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Jennifer R. Brown, MD, PhD


Richter Transformation in CLL: From Pathophysiology to Treatment

By: Joseph Fanelli
Posted: Friday, January 14, 2022

Despite the promising results of new treatment strategies such as bispecific antibodies and chimeric antigen receptor (CAR) T cells, more effective therapies for Richter transformation are needed to improve patient outcomes, according to a review of current and novel therapies for the disease presented in Cancers. According to Ilana Levy, MD, and Tamar Tadmor, MD, both of the Bnai-Zion Medical Center and Technion-Israel Institute of Technology, Haifa, Israel, there is an increasing understanding of the molecular mechanisms at the core of Richter transformation and the relevant risk factors that may help clinicians identify high-risk patients, though treatment is lacking.

“The treatment of Richter transformation is still an unmet clinical need, and current data on treatment approaches have mainly been derived from small nonrandomized trials,” the authors concluded.

At present, the clinical risk factors for Richter transformation in patients with chronic lymphocytic leukemia (CLL) include bulky lymphadenopathy or hepatosplenomegaly, advanced stage, low platelet count, elevated beta-2-microglobulin, past CLL therapy combining purine analogs and alkylating agents, and a high number of lines of therapy. At a molecular level, several genetic markers indicate an increase in the likelihood of developing Richter transformation, such as in patients with BCL2 GG and LRP4 TT germline genotypes.

Currently, the “gold standard” for treatment of Richter transformation (outside of clinical trials) remains chemoimmunotherapy, despite the therapy netting “unsatisfactory” results, the authors noted. A few novel drugs have been used in small trials, including Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib, ibrutinib in combination with the monoclonal antibody ofatumumab, among others, all of which had positive outcomes when combined with chemoimmunotherapy.

In terms of novel treatments, the bispecific anti-CD19/anti-CD3 monoclonal antibody blinatumomab was used to treat a case of refractory Richter transformation with rapid colorectal cancer. In that instance, the treatment allowed bridging to allogeneic stem cell transplantation, and a phase II open-label trial was developed to test the efficacy of the treatment at the MD Anderson Cancer Center, Houston. Additionally, CAR T-cell therapy has shown promising results.

Disclosure: The authors reported no conflicts of interest.

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