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

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.
Competing Interests: TvM: honoraria from Kite, a Gilead Company, Gilead Sciences, Celgene/Bristol Myers Squibb; consulting/advisory role for Janssen, Lilly, and Kite; and research funding from Celgene/Bristol Myers Squibb, Siemens, and Genentech. JK: honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, and Seattle Genetics; consulting/advisory role for AbbVie, Antengene, Bristol Myers Squibb, Gilead Sciences, Karyopharm, Medison Ventures, Merck, Roche, and Seattle Genetics; research funding from AstraZeneca, Merck, and Roche; and other relationship with DSMB, Karyopharm, and Chair of Scientific Advisory Board Lymphoma Canada. KWS: honoraria from Amgen, Bristol Myers Squibb, Janssen, and Kite, a Gilead Company. CT: consulting or advisory role for Amgen, Bristol Myers Squibb, Incyte, Kite, a Gilead Company, Novartis, Roche, and Takeda; research funding from Roche; and travel, accommodations, and expenses from Bristol Myers Squibb, Incyte, Kite, Novartis, Roche, and Takeda. MCM: consulting or advisory role for Bristol Myers Squibb, CDR-life, GSK, and Janssen-Cilag (institution); speaker’s bureau participation for WebMD (institution); and research funding from BeiGene (institution). EF: consulting or advisory role for Novartis; speakers’ bureau participation for Alexion, Astellas, Gilead Sciences, GSK, Novartis, and Sanofi; and travel support from Alexion, Gilead Sciences, MSD, and Novartis. SDG: honoraria from and consulting/advisory role for AbbVie, Gilead Sciences, and Janssen. MJK: honoraria from and consulting/advisory role for Adicet Bio, Celgene/Bristol Myers Squibb, Kite, a Gilead Company, Miltenyi Biotec, Novartis, and Roche; research funding from Kite (all to institution); and travel support from Kite, Miltenyi Biotec, Novartis, and Roche. PGNJM: no relevant financial relationships to disclose. MW: honoraria from AstraZeneca, Bristol Myers Squibb, Merck, Novartis, and Pfizer; consulting/advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genmab, Kite, a Gilead Company, Merck, Novartis, and Pfizer; and travel support from AstraZeneca, Bristol Myers Squibb, and Novartis. YZ: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. AX: Stock or other ownership in Amgen, Biogen, and Kite, a Gilead Company. JNW: employment with and research funding from Kite, a Gilead Company, and stock or other ownership in Gilead. JN: employment with and stock or other ownership in Kite, a Gilead Company. RRS: employment with and stock or other ownership in Kite, a Gilead Company; and patents, royalties, and other intellectual property from Atara and Kite. CS: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. FN: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. JJK: employment with and stock or other ownership in Kite, a Gilead Company. MST: consulting/advisory role for AstraZeneca, Bristol Myers Squibb, Genmab, Kite, a Gilead Company, and Roche; research funding from Kite, Regeneron, Roche, and Takeda; and travel support from Janssen and Kite.
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