Anti-CD19 CAR T cells therapy can overcome the prognostic impact of CD5-positivity in patients with diffuse large B cell lymphomas: Results from the multicenter prospective CAR-T SIE study

Abstract CD5-positive diffuse large B-cell lymphomas (DLBCL) represent 5-10% of all DLBCLs. This rare entity exhibits distinct clinical and biological features, including common extranodal disease involvement, leading to unfavorable prognosis with shorter progression free and overall survival and central nervous system (CNS) relapses frequently reported after conventional immune-chemotherapy. Data on efficacy and safety of anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy in this subgroup of DLBCL patients are lacking. Here we report an analysis on outcome of CD5-positive DLBCL after CAR T-cell therapy from the CAR-T SIE observational prospective multicenter study. We evaluated patients with DLBCL for which complete clinical data and assessment of CD5 status on immunohistochemistry were available. Patients with high-grade B cell lymphoma (with/without MYC and BCL-2 gene rearrangements), DLBCL transformed from indolent lymphomas or primary mediastinal B cell lymphomas were excluded. Primary endpoints included response rates (overall ORR and complete response CR at 90 days), progression-free survival (PFS), overall survival (OS), and safety, focusing on cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). One hundred eighty-three patients were eligible for the analysis and were stratified into CD5-positive (CD5+, n=36) and CD5-negative (CD5-, n=147). Median age was 60 years interquartile range (IQR): 52-66, with CD5+ patients found to be slightly older (median 62.5 vs. 59 years, p=0.026) than CD5- patients. No other significant demographic or clinical differences were observed between the two groups including: ECOG performance status, Ann Arbor stage, bulky disease, extranodal involvement including bone marrow infiltration assessment, disease status at leukapheresis (relapsed vs. refractory), international prognostic index (IPI), prior lines of therapy, response to bridging therapy or CAR T-cell product tisagenlecleucel (tisa-cel) vs. axicabtagene ciloleucel (axi-cel). CRS incidence was lower in CD5+ (81%) vs. CD5- (92%) patients, although this difference did not reach statistical significance (p=0.065), while ICANS rates were significantly lower in CD5+ patients (11% vs. 28%, p=0.025). However, no differences were seen in grade ≥3 CRS (3.4% vs. 6.9%, p 0.083) and grade ≥3 ICANS rates (25% vs. 29.3%, p 0.386). The median follow-up was 15.5 months (IQR: 6.71-24.64). At 90 days, 166/183 patients were evaluable for response. ORR was 57% in the overall population and was similar between CD5+ (53%) and CD5- (58%) patients (p=0.691). CR rate was also comparable (53% overall; CD5-positive 50%, CD5-negative 54%, p=0.844). Only 3 CNS disease relapses were reported, all of which occurred in CD5- patients. No statistically significant difference emerged in PFS between CD5+ and CD5- patients median PFS 3.88 months (95% confidence interval, CI) 3.03-NA vs. 6.09 months (95% CI 3.72-11.97), p=0.812, with a 2-year PFS rate of 36.1% (95% CI 22.2-58.6%) vs. 34.9% (95% CI 27.1-45%) for CD5+ and CD5- patients, respectively. Accordingly, median OS was similar between the two groups median OS 23.88 months (95% CI 11.7-NA) in CD5+ patients vs. 29.01 months (95% CI 14.7-NA) in CD5-, p=0.925, with 2-year OS rates of 47.0% (95% CI 28.7-77.1%) and 51.5% (95% CI 42.2-62.9) in CD5+ and CD5- patients, respectively. A multivariable analysis assessing risk factors for lower PFS and OS rates identified CAR T-cell product (tisa-cel vs. axi-cel, HR=2.05, 95% CI 1.37-3.07, p0.001) and bulky disease (HR=2.10, 95% CI 1.37-3.22, p=0.001) as significant predictors of worse PFS, independent of CD5 status (p=0.795). Similarly, bulky disease and CAR T-cell product significantly predicted worse OS HR=3.15 (95% CI 1.90-5.24) p0.001, and HR=1.75 (95% CI 1.04-2.93) p=0.035 for tisa-cel vs. axi-cel, while CD5 status was not prognostic (p=0.926). Non-relapse mortality at 12 months was low in both groups (2.9% in CD5+ vs. 4.5% in CD5-, p=0.931). Our report shows that anti-CD19 CAR T-cell therapy might overcome the prognostic impact of CD5-positivity in patients with DLBCL, demonstrating comparable outcomes in CD5+ and CD5- patients, with no significant differences in ORR, CR rate, PFS, OS and severe toxicities.