Abstract
Simple SummaryRichter transformation is a significant and devastating complication of chronic lymphocytic leukemia. While its pathogenesis has been well-studied in terms of genetic and molecular changes and its diagnosis has been made easier by imaging and pathological techniques, its treatment is still an issue. Most patients are resistant to chemo-immunotherapy, and even novel agents do not seem to improve the prognosis in a significant way. Therefore, new combinations and novel drugs are currently being tested. In the current review, we summarize new data about the pathophysiology, biological, and clinical basis of Richter transformation, as well as the different treatments of this condition.Richter transformation (RT) is a poorly understood complication of chronic lymphocytic leukemia (CLL) with a dismal prognosis. It is associated with a switch in histopathology and biology, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or less frequently to Hodgkin’s variant of Richter transformation (HVRT). It occurs in 2–10% of CLL patients, with an incidence rate of 0.5–1% per year, and may develop in treatment-naïve patients, although it is more common following therapy. In recent years, there has been a deeper understanding of the molecular pathogenesis of RT that involves the inactivation of the TP53 tumor suppressor gene in 50–60% of cases and the activation of aberrations of NOTCH1 and MYC pathways in about 30% of cases. Compared to the preceding CLL, 80% of cases with DLBCL-RT and 30% of HVRT harbor the same IGHV-D-J rearrangements, indicating a clonal evolution of the disease, while the remaining cases represent de novo lymphomas that are clonally unrelated. Despite advances in understanding the molecular variations and the pathogenesis of the disease, there is still no significant improvement in patient outcomes. However, if no clinical trials were designed for patients with RT in the past, now there many studies for these patients that incorporate new drugs and novel combinations that are being explored. In this review, we summarize the new information accumulated on RT with special emphasis on results involving the novel therapy tested for this entity, which represents an unmet clinical need.
Highlights
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Murine models have shown that Richter transformation (RT) is characterized by constitutive active AKT, which seems to induce NOTCH1-signaling B cells via the NOTCH1 ligand expressed by T cells, and apparently orchestrates RT [48]
A stable RT cell line established from the cervical lymph node of a 60-year-old patient with chronic lymphocytic leukemia (CLL) and clonally-related RT-diffuse large B-cell lymphoma (DLBCL) revealed a complex karyotype with the loss of TP53 and CDKN2A, a chromosomal gain of the NOTCH1 gene locus, and strong immunoreactivity for BCL-2 [50]
Summary
It is of great interest to identify the patients with the highest risk to develop RT. Clinical risk factors for RT include: bulky lymphadenopathy or hepato-splenomegaly, advanced stage, low platelet count, elevated beta-2-microglobulin [5,33,36,37], past CLL therapy combining purine analogues and alkylating agents, and a higher number of lines of therapy [38]. IGHV4–39 gene usage has been shown to carry a 24-fold increased risk of RT and when combined with stereotyped BCR (SUBSET 8) in the same patient, it showed a 5 year risk of RT of 68.7% [6] Another recently noted point is that CLL patients with a complex karyotype at diagnosis seem to have the highest risk and shortest time to Richter transformation [44,45]. Murine models have shown that RT is characterized by constitutive active AKT, which seems to induce NOTCH1-signaling B cells via the NOTCH1 ligand expressed by T cells, and apparently orchestrates RT [48]
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