Richter transformation in diffuse large B-cell lymphoma in patients with chronic lymphocytic leukemia receiving ibrutinib: risk factors and outcomes

Abstract

This study aimed to define the incidence and risk factors for diffuse large B cell lymphoma variant of RT (DLBCL-RT) in 976 patients with CLL who received ibrutinib therapy. DLBCL-RT was recorded in 83 (8.5%) patients, with a 7-year 15.6% rate. Most patients exhibited clinical signs of aggressive lymphoma, enlarged lymph nodes in 83%, cytopenia in 60%, and Suv_max values ≥ 5 at CT/PET in 98%. Among patients for whom the data was available, 83% had unmutated IGHV, 60% TP53 disruption, 26% mutated NOTCH1, 10% were categorized in subset #8 and 82% had a clonally-related lymphoma. Response to chemoimmunotherapy was achieved by 32% of patients. Median OS was 4.7 months, with cytopenia at DLBCL-RT diagnosis being the only significant factor for inferior survival (HR, 1.68). In multivariable analysis, factors predictive for increased risk of DLBCL-RT were age <70 years (HR: 1.98, p = 0.019), TP53 disruption (HR: 1.72, p = 0.044), with a trend to significance for prior treatment (HR: 1.91, p = 0.065). According to the number of these risk factors, DLBCL-RT rate varied from 4% to 22.6% (p < 0.0001). In conclusion, patients with CLL receiving ibrutinib with age <70 years, TP53 disruption and previously treated are at increased risk for developing DLBCL-RT and deserve close monitoring.

Fig. 1. Cumulative incidence of DLBCL-RT cases from the start of treatment with ibrutinib.

A Cumulative incidence of DLBCL-RT cases for all patients included in the study. B Cumulative incidence of DLBCL-RT cases according to the treatment they received. Black line: patients who received front-line treatment (N = 269). Grey line: patients who received ibrutinib after prior treatment (N = 707).

Fig. 2. Cumulative incidence of DLBCL-RT cases according to the number of risk factors.

Black line: low risk patients with no/one risk factors (N = 335). Grey line: intermediate risk patients with two risk factors (N = 356). Blue line: high-risk patients with three risk factors (N = 138).

Fig. 3. Survival probability from diagnosis of Richter transformation.

A Survival according to the treatment patients had previously received Black line: all patients with RT diagnosis (N = 83): Blue line: patients with RT diagnosis who received ≥1 lines of treatment before ibrutinib (N = 71). Grey line: patients with RT diagnosis who received front-line treatment with ibrutinib (N = 12). B Survival measured from the diagnosis of Richter transformation according to the presence or absence of cytopenia (hemoglobin ≤11 g/dL and/or platelets 100 × 10⁹/L). Black line: cytopenia absent (N = 33). Grey line: cytopenia present (N = 50).