When chronic lymphocytic leukemia (CLL) transforms into an aggressive lymphoma — a process called Richter's transformation (RT) — the standard treatment playbook comes up short. R-CHOP, the go-to chemoimmunotherapy regimen, delivers a median survival of just 9–12 months, and only about 10% of patients ever make it to the potentially curative option of allogeneic stem cell transplant. Experts say the field is overdue for a reset.

Clinicians are now layering novel agents onto chemotherapy backbones or exploring non-chemo combinations entirely. Promising approaches include venetoclax plus R-CHOP (with ~50% complete response rates and a median PFS of ~16 months), polatuzumab vedotin-based regimens (pola-R-CHP), and non-chemo combos like BTK inhibitors paired with checkpoint inhibitors. The first-ever phase III trial in previously untreated RT — SWOG S2504 — is now evaluating pirtobrutinib plus R-CHOP vs. R-CHOP alone.

Key Takeaways:

• NCCN guidelines recommend clinical trial enrollment as the preferred approach for RT-DLBCL
• Epcoritamab (bispecific antibody) showed a 60% overall response rate and 50% complete response rate in early RT data
• Zanubrutinib + tislelizumab achieved a 58.3% overall response rate in a phase II trial
• CAR T-cell therapy is viewed as a potentially transformative option, though still under active investigation

Why it matters: RT affects up to 10% of CLL patients and carries a devastating prognosis with current therapies. As novel agents advance through trials, the window for meaningful improvement is opening — but the field urgently needs better options for patients who can't tolerate intensive regimens or reach transplant.