALL patients transplanted in the first complete remission (CR).…”

Section: Introductionmentioning

confidence: 99%

Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR–ABL-positive acute lymphoblastic leukemia

et al. 2010

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A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph þ ALL) following imatinib-based therapy. However, the overall effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph þ ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph þ ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49-78%) for the imatinib cohort and 44% (95% CI, 35-52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P ¼ 0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P ¼ 0.007) and relapse (P ¼ 0.002), but not for non-relapse mortality (P ¼ 0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph þ ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT.

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“…Approximately two thirds of the BCR-ABL positive precursor-B-ALL patients have m-bcr breakpoints and one third has M-bcr breakpoints. 13,14 A small fraction (B1%) of acute myeloid leukemia (AML) patients also has p190 or p210 BCR-ABL fusion genes. 13 The m-bcr with p230 BCR-ABL fusion proteins is less frequently observed and was initially described to be associated with neutrophilic CML, a mild myeloproliferative disease, 12 but later, the m-bcr with p230 proteins was also found in classical CML and AML.…”

Section: Introductionmentioning

confidence: 99%

Flow cytometric immunobead assay for the detection of BCR–ABL fusion proteins in leukemia patients

Weerkamp

Dekking

et al. 2009

Leukemia

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BCR-ABL fusion proteins show increased signaling through their ABL tyrosine kinase domain, which can be blocked by specific inhibitors, thereby providing effective treatment. This makes detection of BCR-ABL aberrations of utmost importance for diagnosis, classification and treatment of leukemia patients. BCR-ABL aberrations are currently detected by karyotyping, fluorescence in situ hybridization (FISH) or PCR techniques, which are time consuming and require specialized facilities. We developed a simple flow cytometric immunobead assay for detection of BCR-ABL fusion proteins in cell lysates, using a bead-bound anti-BCR catching antibody and a fluorochromeconjugated anti-ABL detection antibody. We noticed protein stability problems in lysates caused by proteases from mature myeloid cells. This problem could largely be solved by adding protease inhibitors in several steps of the immunobead assay. Testing of 145 patient samples showed fully concordant results between the BCR-ABL immunobead assay and reverse transcriptase PCR of fusion gene transcripts. Dilution experiments with BCR-ABL positive cell lines revealed sensitivities of at least 1%. We conclude that the BCR-ABL immunobead assay detects all types of BCR-ABL proteins in leukemic cells with high specificity and sensitivity. The assay does not need specialized laboratory facilities other than a flow cytometer, provides results within B4 h, and can be run in parallel to routine immunophenotyping.

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Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis

Abstract: The BCR-ABL fusion, the molecular equivalent of the Philadelphia translocation, gains importance for treatment stratification in adult acute lymphoblastic leukemia (ALL). In this prospective study, samples from 478 patients with CD10

Cited by 293 publications

References 39 publications

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR–ABL-positive acute lymphoblastic leukemia

Flow cytometric immunobead assay for the detection of BCR–ABL fusion proteins in leukemia patients

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