“Double Hit” in Chronic Lymphocytic Leukemia: Therapeutic Strategies for Patients with 17p Deletion and TP53 Mutation

Author(s): Daniel E. Ezekwudo, Tolulope Ifabiyi, Angela Usim, Ishmael Jaiyesimi

We aim to review the use of molecular markers for risk stratification and to describe the current standard and new targeted treatment options for the subgroup of patients with 17p deletion chronic lymphocytic leukemia (CLL) with an accompanying TP53 mutation, known as “double hit” CLL. Chromosome 17p deletion is seen in 5-9% of patients with newly diagnosed CLL; however, it represents the most common genetic aberration (≈50%) in patients with refractory/relapsed CLL. Identification of genomic and molecular markers allows risk stratification and has prognostic value. Chromosome 17p deletion has been strongly correlated with poor response to standard therapy as well as shorter overall survival. Accompanying TP53 mutation confers an even poorer response to standard therapy than 17p deletion alone. A review of current treatment options reveals the ongoing debate as to the appropriate timing of treatment initiation in this patient subpopulation. Moreover, standard treatment options still confer suboptimal benefit. Small molecule inhibitors targeting intracellular B-cell receptor signaling components such as Bruton’s tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), anti BCL-2 molecules, and more recently CD19-targeted CAR T-cell therapy, have shown significant progression-free survival and overall survival advantages in patients with 17p deletion and/or TP53 mutation, while allogeneic hematopoietic cell transplant has proven clinical benefit in selected patients.

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