Treatment Strategies for Richter’s Transformation to DLBCL Are Evolving

Richter’s transformation (RT) occurs when chronic lymphocytic leukemia (CLL) changes into an aggressive lymphoma.

Approximately 2% to 10% of patients with CLL progress to RT within a median time of 2 to 4 years from diagnosis, with roughly 95% of patients having RT-diffuse large B-cell lymphoma (DLBCL).

Most cases are clonally related to pre-existing CLL and carry a poor prognosis, with a median survival that is substantially lower versus de novo DLBCL with standard therapy of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today.

“There have been many trials ongoing right now to improve upon that because R-CHOP gives us a 9- to 12-month survival, which is obviously suboptimal,” Jain said, noting that trials combining venetoclax (Venclexta) or Bruton’s tyrosine kinase (BTK) inhibitors with R-CHOP are ongoing.

Researchers are also investigating strategies involving checkpoint inhibitors, bispecific antibodies, and non-chemotherapy combinations, he added.

Last year, the European Research Initiative on CLL (ERIC) published a consensus statement on the diagnosis, management, and optimal clinical trial design for RT-DLBCL, which acknowledged that chemoimmunotherapy regimens like R-CHOP “remain the de facto standard of care despite poor outcomes with its use.”

“It doesn’t say you can’t use it or shouldn’t use it,” Adam Kittai, MD, director of the CLL program at NYU Langone Health’s Perlmutter Cancer Center in New York City and lead author of the consensus statement, told MedPage Today. “It’s just highlighting that our current therapies don’t really work so great.”

In light of these poor outcomes, National Comprehensive Cancer Network guidelines recommend enrollment in a clinical trial for RT-DLBCL, preferably for clonally related disease, and as an option for clonally unrelated disease.

The guidelines panel also noted that while data supporting the use of non-chemoimmunotherapy regimens are limited in this setting, “given the unmet clinical need and lack of effective treatment options … including [non-chemoimmunotherapy] regimens as treatment options is reasonable.”

Evolving Strategies

Right now, Jain said, a standard approach for RT-DLBCL is to get patients to allogeneic stem cell transplant once they’ve achieved a deep remission, since it can provide a prolonged survival benefit.

“We are not talking about curing Richter’s transformation without the need for stem cell transplant, and the reality is only 10% of patients with Richter’s transformation are actually able to get to a transplant either because they are too old or frail, or have comorbidities, or they don’t achieve a remission,” he explained.

Thus, there is a need for new strategies to improve outcomes for these patients.

Because the efficacy of R-CHOP alone is poor, “I try to encourage people to do a chemoimmunotherapy regimen plus something else,” Kittai said. “Richter’s transformation is typically a non-GCB [germinal center B-cell] subtype DLBCL, so I definitely like to use pola-R-CHP [polatuzumab vedotin (Polivy) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone], based on results from the POLARIX study.”

In that study, adding polatuzumab vedotin and dropping vincristine from R-CHOP significantly improved progression-free survival (PFS) versus R-CHOP in previously untreated DLBCL.

Meanwhile, a phase II study of venetoclax plus dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) in patients with RT suggested the regimen was effective, with a complete response rate of 50%, though it was associated with significant toxicity.

In addition, a cohort study presented at the 2025 International Conference on Malignant Lymphoma showed that about half of patients with RT achieved a complete response with venetoclax plus R-CHOP. Median PFS was about 16 months, median overall survival was not reached, and rates of serious infections and cytopenias were low.

Other strategies involving targeted and immunotherapy combinations have also been evaluated in small studies.

In a phase II trial, patients receiving the BTK inhibitor zanubrutinib (Brukinsa) and the PD-1 inhibitor tislelizumab (Tevimbra) achieved an overall response rate of 58.3%, including nine complete responses among 48 evaluable patients, 95.8% of whom had RT-DLBCL.

In another phase II study of previously untreated patients with RT-DLBCL, the overall response rate was 67.9% with the combination of atezolizumab (Tecentriq) plus venetoclax and obinutuzumab (Gazyva), and the complete response rate was 28.6%.

Early results of the EPCORE CLL-1 study showed that patients with RT who received the bispecific antibody epcoritamab (Epkinly) had an overall response rate of 60% and a complete response rate of 50%.

Finally, in a phase II study evaluating nivolumab (Opdivo) plus ibrutinib (imbruvica) in patients with RT-DLBCL, 42% responded with a median duration of response of 15 months, and the median overall survival was 13 months.

Meanwhile, SWOG S2504, the first phase III trial in patients with previously untreated RT, is evaluating the BTK inhibitor pirtobrutinib (Jaypirca) plus R-CHOP versus R-CHOP alone.

The potential efficacy of pirtobrutinib was previously demonstrated in a subgroup of 82 patients with RT in a multicenter study, in which half of these patients responded, with eight patients discontinuing the therapy while still in response to undergo stem cell transplantation.

Kittai noted that chimeric antigen receptor (CAR) T-cell therapy could also be of benefit.

“I think what is going to be most effective is CAR T-cell therapy,” he said. “We  know that CAR T-cell therapy works in patients who have relapsed or refractory DLBCL, regardless of prognostic factors beforehand, and we’ve seen the same thing in CLL, where the biggest prognostic factor with CAR-T is disease bulk. So, if that same paradigm holds for Richter’s transformation, developing CAR T-cell therapies that are more effective and safer is an unmet need.”