The therapeutic approach of CLL has evolved significantly over the past decade from chemoimmunotherapy to targeted therapies including Bruton tyrosine kinase inhibitors (BTKi, ibrutinib and acalabrutinib and venetoclax (that targets BCL2). Whereas a large subset of CLL patients will have a favorable outcome with targeted therapies, select high-risk patients develop disease progression that can often manifest as Richter?s transformation (RT), a rapidly growing aggressive lymphoma with morphologic similarity to diffuse large B-cell lymphoma. As the use of targeted therapies continues to grow, emergence of resistance and progression to RT are of increasing clinical concern. Identifying pre-treatment biomarkers associated with this transformation and strategies to prevent and also treat RT in the era of targeted therapies is therefore of utmost importance. In the era of chemoimmunotherapy, early mutations including NOTCH1, XPO1, TP53, and 2p amplification at time of CLL diagnosis were found to be associated with RT development. Other studies examining RT tumors have identified c-MYC expression/amplification or newly acquired TP53 mutations as additional common lesions. However, since the advent of targeted therapy, there have been no reports examining founder mutations or other features predisposing to RT. As chemoimmunotherapy and targeted therapy have different escape pathways, it is likely that these pre-treatment risk factors will differ. Using a large series of pre-treatment samples for CLL patients enrolled across four ibrutinib clinical trials at The Ohio State University, for which follow up data were available, we have described the presence of near-tetraploidy and complex karyotype prior to the start of ibrutinib treatment to be independent risk factors for discontinuing ibrutinib due to RT supporting our hypothesis of the existence of novel biomarkers of transformation that are yet unidentified. We herein propose to: 1) examine the CLL genomic and epigenetic features of patients who develop RT, validate the importance of select gene alterations on development of Richter?s using mouse models of human CLL, and systematically assay phenotypes involved in CLL to RT using in vivo CRISPR screen methods; 2) perform a three institution phase 1b/2 study of ibrutinib and PLX51107 (target BRD4) in patients with previously treated CLL with high risk of developing RT or RT. At completion of this project we will have a much better understanding of risk factors for RT following targeted therapy, have applied novel mouse models to better inform future trials to prevent/treat this CLL complication. Additionally, we will have completed the very first trial with BRD4 inhibitor PLX51107 combined with ibrutinib in CLL patients at high risk for RT and also in RT. Additionally, we will be poised to launch future trials focused on both preventing and treating RT in patients with CLL.
Richter?s transformation (RT) is a morphologic change of chronic lymphocytic leukemia (CLL) to an aggressive llymphoma for which no effective therapies exist and all patients rapidly die from. Our preliminary data support the existence of novel biomarkers of transformation in the era of targeted therapies that could present an opportunity to treat CLL with a different approach that may prevent this complication. We employ a comprehensive approach to characterize both CLL prior to developing RT and also RT in the era of targeted therapies and seek to initiate the very first phase 1b/2 trial with BRD4 inhibitor PLX51107 combined with ibrutinib in CLL patients at high risk for RT and also in RT.
