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Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects

Leukemia volume 20, pages 1441–1445 (2006)Cite this article

Among the biological prognostic factors so far identified in chronic lymphocytic leukemia (CLL), mutation or deletion of the p53 gene encoded at 17p13 is the most powerful predictor of short survival. p53 is a transcription factor that is activated by DNA damage and coordinates the cellular response to such damage by triggering apoptosis or cell-cycle arrest. In doing so, it fulfils an important function in regulating cell growth and survival in the face of cellular stresses and plays a pivotal role in maintaining genomic integrity. In keeping with this, p53 is inactivated in about half of all human cancers, the usual defect being mutation of one allele and deletion of the other.1

p53 defects are rare among patients with newly diagnosed CLL, but are more prevalent among patients with advanced disease.2 In keeping with the fact that p53-mediated apoptosis underpins the cytotoxicity of many anticancer drugs,3 p53 defects in CLL have been strongly linked to resistance to alkylating agents and purine analogs in ex vivo experiments, in retrospective clinical studies and most importantly in three large prospective clinical trials of first-line chemotherapy. In the German CLL4 trial comparing F with FC (ref 4), p53 deletion was found to be the most powerful predictor of therapeutic resistance and short progression-free survival, and the only predictor of short survival (median 15.9 months) in multivariate analysis (Stilgenbauer et al., Blood 2005; 106: 212a; abstract 715).4 Recent analysis of the UK CLL4 trial comparing chlorambucil with F and FC (fludarabine and fludarabine plus cyclophosphamide, respectively) has shown that none of the 15 patients with >20% p53 deletion achieved a complete remission (CR) or nodular partial remission (nPR), compared with 144 of the other 328 informative cases (Catovsky et al. Blood, 2004; 104: 8a; abstract 13). Most strikingly, in a single-arm Spanish trial of fludarabine in combination with cyclophosphamide and mitoxantrone, none of the eight patients with p53 deletion responded to treatment, compared to all of the 56 patients with no p53 deletion (Bosch et al. Blood, 2005; 106: 213; abstract 718). In the light of these observations, it is clear that one of the most pressing therapeutic challenges in CLL is to devise novel and effective ways of treating patients with p53 defects.

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Authors and Affiliations

  1. Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK

    A R Pettitt

  2. Section of Haemato-oncology, Institute of Cancer Research, Sutton, Surrey, UK

    E Matutes

  3. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    D Oscier

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  1. A R Pettitt
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  2. E Matutes
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Correspondence to A R Pettitt.

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Pettitt, A., Matutes, E. & Oscier, D. Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects. Leukemia 20, 1441–1445 (2006). https://doi.org/10.1038/sj.leu.2404265

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