Oncology

Chronic Lymphocytic Leukemia

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Current Research on Predicting and Treating Richter Transformation

clinical topic updates by Jennifer R. Brown, MD, PhD

Overview

The pathogenetic mechanisms underlying chronic lymphocytic leukemia (CLL) transformation to Richter transformation (RT) remain poorly understood, and optimal treatments for those at risk for transformation are unknown. Identifying RT amidst multiple discordant CLL disease sites is challenging, as is assessing its clonality. Currently available treatments are unsatisfactory, although investigations are ongoing.

Expert Commentary

Jennifer R. Brown, MD, PhD

Director, Center for Chronic Lymphocytic Leukemia
Institute Physician
Dana-Farber Cancer Institute
Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology
Harvard Medical School
Boston, MA

“The distinction between an evolving, more aggressive, TP53-mutated CLL and RT is an important one because patients with the former can sometimes do relatively well on ibrutinib or venetoclax.” 

Jennifer R. Brown, MD, PhD

RT, also known as Richter syndrome, remains a major unmet need in CLL. A panoply of risk factors for RT have been reported in the literature, including having 17p deletion or TP53 and NOTCH1 mutations, but the pathogenetic mechanisms underlying RT are still poorly understood. Clinically, RT is suspected in patients with rapidly progressive disease, especially if there are 1 or 2 sites that are outpacing other sites of disease, or when there are B symptoms, which would not be typical in CLL. 

A number of challenges are associated with the diagnosis of RT, including access to and suitability of biopsy specimens. Positron emission tomography imaging is used to detect discordance and to target one of the higher-risk regions for biopsy. Standard uptake values (SUVs) are often greater than 10 in those with RT. Values in patients with typical CLL are often in the range of 2 to 3 SUVs, but they can range from 5 to 10 and not be transformed in 17p deletion. There can also be a discrepancy amongst pathologists in identifying RT. If the biopsy reveals just an increased presence of large cells, and not sheets of cells, it is more likely an evolving, more aggressive CLL. The distinction between an evolving, more aggressive, TP53-mutated CLL and RT is an important one because patients with the former can sometimes do relatively well on ibrutinib or venetoclax. Almost all cases of RT are the diffuse large B-cell lymphoma (DLBCL) type, and DLBCL in RT is usually clonally related to the CLL, aggressive, and resistant to therapy. Less commonly, DLBCL may arise from a separate clone, in which case it has a prognosis that is similar to other de novo DLBCLs. Distinguishing between the 2 via genetic testing is not routinely done, so clinical features are used to try to determine a clonal relationship. 

De novo DLBCL is potentially curable, while an RT-related DLBCL, at this point, is likely not. For initial treatment of DLBCL in RT, patients are usually offered an anthracycline-based chemotherapy regimen such as R-CHOP or EPOCH-R. For some patients with obvious RT with TP53 mutation or deletion, or those who do not respond or who have progression on anthracycline-based treatment, I usually start with or switch to novel agent therapy with ibrutinib or venetoclax. These agents have an approximate 40% response rate in RT, but the duration of response is very short (ie, a few months). Alternatively, there are some data for and ongoing clinical trials of PD1 inhibition or combined Bruton tyrosine kinase–PD1 inhibition. The ultimate goal for patients with RT is to achieve remission and proceed to stem cell transplantation, usually allogeneic, or to consider chimeric antigen receptor T-cell therapy on clinical trial. At present, stem cell transplantation is the only option with known potential for long-term survival.

References

Allan JN, Furman RR. Current trends in the management of Richter’s syndrome. Int J Hematol Oncol. 2019;7(4):IJH09. 

Balatti V, Tomasello L, Rassenti LZ, et al. miR-125a and miR-34a expression predicts Richter syndrome in chronic lymphocytic leukemia patients. Blood. 2018;132(20):2179-2182. 

ClinicalTrials.gov. A study to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the combination of ibrutinib with nivolumab in participants with hematologic malignancies. https://clinicaltrials.gov/ct2/show/NCT02329847. Accessed September 19, 2019.

Pula B, Salomon-Perzyński A, Prochorec-Sobieszek M, Jamroziak K. Immunochemotherapy for Richter syndrome: current insights. Immunotargets Ther. 2019;8:1-14. 

Rossi D, Spina V, Cerri M, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res. 2009;15(13):4415-4422.

Jennifer R. Brown, MD, PhD

Director, Center for Chronic Lymphocytic Leukemia
Institute Physician
Dana-Farber Cancer Institute
Worthington and Margaret Collette Professor of Medicine in the Field of Hematologic Oncology
Harvard Medical School
Boston, MA

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