COMMENTARY

CLL Genomics: Converting a Prognostic Factor Into a Target

Maurie Markman, MD

Disclosures

July 26, 2012

Alemtuzumab in Combination With Methylprednisolone Is a Highly Effective Induction Regimen for Patients With Chronic Lymphocytic Leukemia and Deletion of TP53: Final Results of the National Cancer Research Institute CLL206 Trial

Pettitt AR, Jackson R, Carruthers S, et al
J Clin Oncol. 2012;30:1647-1655

Summary

The subset of patients with chronic lymphocytic leukemia (CLL) whose cancers harbor a TP53 deletion or mutation on chromosome 17p are known to be relatively resistant to standard cytotoxic chemotherapy, but research has suggested that these tumors are not inherently resistant to methylprednisolone and alemtuzumab, an anti-CD52 monoclonal antibody.[1,2,3]

Building on these data, investigators in the United Kingdom treated 39 patients with TP53-deleted CLL with the combination of alemtuzumab plus methylprednisolone; 22 of these patients had been previously treated with chlorambucil, fludarabine, and/or other agents, and 17 were chemotherapy-naive. In the group as a whole, the overall response rate was 85%, and 36% experienced a complete response; among those who were chemotherapy-naive, the complete response rate was 65%, which compares quite favorably with the 7% complete response rate seen in data from Hallek and colleagues in the German Chronic Lymphocytic Leukaemia Study Group CLL8 trial[4] for this CLL patient subset given standard cytotoxic chemotherapy-based therapy.

Median progression-free and overall survival for the entire population (11.8 months and 23.5 months, respectively) and particularly for the previously untreated patients (18.3 months and 38.9 months, respectively) were also notable in this study, even recognizing the limitations associated with such nonrandomized comparisons. Indeed, in the original Hallek report,[5] the median progression-free and overall survival for previously untreated patients were 11 months and 28.8 months, respectively.

Viewpoint

In general, CLL is recognized to be a chemotherapy-sensitive malignancy. However, a well-defined molecularly characterized subset of patients, specifically, those with TP53 deletion or mutation, has been shown to be quite resistant to standard cytotoxic therapy.

Although documenting the presence of this mutation/deletion that strongly suggests a relatively poor prognosis may provide both the oncologist and the patient with important prognostic information, until now it did not help in predicting the clinical utility of a more effective alternative strategy for disease management. With the current report, documenting the presence of a TP53 deletion or mutation in the cancer of a patient with CLL can now be seen as having considerable value in the selection of a far more effective noncytotoxic chemotherapy-based strategy.

Most important, it is reasonable to speculate that this report is just one example of an event that is likely to become far more common in the future: the conversion of a molecularly based prognostic test into a clinical factor that will be useful in the specific selection of the most beneficial therapy in an individual cancer patient’s management.

Abstract

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