Impact of vein-to-vein time in patients with R/R LBCL treated with axicabtagene ciloleucel

Abstract

Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days vs ≥28 to <40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt <28 days (odds ratio [OR], 0.61) or ≥28 to <40 days (OR, 0.66) and significantly worse overall survival than V2Vt <28 days (hazard ratio [HR], 1.33) or ≥28 to <40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to <40 days or ≥40 days compared with <28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Graphical abstract

Figure 1.

Overview of the patient journey with CAR T-cell therapy.^aATCs are also referred to as qualified treatment centers. ^bTisa-cel leukapheresis products are frozen before transport to the manufacturing facility.^,cProduct release includes QC testing and QA review. QA, quality assurance; QC, quality control.

Figure 2.

Meta-analysis for V2Vt and V2Vt subintervals. V2Vt and V2Vt subintervals for axi-cel (A), tisa-cel (B), and liso-cel (C). The median days of V2Vt and V2Vt subintervals and 95% CIs are represented by brown diamonds for all studies and by green squares with error bars for subgroups. One clinical trial in patients treated with axi-cel that reported a median of 13.0 days for leukapheresis-to-product release (eg, when the product passed quality control testing and was made available to the investigator) interval was not presented because the study did not report a 95% CI.

Figure 3.

Axi-cel response rates by V2Vt. Response rate (A), adjusted ORs of ORR and CR (B), and adjusted DOR (C) by V2Vt in patients treated with axi-cel. Patients were from the CIBMTR registry PASS Cohort. Covariates for stepwise selection and multivariable adjustment were age, sex, race, ethnicity, ECOG PS before infusion, comorbidities (pulmonary, cardiac/cerebrovascular/heart valve disease, hepatic, and renal), histologic transformation, disease characteristics at initial diagnosis (double/triple hit, disease stage, elevated LDH, and >1 extranodal involvement), chemosensitivity before infusion, number of lines of prior therapy, prior HCT, year of infusion, time from initial diagnosis to infusion, and use of bridging therapy. PR, partial response.

Figure 4.

Axi-cel adjusted PFS and OS by V2Vt. Adjusted PFS (A) and adjusted OS (B) by V2Vt in patients treated with axi-cel. Patients were from the CIBMTR registry PASS cohort. For PFS, subsequent cellular therapy and HCT were censored. Covariates for stepwise selection and multivariable adjustment were age, sex, race, ethnicity, ECOG PS before infusion, comorbidities (pulmonary, cardiac/cerebrovascular/heart valve disease, hepatic, and renal), histologic transformation, disease characteristics at initial diagnosis (double/triple hit, disease stage, elevated LDH and >1 extranodal involvement), chemosensitivity before infusion, number of prior lines of therapy, prior HCT, year of infusion, time from initial diagnosis to infusion, and use of bridging therapy.

Figure 5.

Incidence of axi-cel AEs by V2Vt. Incidence of AEs (A) and cumulative incidence of CRS and ICANS resolved within 21 days of onset (B) by V2Vt in patients treated with axi-cel. ^aEvaluated based on events reported on the 100-day follow-up case-report form in patients from the CIBMTR registry PASS Cohort. ^bEvaluated among patients alive at day 30 after infusion in patients from the CIBMTR registry PASS cohort. AE, adverse event.

Figure 6.

Multivariate analyses of axi-cel safety outcomes by V2Vt. Multivariate analyses of CRS (any-grade or grade ≥3), ICANS (any-grade or grade ≥3), prolonged neutropenia, and prolonged thrombocytopenia in patients treated with axi-cel. Patients were from the CIBMTR registry PASS cohort. CRS and ICANS were evaluated based on events reported on the 100-day follow-up case-report form, and prolonged neutropenia and thrombocytopenia were evaluated among patients alive at day 30 after infusion. Covariates for stepwise selection and multivariable adjustment were age, sex, race, ethnicity, ECOG PS before infusion, comorbidities (pulmonary, cardiac/cerebrovascular/heart valve disease, hepatic, and renal), histologic transformation, disease characteristics at initial diagnosis (double/triple hit, disease stage, elevated LDH and >1 extranodal involvement), chemosensitivity before infusion, number of prior lines of therapy, prior HCT, year of infusion, time from initial diagnosis to infusion, and use of bridging therapy.