clinical topic updates

Clinical Impact of Clonal and Subclonal TP53 Mutations in Chronic Lymphocytic Leukemia

by Susan O’Brien, MD

Overview

Both clonal and subclonal TP53 mutations can be important predictors of survival in patients with chronic lymphocytic leukemia (CLL). Recent data suggest that a significant group of patients with CLL have subclonal TP53 mutations that, if detected, would direct treatment away from commonly used regimens (eg, bendamustine plus rituximab) toward ibrutinib.

“It is important to know the patient’s clonal and subclonal TP53  mutation status because the most commonly used regimen in the United States (bendamustine plus rituximab) should not be used in TP53 -mutated patients—such individuals should receive ibrutinib instead.”

Susan O’Brien, MD

Expert Commentary

Susan O’Brien, MD

Associate Director for Clinical Science
Chao Family Comprehensive Cancer Center
Medical Director
Sue and Ralph Stern Center for Cancer Clinical Trials and Research
University of California, Irvine Health
Irvine, CA

Evidence supports the notion that TP53 mutations at the subclonal level are associated with poor prognosis. This was first suggested by Rossi and Gaidano in 2016 when they reported that the presence of small subclones harboring drug-resistant mutations predicted the development of a chemorefractory phenotype. Bomben et al recently investigated the impact of isolated TP53 mutations and 17p deletions (del[17p]) using an ultra-deep next-generation sequencing, reporting that TP53 mutations were associated with a shorter overall survival, irrespective of variant allele frequency percent, while del(17p) was associated with decreased overall survival when more than 10% of nuclei were affected. These data underscore the fact that, while del(17p) may be associated with TP53 mutations, a substantial proportion of patients (8.2% in this study) are TP53 mutated only—a finding that has several implications. First, it is important to know the patient’s clonal and subclonal TP53 mutation status because the most commonly used regimen in the United States (bendamustine plus rituximab) should not be used in TP53-mutated patients—such individuals should receive ibrutinib instead. Additionally, standard testing, including fluorescence in situ hybridization and Sanger sequencing, will not necessarily detect all cases of isolated, subclonal TP53 mutations, which suggests the importance of next-generation genetic testing. These data also highlight the need for testing prior to treatment and possibly retesting after treatment to identify clonal evolution. Testing should generally occur at the time of diagnosis and/or at the time that treatment is indicated. My opinion is that you should not test asymptomatic patients if you want the test to inform treatment decisions. For most of these patients, a watch and wait approach is still the standard of care. Generally, the presence of a del(17p) is most important when deciding between chemotherapy and a small-molecule inhibitor. As the number of prior treatment regimens increases, the frequency of del(17p) becomes more common. For patients who receive ibrutinib as second-line therapy, one could make the argument that genetic testing is less important, as it appears, so far, that all of the small-molecule inhibitors are effective in patients with del(17p).

References

Bomben R, Rossi F, D'Agaro T, et al. Clinical impact of clonal and subclonal TP53 mutations in chronic lymphocytic leukemia. Abstract 945. Abstract presented at: 60th ASH Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA.

Campo E, Cymbalista F, Ghia P, et al. TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics. Haematologica. 2018; pii: haematol.2018.187583.

Mato A, Nabhan C, Kay NE, et al. Prognostic testing patterns and outcomes of chronic lymphocytic leukemia patients stratified by fluorescence in situ hybridization/cytogenetics: a real-world clinical experience in the Connect CLL Registry. Clin Lymphoma Myeloma Leuk. 2018;18(2):114-124.e2.

Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016;127(17):2122-2130.

Rossi D, Gaidano G. The clinical implications of gene mutations in chronic lymphocytic leukaemia. Br J Cancer. 2016;114(8):849-854.

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