Impact of debulking therapy on the clinical outcomes of axicabtagene ciloleucel in the treatment of relapsed or refractory large B-cell lymphoma

Abstract

Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, was approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the results from pivotal Cohorts 1+2 of ZUMA-1 (NCT02348216). ZUMA-1 was expanded to investigate safety management strategies aimed at reducing the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs). Prospective safety expansion Cohort 5 evaluated the impact of debulking therapy, including rituximab-containing immunochemotherapy regimens and radiotherapy, in axi-cel-treated patients; the CRS and NE management strategy paralleled those in Cohorts 1+2. Among the 50 patients in Cohort 5 who received axi-cel, 40% received ≥3 prior lines of chemotherapy, and 40% had disease that progressed while on the most recent chemotherapy. Forty-eight patients (96%) received debulking therapy, 14 (28%) radiotherapy only, and 34 (71%) systemic immunochemotherapy. Median decrease in tumor burden (per sum of product of diameters of target lesions) relative to screening was 17.4% with R-ICE/R-GDP, 4.3% with other debulking chemotherapies, and 6.3% with radiotherapy only. All patients were followed for ≥8 months. CRS was reported in 43 patients (86%), with 1 patient (2%) experiencing grade ≥3. NEs were reported in 28 patients (56%), with 6 (12%) experiencing grade ≥3. Cytopenias were the most frequent grade ≥3 adverse event (AE); 19 (38%) and 18 (36%) treated patients had any and grade ≥3 prolonged thrombocytopenia, respectively, and 25 (50%) and 24 (48%) patients had any and grade ≥3 prolonged neutropenia, respectively. Overall, patients who received debulking chemotherapy had higher incidences of serious treatment-emergent AEs than those who received radiotherapy only. At the 24-month analysis, objective response rate was 72%, and complete response rate was 56%. Median duration of response, progression-free survival, and overall survival were 25.8, 3.1, and 20.6 months, respectively. These results from exploratory Cohort 5 demonstrate the feasibility of debulking prior to axi-cel, and together with current real-world evidence, suggest that debulking regimens may help minimize the frequency and severity of CRS and NEs in patients with R/R LBCL. The incidence of other AEs observed in Cohort 5 suggest the risk/benefit profile was not improved via the debulking regimens studied here.

Keywords: Large B-cell lymphoma; axi-cel; chimeric antigen receptor T cell; cytokine release syndrome; debulking; neurotoxicity.

Figure 1

Best overall response (primary analysis). One patient died 27 days after axi-cel infusion and did not have a response assessment. CR, complete response; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 2

Duration of response, progression-free survival, and overall survival (primary analysis). A. Duration of response. B. Progression-free survival. C. Overall survival. Disease assessment after initiation of new anticancer therapy (not including stem cell transplant) was not included in the duration of response or progression-free survival derivations. DOR, duration of response; NE, not estimable; OS, overall survival; PFS, progression-free survival.

Figure 3

Duration of response, progression-free survival, and overall survival (24-month analysis). A. Duration of response. B. Progression-free survival. C. Overall survival. Disease assessment after initiation of new anticancer therapy (not including stem cell transplant) were not included in the duration of response or progression-free survival derivations. DOR, duration of response; NE, not estimable; OS, overall survival; PFS, progression-free survival.

Figure 4

CAR T-cell expansion. A. CAR T-cell expansion through 24 months. B. Association of CAR T-cell peak expansion with ongoing response at 24 months. Peak was defined as the maximum number of CAR T cells measured post infusion. Responses were determined by study investigators per the revised International Working Group Response Criteria for Malignant Lymphoma [16]. Ongoing response was defined as responders (CR/PR) who did not have PD or die by the data cutoff. Relapse was defined as responders who had documented PD or died by the data cutoff. Nonresponder was defined as those who did not have either CR or PR by the data cutoff. Patients who were responders (CR/PR) and had the following events by the data cutoff were not included for the ongoing response assessment: allogeneic stem cell transplantation, started new anticancer therapy, withdrawal of consent, lost to follow-up, or other reasons listed for end of study. CAR, chimeric antigen receptor; CR, complete response; PD, progressive disease; PR, partial response.