December 11, 2023
By Dibash Kumar Das, PhD
In the evolving landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment, a comprehensive cohort study conducted at the Mayo Clinic has shed light on the incidence of Richter transformation (RT). The study was presented at the 65th ASH Annual Meeting and Exposition held from December 9-12, 2023 (Abstract 3271). This histologic transformation, characterized by the conversion of CLL/SLL into an aggressive lymphoma, notably diffuse large B-cell lymphoma (DLBCL), has long been a concern in the management of these conditions.
The study, spanning from January 2000 to April 2023, meticulously analyzed data from 3,347 patients seen at the Mayo Clinic. Striving to uncover trends across different therapeutic eras, the investigation delineated patients into the pre-novel agent era (up to February 2014) and the novel agent era (starting February 2014). This demarcation allowed for a nuanced exploration of how advancements in CLL/SLL therapies, particularly the introduction of novel agents, might impact the occurrence of RT.
Key Findings & Analysis
The median age at CLL diagnosis was 65 years with a majority being male (66%). Remarkably, baseline characteristics between patients in the two treatment eras were strikingly similar. Over the entire cohort's median follow-up of 5.6 years, 82 patients were diagnosed with RT, with 69 in the pre-novel agent era and 13 in the novel agent era.
The cumulative incidence rates for RT revealed intriguing patterns. Over 1, 5, and 10 years from the time of CLL/SLL diagnosis, the rates were 0.6 percent, 1.8 percent, and 3.0 percent, respectively. Importantly, among patients receiving CLL/SLL therapy, the 1-, 5-, and 10-year incidence rates for RT from the time of treatment start were 0.3 percent, 3.3 percent, and 4.9 percent, respectively.
In a nuanced comparison between the pre-novel agent and novel agent eras, the study found no significant difference in RT incidence from the time of CLL/SLL diagnosis. However, an intriguing observation emerged when assessing patients who received CLL/SLL-directed therapy. While the 1-year incidence rates for RT were 0.3 percent in the pre-novel agent era and 0.2 percent in the novel agent era, the 5-year incidence rates were 3.7 percent and 1.9 percent, respectively. Although this demonstrated an increased risk in the pre-novel agent era, it did not reach statistical significance.
Treatment Dynamics Impact RT Risk
A deeper dive into the treatments received before RT development unveiled notable distinctions. In the pre-novel agent era, patients often underwent chemoimmunotherapy, while in the novel agent era, none of the patients received chemoimmunotherapy before RT. This distinction prompts further investigation into whether novel agents play a role in suppressing RT development or mitigating the risks associated with cytotoxic chemotherapy-induced clonal evolution.
To gain additional insights into the study, Oncology Times chatted with study author, Paul J. Hampel, MD, a board-certified hematologist and oncologist in the Division of Hematology of the Department of Medicine at Mayo Clinic, Rochester, MN. His dedication extends to both clinical practice and research focusing on enhancing patient outcomes. Hampel is particularly invested in unraveling resistance mechanisms to targeted therapeutics and determining the most effective sequencing of treatments for individuals with CLL and other lymphoproliferative diseases.
Oncology Times: What are the potential mechanisms by which novel agents may suppress RT development or avoid the risks associated with cytotoxic chemotherapy-induced clonal evolution? How might this knowledge inform future treatment strategies for CLL/SLL patients?
Hampel: “Recent studies have provided unprecedented characterization of the genomics, transcriptomics, and epigenomics of Richter transformation. These reports have identified frequently disrupted driver genes and cellular pathways in Richter transformation.
“This elegant work has demonstrated the early subclones that may precede overt, clinical transformation by over a decade. A potentially lower incidence of Richter transformation in patients treated in the novel agent era may be a result of averting chemotherapy-induced clonal evolution and the selection of these cells.
“Alternatively, targeting the key pathways of B-cell receptor signaling and anti-apoptotic signaling with BTK inhibition and BCL2 inhibition, respectively, may suppress or eliminate these clones long before their expansion. These mechanisms are speculative, particularly since much of our understanding of Richter transformation comes from cohorts including predominantly chemoimmunotherapy-treated CLL patients. We are lacking detailed mechanisms and biological insights into Richter transformation occurring in novel agent-exposed, chemotherapy-naïve patients.”
Oncology Times: Considering the changing landscape of CLL treatment, how do these findings contribute to our understanding of RT incidence as CLL patients live longer with novel agent treatments? What research directions are needed to build upon these insights?
Hampel: “Most of the data regarding Richter transformation incidence have come from clinical trials or retrospective series, particularly when considering incidence in the era of novel or targeted agent treatments. Earlier reports of Richter transformation incidence in patients treated with BTK inhibitors or venetoclax were in the setting of patients receiving these treatments for relapsed/refractory CLL, describing Richter transformation as an early progression event.
“In our study presented at ASH 2023, using the Mayo Clinic CLL Database we present the first Richter transformation incidence data from unselected patients followed prospectively from the time of diagnosis in the novel agent era (February 2014 to current) and compare this to patients diagnosed in the pre-novel agent era (pre-February 2014). Here, patients who received CLL/SLL-directed treatment appear to have a lower risk of Richter transformation in the novel agent era. This is an important and welcomed finding since BTK inhibitors and BCL2 inhibitors have replaced chemotherapy as standard-of-care first-line treatments. These results also challenge the notion that the incidence of Richter transformation may increase as patients live longer in the novel agent era. In addition to further analyses evaluating incidence not just by era but by treatment exposure, longer follow-up will ultimately be required to more fully appreciate these differences.”
Dibash Kumar Das is a contributing writer.