Approach to Richter transformation of chronic lymphocytic leukemia in the era of novel therapies

Abstract

Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. About 2-10% of CLL patients develop aggressive histological transformation, most commonly to diffuse large B cell lymphoma (DLBCL), historically called Richter transformation (RT). Clinical features suggestive of RT include elevated LDH and non-specific symptoms such as fever, weight loss, and lymphadenopathy. 18-fluorodeoxyglucose (18-FDG) uptake is increased on PET scan (standardized uptake value max most commonly ≥ 10). PET/CT study can identify optimal site for excisional biopsy, which is the gold standard for RT diagnosis, as well as aid in disease staging and prognostication. In addition to clinical prognostic features such lactate dehydrogenase level, platelet count, and performance status, important predictors of poor outcome in RT are TP53 disruption and clonal relationship of DLBCL to underlying CLL. Chemoimmunotherapy constitutes the standard treatment for RT, followed by stem cell transplant (SCT) in eligible patients. However, the majority of patients do not proceed to allogeneic SCT, either due to inadequate disease control with initial therapy, poor performance status, or lack of donor availability. Overall outcome is dismal. Some novel agents under investigation, particularly PD-1 inhibitors, are showing clinical activity in Phase I and II trials. An ongoing incidence of RT has been noted in studies of previously treated patients receiving targeted therapies such as ibrutinib and venetoclax; the frequency of RT in patients initially treated with novel agents rather than chemoimmunotherapy will be important to determine with longer follow-up. This review focuses on the development, clinicopathologic features, and treatment of RT in the context of novel therapies.

Entospletinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia previously treated with B-cell receptor inhibitors: results of a phase 2 study

“…Interestingly, in patients with RT and prior BTKi exposure, therapy with entospletinib led to an ORR of 40.0% and median PFS of 2.9 months, while there were no responses to entospletinib in RT patients with prior PI3Kdi exposure and a median PFS of 4.6 months. Our study demonstrated encouraging responses to entospletinib in patients with R/R CLL who have failed BTK and/or PI3Kd inhibitors, especially in patients with RT, a group that has historically demonstrated a very poor prognosis [26,27]. This provides rationale for the combination use of this agent and the possibility of using this for disease control while transitioning to more definitive treatment like chimeric antigen T-cell receptor therapy and/or allogeneic hematopoietic cell transplant.…”

Novel Richter Syndrome Xenograft Models to Study Genetic Architecture, Biology, and Therapy Responses

“…Clinical and experimental evidence indicate that Richter syndrome cells are poorly responsive to drugs that are typically highly effective for patients with CLL, such as Ibrutinib or idelalisib (21), suggesting that novel therapeutic opportunities should be explored on the basis of the genetic and expression profile. In line with this concept, preliminary results obtained with a selective NFkB inhibitor, IT-901, confirm that these cells are, to a considerable extent, sensitive to this drug, which interrupts a critical growth circuit (22).…”

Clinical, pathological, and biological characterization of Richter syndrome developing after ibrutinib treatment for relapsed chronic lymphocytic leukemia

“…More than 80% of patients that developed RT are clonally related to the pre‐existent CLL phase. Molecular features associated specifically with RT include CDKN2A/B loss, TP53 disruption, NOTCH1 mutations that confer an 11‐fold increased risk of RT, CD38 expression (CD38 ≥ 30%), stereotyped B cell receptor, and unmutated IGHV status that confer a 4‐fold increased risk . Both our patients are clonally related to the pre‐existent CLL phase representing transformation from CLL.…”