Abstract
Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling. Known and previously undescribed mutations in BTK and PLCG2, or uncommonly, other candidate alterations are present in seventeen subjects at the time of progression. Thus, the frequently observed clonal shifts during the early treatment period and its potential association with adverse outcome may reflect greater evolutionary capacity, heralding the emergence of drug-resistant clones.
Highlights
Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents
Since the B cell receptor (BCR) and nuclear factor-κB (NF-κB) pathways are directly inhibited by ibrutinib, we examined whether the presence of mutations in these pathways prior to ibrutinib therapy was associated with inferior outcome
We examined the changes in cancer cell fraction (CCF) over time in those CLL drivers detected at subclonal frequency, focusing on the 14 candidate CLL genes and CNVs present in at least six cases across the 61 baseline samples
Summary
Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. The therapeutic landscape of CLL has been dramatically altered through the introduction of multiple highly effective targeted agents[7] Leading these is ibrutinib, a first-in-class Bruton tyrosine kinase (BTK) inhibitor, which blocks B cell receptor (BCR) signaling, a key pathway for CLL cell survival and proliferation. Approved for all CLL patients based on improved progression free survival in treatment-naive disease and a favorable safety profile[8,11,12,13], ibrutinib is increasingly used as monotherapy or tested in combination regimens Despite this high level of clinical activity, disease progression on ibrutinib has been increasingly appreciated, with mutations in BTK and in PLCG2 (a key signaling molecule immediately downstream of BTK in the BCR pathway), as the most common adaptations to therapy[14,15,16,17]. We further identified that the capacity for resistance (e.g., the observation of minute PLCG2 mutated clones) was already present at the time of study entry, emphasizing the role of ibrutinib in providing strong selection pressure for the emergence of resistant clones
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