BTKis Show Promise in Richter Transformation, but More Data Are Needed

Available data suggest that Bruton tyrosine kinase inhibitors (BTKi) yield promising efficacy for Richter transformation (RT), one of the most consequential complications of chronic lymphocytic leukemia (CLL).¹

Marked by the sudden evolution of an aggressive lymphoma, RT has historically been associated with poor outcomes, with median overall survival (OS) hovering around 12 months despite intensive chemoimmunotherapy.

A new systematic review published in Frontiers in Oncology suggests that BTKi, which have revolutionized CLL treatment,² may offer new hope for patients with this high-risk transformation, though the researchers cautioned that outcomes vary based on treatment context and patient characteristics.

Richter’s transformation occurs in approximately 2% to 10% of patients with CLL and carries an annual incidence of 0.5% to 1%. While standard regimens like R-CHOP or dose-adjusted R-EPOCH are commonly used, responses are often short-lived, particularly in patients previously treated for CLL. The biological complexity of RT, including frequent TP53, NOTCH1, and MYC alterations, contributes to its aggressive behavior and resistance to therapy.

Following PRISMA guidelines, investigators of the new review analyzed 7 studies (6 clinical trials and 1 case series) including a total of 220 patients treated with BTK inhibitor–based therapies, both monotherapy approaches and combination regimens incorporating immunotherapy or chemotherapy. The patient population was heavily pretreated, with nearly two-thirds of patients having relapsed or refractory disease and 44.5% having previously received a BTKi. Importantly, all included studies were nonrandomized, resulting in a moderate to serious risk of bias.

Among BTK inhibitor monotherapies, the noncovalent BTKi pirtobrutinib (Jaypirca; Eli Lilly) showed the strongest activity. In an 82-patient phase 1/2 study, the overall response rate (ORR) was 50%, with a median OS of 12.5 months. Notably, response rates reached 65.2% in treatment-naïve patients and remained high even among those previously exposed to a BTKi.

Acalabrutinib (Calquence; AstraZeneca) demonstrated a more modest ORR of 40% in a smaller 25-patient cohort, with median progression-free survival (PFS) of 3.2 months. While less robust than pirtobrutinib, acalabrutinib was generally well tolerated.

“These data suggest a role for BTK inhibitors as a tolerable option for select patients with RT, particularly those who are frail or ineligible for cytotoxic chemotherapy,” wrote the researchers.

The review suggested that combination regimens enhance efficacy. The pairing of zanubrutinib (Brukinsa; BeiGene) with the PD-1 inhibitor tislelizumab (Tevimbra; BeiGene) achieved an ORR of 58.3%, with a 12-month OS rate of 74.7%. This, explained the researchers, supports the hypothesis that BTK inhibition may synergize with immune checkpoint blockade.

Similarly, nivolumab (Opdivo; BMS) plus ibrutinib (Imbruvica; Pharmacyclics and Janssen) yielded ORRs ranging from 41.6% to 65% across 2 trials, with significantly longer survival observed in treatment-naïve patients (median OS 24.1 months versus 9.1 months in relapsed/refractory cases).

A small retrospective case series combining platinum-based R-ICE chemotherapy with BTKi reported particularly striking outcomes, including an ORR of 83% and a median OS of 57 months. However, the small sample size limits broad conclusions.

Not all combinations explored by the researchers proved successful. For example, the ibrutinib–selinexor regimen demonstrated limited activity, underscoring the variability among therapeutic pairings.

Across studies, side effects were common but generally manageable. Cytopenias, infections, and gastrointestinal symptoms were the most frequently reported complications. For example, in the pirtobrutinib study, 60% of patients experienced grade 3 or higher side effects, though discontinuation rates remained low at 6%. Similarly, acalabrutinib and combination regimens reported frequent grade 3 or higher toxicities but relatively few treatment discontinuations.

While the data are encouraging, the review authors caution that current evidence is limited by small, single-arm studies and heterogeneous patient populations. Molecular characteristics such as clonal relationship to CLL and TP53 status were inconsistently reported, making it difficult to identify which patients derive the greatest benefit.

References

1. Dirican CD, Ajayi F, Mardini AA, et al. Efficacy and safety of BTK inhibitors in Richter’s transformation: a systematic review of clinical evidence. Front Oncol. Published online January 19, 2026. doi:10.3389/fonc.2025.1681589

2. Molica S, Allsup D. Bruton’s tyrosine kinase (BTK) mutations in chronic lymphocytic leukemia (CLL): a clinical review. Mediterr J Haematol Infect Dis. 2025;17(1):e2025053. doi:10.4084/MJHID.2025.053