Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

Byrd, John C.; Gribben, John G.; Peterson, Bercedis L.; Grever, Michael R.; Lozanski, Gerard; Lucas, David M.; Lampson, Ben; Larson, Richard A.; Caligiuri, Michael A.; Heerema, Nyla A.

doi:10.1200/jco.2005.03.1021

Cited by 228 publications

(156 citation statements)

References 27 publications

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“…As response to different types of treatment varies according to genetic abnormalities, 8,[46][47][48] future prospective clinical trials in CLL should urgently test the prognostic value of CBA in direct comparison to FISH, IgVH status, ZAP70 and CD38 expression. These trials should also clarify which combination of techniques is necessary for the most accurate risk assignment in order to propose a costeffective strategy for routine diagnostics.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgVH status and immunophenotyping

et al. 2007

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In CLL data from chromosome banding analysis (CBA) have been scarce due to the low proliferative activity of CLL cells in vitro. We improved the cultivation technique using an immunostimulatory CpG-oligonucleotide DSP30 and IL-2. A total of 506 CLL samples were analysed with CBA and interphase FISH using probes for the detection of trisomy 12, IgH rearrangements and deletions of 6q21, 11q22.3 (ATM), 13q14 (D13S25 and D13S319) and 17p13 (TP53). A total of 500 of 506 (98.8%) cases were successfully stimulated for metaphase generation and are subject to this study. Aberrations were detected in 415 of 500 (83.0%) cases by CBA and in 392 of 500 (78.4%) cases by FISH. CBA detected 832 abnormalities and FISH only 502. Therefore, CBA offers important information in addition to FISH. (1) CLL is characterized mainly by genomic imbalances and reciprocal translocations are rare. (2) A subgroup with complex aberrant karyotype (16.4%) is identified which is associated with an unmutated IgV H status and CD38 expression (P ¼ 0.034 and 0.02, respectively). (3) Additional abnormalities are detectable providing new biological insights into different CLL subclasses revealing a much more heterogeneous pattern of cytogenetic abnormalities as assumed so far based on FISH data only. Therefore, prospective clinical trials should evaluate the prognostic impact of newly available CBA data.

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Section: Discussionmentioning

confidence: 99%

Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgVH status and immunophenotyping

et al. 2007

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“…1,2 The chromosomal aberrations del17p13 and del11q22, found in over 10% of patients with early-stage disease, are both associated with inferior outcome and in most cases lead to abrogation of the genes encoding the tumor suppressor p53 and the DNA damage response protein ATM, respectively. [3][4][5][6][7][8] It was recently shown that p53 point mutations have the same negative prognostic power as del17p13. 9,10 About 10-15% of CLL patients are 'ultra high risk', with a median survival of o2 years; however, not all of them have p53 aberrations.…”

Section: Introductionmentioning

confidence: 99%

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

et al. 2012

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Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in the elderly of the Western world. Although treatment options have improved over the past two decades, 10-15% of patients still have a poor prognosis and are often resistant to therapy. Aberrations in the p53 pathway, such as a deleted (del17p13) or mutated p53 gene, are highly enriched in this class of patients. In an extensive screen for p53-independent apoptosis inducers, actinomycin D was identified from 1496 substances and shown to induce apoptosis in primary CLL cells derived from high-risk patients including those with aberrant p53, revealing a novel p53-independent mechanism of action. Both pro-survival genes BCL2 and MCL1 are targeted by actinomycin D, in contrast to fludarabine the backbone of current treatment schedules. In the well-established TCL1 transgenic mouse model for high-risk CLL, actinomycin D treatment was more effective in reducing tumor load than fludarabine, with no evidence of resistance after three treatment cycles and an overall survival increase of over 300%. Tumor load reduction was coupled to BCL2 downregulation. Our results identify the clinically approved compound actinomycin D as a potentially valuable treatment option for CLL high-risk patients.

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“…1 TP53 loss is frequently accompanied by a mutation of the remaining allele. 2 The mutations are usually missense mutations and the mutant protein has a prolonged half-life enabling its detection by flow cytometry, western blotting or immunostaining. Less than 5% of patients have a TP53 mutation without loss of the normal allele and would not be identified if fluorescence in situ hybridization was used as the sole screening test.…”

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confidence: 99%

“…The etoposide/nutlin-3a functional assay provides a rapid and widely applicable screening method for clinically relevant mutations of both genes and also, potentially, for other defects in the doublestranded DNA damage repair pathway. 1,2 We report for the first time a patient who developed AML with NPM1 mutation 6 years after a JAK2-V617F þ primary myelofibrosis (PMF).…”

mentioning

confidence: 99%

A novel functional assay using etoposide plus nutlin-3a detects and distinguishes between ATM and TP53 mutations in CLL

et al. 2008

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Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

Cited by 228 publications

References 27 publications

Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgVH status and immunophenotyping

Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgVH status and immunophenotyping

Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

A novel functional assay using etoposide plus nutlin-3a detects and distinguishes between ATM and TP53 mutations in CLL

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