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John Allan, M.D. Specific clinical, biological and genomic characteristics have been established as Richter’s syndrome risk factors and predictors of outcome, according to a presenter at Lymphoma & Myeloma 2015.

Richter’s transformation of chronic lymphocytic leukemia to diffuse large B-cell lymphoma (DLBCL) should be restricted to CLL transformations and distinguished from de novo Hodgkin’s lymphoma, John N. Allan, MD, assistant professor of medicine in the division of hematology and medical oncology at Weill Cornell Medicine, said during his presentation.

“We now know that there are stark differences between follicular transformation vs. Richter’s transformation,” Allan said.

Ninety percent of cases are transformed DLBCL, whereas the rarer Hodgkin’s variant Richter’s syndrome (HVRS) accounts for 10% of cases. The 10-year annual incidence rate of transformed DLBCL from CLL diagnosis approaches 5%, whereas the 10-year annual incidence rate of HVRS is 0.5%. However, the incidence of transformed DLBCL increases after treatment, with a 10-year annual incidence rate from the time of first CLL treatment approaching 15%.

Risk factors

Bulky lymphadenopathy appears to be the greatest clinical risk factor for Richter’s transformation among patients with CLL, whereas patients with deletion 13q appear at lowest risk, Allan said.

In terms of biological factors, many high-risk factors of CLL — such as IGHV mutational status, ZAP70 status, CD39 and CD48 — also increase risk for later transformation. Further, researchers have showed shorter telomere at CLL diagnosis increases risk for Richter’s transformation.

Another biological risk factor for Richter’s transformation is immunoglobulin stereotype B-cell receptors. Thirty percent of patients with CLL exhibit a stereotype B-cell receptor, and these patients have nearly a 20% risk for transformation after 6 to 7 years.

Notch1 mutations have been the major molecular risk factor for Richter’s transformation.

Allan also noted the mutational profile changes after transformation, and it appears different between patients with transformed DLBCL and de novo DLBCL.

Therapy options

Although there is no standard first-line therapy for Richter’s syndrome, patients often receive CHOP-like regimens, Allan said. However, the number of patients who respond or achieve a complete response with chemotherapy appears poor compared with patients who have de novo DLBCL. Median OS with chemotherapy ranges from 9 months to 12-15 months.

Stem cell transplantation may improve outcomes; however, only about 10% to 15% of patients qualify for this procedure, Allan said. Data have shown that transplantation outcomes are improved among patients who go to transplant while in complete or partial remission compared with patients who go to transplant as salvage therapy while refractory.

“We need to start to capitalize on what we know and the difference in CLL and Richter’s syndrome, as well as those difference between Richter’s syndrome and de novo DLBCL,” Allan said. “There aren’t very many trials specifically for Richter’s syndrome, but there are a few.”

Investigational agents include selinexor (KPT-330, Karyopharm), PNT2258 (ProNAi), azacitidine (CC-486, Celgene), ACP-196 (Acerta Pharma) alone and with pembrolizumab (Keytruda, Merck) and CAR T cells.

“Although there are currently only a few targeted approaches available specifically for Richter’s syndrome, they are starting to prove effective in achieving responses in these refractory patients,” Allan said.

This article first appeared in HemOnc Today. Read the original article here.