Specific p53 mutations do not impact results of alemtuzumab therapy among patients with chronic lymphocytic leukemia

Abstract

A poor prognosis in chronic lymphocytic leukemia (CLL) is associated particularly with the presence of del(17p) aff ecting tumor suppressor gene TP53 . Th is deletion is in almost all cases of progressive leukemia accompanied by a mutation in the other TP53 allele, and in a smaller proportion of patients the TP53 mutation occurs also independently of del(17p) [1]. Recently, we demonstrated that patients with CLL harboring a missense mutation located in the p53 DNA-binding motifs (DBMs) (structurally well-defi ned parts of the DNA-binding domain) manifested a clearly shorter median survival in comparison with those having a missense mutation outside DBMs or a non-missense alteration [2]. However, a limitation of this study resulted from the unpredictable survival impact of diverse therapy given to patients with p53 mutations. Th e therapeutic approach currently taken for patients with CLL with loss and/or mutation of TP53 relies mostly on the use of agents which do not act through DNA damage followed by apoptosis induction. Th e success of this approach has been documented for the monoclonal antibody alemtuzumab. Monotherapy with alemtuzumab is now being recommended as fi rst-line therapy for patients with CLL with del(17p) [3]; however, many unresolved questions need to be addressed. For example, it is unclear whether the type of p53 mutation infl uences the outcome of alemtuzumab therapy. In an eff ort to evaluate the effi cacy of alemtuzumab therapy in relation to specifi c p53 mutations in patients with CLL, we performed a retrospective analysis. Th e patients examined ( n 111) were treated by alemtuzumab between 2003 and 2010. Th e majority of cases concerned pretreated patients ( n 108; see Table I). Our present analysis was performed in the patient cohort which was largely included in the previous survival analysis related to p53 mutation types; this study also involved patients treated with other drugs in addition to alemtuzumab [2] (overlap 88% in group 1; 82% in group 2; 0% in group 3; the groups are defi ned further below). Defects in p53 were assessed by the yeast functional assay coupled to sequencing of DNA templates from mutated yeast colonies. Th e remaining TP53 allele was analyzed using