Introduction: Richter transformation (RT), defined as the progression of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL-RT), remains a major clinical challenge with dismal outcomes under conventional treatments. Occurring in 2–10% of CLL patients, RT typically emerges within a few years of diagnosis and is associated with complex biology including TP53 disruption, clonal evolution, and resistance to standard therapies. Given the transformative impact of chimeric antigen receptor T-cell (CAR-T) therapies in relapsed/refractory (R/R) DLBCL, there is growing interest in their role in RT. However, RT-specific outcomes remain limited. This systematic review synthesizes available data on the efficacy and safety of anti-CD19 CAR-T therapy in adult patients with RT.

Methods: This PRISMA compliant systematic review searched Medline (PubMed), Scopus, and major hematology/oncology meeting abstracts through June 1, 2025. Eligible studies included adults (≥18 years) with biopsy-confirmed RT treated with anti-CD19 CAR-T therapies. Outcomes of interest included overall response rate (ORR), complete response (CR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Quality assessment was performed using the MINORS tool. Due to heterogeneity in study designs, findings were narratively synthesized.

Results: Nine studies (7 cohorts, 2 case series) including 402 patients with RT were analyzed. Patients were predominantly male with median age 59–68 years. Vast majority had DLBCL-RT and were heavily pretreated (median 2–5 prior therapies); 50–94% had prior BTK inhibitor exposure. Common adverse features included TP53 mutations, unmutated IGHV, del(17p), bulky disease, CNS involvement, and poor ECOG status. Lymphodepletion regimens included fludarabine/cyclophosphamide (FC) or bendamustine. CAR-T products administered were axi-cel (n=148), tisa-cel (n=131), liso-cel (n=57), brexu-cel (n=1), and investigational agents (n=29).

Across studies, ORR ranged from 57% to 89%, and CR rates ranged from 47% to 67%. In small case series, response rates were notably high (e.g., ORR 83–89%). However, response durability varied widely. Median PFS spanned 4.3 to 24.6 months, with one-year PFS ranging from 34% to 68.8%, and two-year PFS from 22% to 61.1%. Median OS ranged from 8.5 to 24.6 months; one-year OS was 42.9–75%, and two-year OS 24–67.5%. Notably, these survival outcomes were generally shorter than those observed in pivotal trials of CAR-T for de novo DLBCL.

Safety outcomes were notable for high rates of CRS (70–90%), with grade ≥3 events in up to 21%. ICANS incidence ranged from 22% to 100%, with severe neurotoxicity (grade ≥3) in 9–42%. Hematologic toxicities were frequently reported: prolonged neutropenia occurred in up to 80%, and thrombocytopenia in 28%. Infections were common and often fatal, including COVID-19-related deaths. Treatment-related mortality (TRM) was related to infections, multiorgan dysfunction, and transplant-related complications.

Multiple prognostic factors were associated with outcomes. Elevated LDH, bulky disease, poor ECOG status, and multiple prior therapies correlated with inferior PFS and OS. Elevated inflammatory markers (e.g., CRP), and resistant disease at infusion were also adverse. ICANS occurrence, especially severe cases, was independently predictive of higher mortality.

Conclusion: CAR-T therapy shows promising initial responses in RT, with ORR and CR rates comparable to de novo DLBCL. However, responses are often short-lived, with inferior PFS and OS compared to outcomes in aggressive lymphoma trials. RT patients face higher toxicity—particularly ICANS, cytopenias, and infections—reflecting disease biology and prior treatments. Poor baseline features like elevated LDH, poor performance status, and high tumor burden are associated with worse outcomes, more so than in de novo DLBCL. These findings suggest that while CAR-T is feasible and active in RT, optimization strategies are urgently needed. Ongoing trials are assessing combination therapies and next-generation CAR-Ts. Prospective RT-specific studies are essential to refine patient selection, improve safety, and enhance the durability of responses in this challenging population.

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2025
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