Treatment of Richter Transformation of Chronic Lymphocytic Leukemia in the Modern Era

Abstract

Richter Transformation (RT) refers to the development of an aggressive lymphoma in the setting of chronic lymphocytic leukemia (CLL). While many variants of RT are recognized, diffuse large B-cell lymphoma (RT-DLBCL) is the most common (80%), followed by Hodgkin's lymphoma (RT-HL, 19%). Diagnosis is based upon histologic evaluation of clinically suspicious lymph nodes. Positron emission tomography (PET) may be used to select the node of interest for biopsy. Although clonality testing is not a prerequisite of RT diagnosis, it has significant implications for survival. Clonally related DLBCL carries the worst prognosis with a median overall survival (OS) of less than one year in the era of combination chemotherapies with or without anti-CD20 antibodies. Prognosis has improved with the use of stem cell transplant and newer agents such as targeted therapy and newer forms of immunotherapy. Consideration of a clinical trial is encouraged. This review describes our current understanding of RT and focuses on treatment of RT-DLBCL, including clinical trials in progress and new therapies in development. We also report an illustrative example of a patient with clonally related DLBCL who survived two years after diagnosis without the use of combination chemotherapy.

Keywords: Bruton’s tyrosine kinase inhibitors; Richter transformation; bispecific antibodies; checkpoint inhibitors; chimeric antigen receptor t-cells; chronic lymphocytic leukemia; precision medicine; stem cell transplant; targeted therapy.

Figure 1

Mechanisms of action for novel targeted therapies in Richter Transformation. BTK inhibitors disrupt signaling from the surface B-cell receptor (BCR) to the canonical nuclear factor κB (NF-κB) pathway. PI3k inhibitors primarily disrupt signaling from surface CD19 to the mammalian target of rapamycin (mTOR) pathway although there is debate that PI3K may interact with other pathways. BCL-2 inhibitors disrupt mitochondrial associated anti-apoptotic pathways and induce cell death. Antibodies directed at program cell death-1 receptor or its ligand (PD-1 and PD-L1 respectively) seem to interfere with tumor microenvironment stimulation of neoplastic cell growth. Bi-specific T-cell engagers (BiTEs) are a class of bispecific antibodies which bring T-cells in proximity of cancer cells (the example shown here is an anti-CD3xCD20 bispecific). Anti-CD19xCD47 antibodies represent another class of bispecific antibodies which target two antigens on a neoplastic cell, making these antibodies more selective for neoplastic cells than traditional monoclonal antibodies. CAR-T cells are engineered T-cells with chimeric receptors designed to target cancer cells (the example shown here is an anti-CD19 CAR T-cell). Antibody-MMAE conjugates allow for the delivery of the potent anti-tubulin drug MMAE, which halts cytoskeletal elements and inhibits cell division.