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A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease

Leukemia volume 23, pages 212–214 (2009)Cite this article

TP53 abnormalities consistently emerge as the most significant adverse prognostic factor in multivariate analyses of both prospective and retrospective studies in early and advanced chronic lymphocytic leukaemia (CLL).1 In view of the higher response rates often achieved with alemtuzumab-containing regimens compared with alkylating agent and/or purine analogue therapy2 and the possibility of long-term disease-free survival following allogeneic transplantation in some patients, there is an increasing consensus for screening for TP53 abnormalities in CLL patients who fulfil the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) recommendations for initiating therapy. It has also been suggested that the detection of a TP53 abnormality in early CLL should be an indication for treatment with an alemtuzumab-containing regimen.3 However, a small subset of patients with TP53 abnormalities pursue a benign clinical course.

Since 1994, we have examined fresh or dimethyl sulphoxide frozen cells from CLL patients presenting to the Royal Bournemouth Hospital, both for TP53 loss by fluorescence in situ hybridization (FISH) and karyotypic abnormalities determined by G-banding. Analysis of G-banded metaphases was from peripheral blood lymphocyte cultures stimulated with Phorbol-12-myristate 13 acetate for 3, 4 and 5 days and prepared according to standard techniques. Interphase FISH for the loss of TP53 was undertaken using commercially available probes (LSI p53 and CEP 17, Vysis, Downers Grove, IL, USA) according to the manufacturer's protocol. Metaphase FISH was also undertaken in some cases to clarify the cytogenetic rearrangement involved in TP53 loss. Karyotype analysis and FISH were performed on 348 patients at presentation, of whom 302 had Binet stage A and 46 had Binet stage B/C disease. TP53 loss was found in 11 (4%) Binet stage A and 5 (11%) stage B/C cases. Eight of the eleven stage A patients with TP53 loss had Rai stage 0 CLL and were identified from a full blood count performed for an incidental reason. All eight patients have had stable disease, not requiring therapy, with a median follow-up of 64 months (range 13–165). Two patients have died of unrelated causes. In an attempt to identify features that might explain and predict the benign course of these cases, we investigated karyotypic complexity, the size of the TP53 deleted clone, the presence of a functional TP53 mutation on the remaining allele, VH gene mutational status and CD38 and ZAP-70 expression. Karyotypic abnormalities of 17p13 were found in seven of the eight patients; 2/7 had loss of one homologue of chromosome 17, whereas 5/7 had structural rearrangements involving chromosome 17p13 resulting in the loss of TP53 (see Supplementary data). Interestingly, four patients had a chromosome translocation involving chromosome 13q14 and chromosome 17p. Karyotypic complexity, with multiple cell lines, was observed in six of the eight patients with TP53 loss; five patients had two or more cell lines with TP53 loss. In addition to TP53 loss, one patient showed a small clone with hemizygous loss of ATM, ascertained by FISH (patient 8). No ATM loss was detected in the remaining patients.

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Authors and Affiliations

  1. Department of Molecular Biology and Cytogenetics, Royal Bournemouth Hospital, Bournemouth, UK

    O G Best, A C Gardiner, Z A Davis, I Tracy, R E Ibbotson & D G Oscier

  2. MRC Toxicology Unit, University of Leicester, Leicester, UK

    A Majid

  3. Department of Haematology, University Hospitals, Leicester, UK

    M J S Dyer

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  1. O G Best
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  2. A C Gardiner
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  3. Z A Davis
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  4. I Tracy
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  5. R E Ibbotson
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  7. M J S Dyer
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  8. D G Oscier
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Correspondence to D G Oscier.

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Supplementary Information accompanies the paper on the Leukaemia website (http://www.nature.com/leu)

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Best, O., Gardiner, A., Davis, Z. et al. A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease. Leukemia 23, 212–214 (2009). https://doi.org/10.1038/leu.2008.260

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