TP53 Mutations and Fludarabine-Based Chemotherapy in CLL: The Evidence Mounts

Maurie Markman, MD


December 08, 2010

TP53 Mutation and Survival in Chronic Lymphocytic Leukemia

Zenz T, Eichhorst B, Busch R, et al
J Clin Oncol. 2010;28:4473-4479


Previous reports have suggested that documented TP53 mutations in patients with chronic lymphocytic leukemia (CLL) are associated with a poor prognosis.[1] To further evaluate this issue, investigators from the German Chronic Lymphocytic Leukemia Study Group examined the effect of these mutations on outcome in 328 patients with CLL who were enrolled in a phase 3 trial that compared single-agent fludarabine with fludarabine plus cyclophosphamide.

Twenty-eight patients (8.5% of the entire population) were found to have a TP53 mutation, and none of these patients achieved a complete hematologic response. In contrast, 14% of patients without a TP53 mutation achieved a complete response (P = .055). Overall, 40% of patients with a mutation did not achieve complete or partial response, compared with 9% of patients without a mutation (P < .001). The median progression-free survival rates for patients with and without a TP53 mutation were 23.3 months and 62.2 months (P < .001), respectively, and the median overall survival rates were 29.2 months and 84.6 months (P < .001).


The current data provide striking evidence for the relevance of TP53 mutations in defining a CLL patient population that is unlikely to have a biological or clinical response to fludarabine-based chemotherapy. In multivariate analysis, the presence or absence of a TP53 mutation was the strongest prognostic factor for whether a patient would experience extended progression-free survival.

The data provide important support for the conclusion that patients with CLL who are being considered for fludarabine-based chemotherapy should undergo analysis for the presence of a TP53 mutation and, if a mutation is found, alternative treatment approaches should be seriously considered. One such strategy would be early allogeneic stem cell transplantation, assuming that the patient is otherwise an appropriate candidate for this intensive management program.[2]

This study adds to the rapidly growing body of oncology literature that demonstrates how knowledge of specific genetic abnormalities (eg, mutated KRAS and EGFR and overexpression of HER2) may be very helpful not only in defining prognosis but also in the selection of an optimal management plan designed to maximize the chance of a successful therapeutic outcome.



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