# Understanding Richter's Transformation in the targeted therapies era

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $474,404

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 10052252
- **Project number:** 1R01CA240493-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Rosa Lapalombella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,404
- **Award type:** 1
- **Project period:** 2020-09-11 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052252

## Citation

> US National Institutes of Health, RePORTER application 10052252, Understanding Richter's Transformation in the targeted therapies era (1R01CA240493-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10052252. Licensed CC0.

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