In patients with large B-cell lymphoma undergoing chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel, earlier-than-usual intervention with corticosteroids and tocilizumab may reduce the incidence of severe cytokine-release syndrome, according to the findings of a nonrandomized expansion cohort of the ZUMA-1 study that evaluated this intervention.1,2
Max S. Topp, MD
In cohort 4 of ZUMA-1, patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel were started on steroids and tocilizumab if grade 1 cytokine-release syndrome and neurotoxicity did not resolve after 3 days of supportive care. A total of 2% of the early-intervention group experienced grade ≥ 3 cytokine-release syndrome, and 17% experienced a grade ≥ 3 neurologic event. In previous cohorts in whom the intervention was employed later, these rates were 13% and 28%, respectively, according to Max S. Topp, MD, of the University Hospital of Würzburg, Germany, who reported the study at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition.
“Earlier steroid intervention has the potential to improve the risk/benefit profile of CAR T-cell therapy with axicabtagene ciloleucel,” said Dr. Topp. “This intervention led to lower total cumulative steroid usage in this cohort, with no impact on expansion of T cells. It reduced markers of inflammatory response and had no impact on ongoing response with or without adjustment for tumor burden at a median follow-up of 8.7 months.”
In the phase I/II ZUMA-1 trial, axicabtagene ciloleucel treatment in patients with relapsed or refractory large B-cell lymphoma induced an objective response rate of 83% and a median overall survival of 25.8 months.3 Cohort 4 (n = 41), an additional safety cohort, was added to determine whether earlier corticosteroid use could reduce the incidence of severe cytokine-release syndrome and neurotoxicity. In this cohort, dexamethasone at 10 mg and tocilizumab at 8 mg/kg over 1 hour, repeated every 4 to 6 hours as needed, were initiated if grade 1 cytokine-release syndrome and grade 1 neurotoxicity did not improve within 3 days.
Cytokine-Release Syndrome and Neurotoxicity
Dr. Topp compared the outcomes for cohort 4 with those of cohorts 1 and 2 combined. The rate of cytokine-release syndrome of any grade was similar: 93% in cohorts 1 and 2 and 93% in cohort 4. The median time to onset of cytokine-release syndrome was 2 days in each cohort; the median duration of cytokine-release syndrome was 8 days in cohorts 1 and 2 and 7 days in cohort 4.
“Earlier steroid intervention has the potential to improve the risk/benefit profile of CAR T-cell therapy with axicabtagene ciloleucel."— Max S. Topp, MD
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Similarly, the rates of neurologic events of any grade were similar: 64% in cohorts 1 and 2 and 61% in cohort 4, with median durations of 12 days and 9 days, respectively. However, early intervention strongly impacted the development of grade ≥ 3 cytokine-release syndrome and neurotoxicity, Dr. Topp reported. For grade ≥ 3 cytokine-release syndrome, the incidence was 2% with early intervention and 13% with later intervention in cohorts 1 and 2. Similarly, the incidence rates of grade ≥ 3 neurologic events were 17% and 28%, respectively.
In patients with a tumor burden above the median, the rate of grade ≥ 3 cytokine-release syndrome was reduced from 6% to 1%, and grade ≥ 3 neurologic events diminished from 20% to 4%, he added.
Despite earlier use, the mean cumulative dose of steroids was actually lower in patients in cohort 4: 5,235 mg vs 13,156 mg for cohorts 1 and 2. The median doses were 939 mg and 5,451 mg, respectively. Tocilizumab was used in 76% of cohort 4 and 43% of cohorts 1 and 2. Inflammatory serum cytokines associated with CAR T-cell–related toxicity were reduced, whereas overall CAR T-cell expansion was not significantly different between the cohorts. “Giving corticosteroids early had a positive effect on these markers,” noted Dr. Topp.
Early intervention did not negatively impact clinical outcomes. The objective response rate in cohort 4 was 73%, with 51% complete responses; 54% of these patients had a sustained response after at least 6 months of follow-up. In cohorts 1 and 2, ongoing responses were observed in 44% of patients, with a median duration of response of 8.9 months; this result is consistent with the 8.1 months of response in the primary analysis of cohorts 1 plus 2, he added.
In the discussion period, Dr. Topp said that early use of steroids is making axicabtagene ciloleucel easier to use and may facilitate the use of this CAR T-cell product in the outpatient setting.
DISCLOSURE: Dr. Topp has served as a consultant for or received honoraria, travel funding, or research support from Amgen, Novartis, Roche, Regeneron, Prime, Celgene, Kite, Novartis, and Gilead.
REFERENCES
1. Topp M, Van Meerten T, Houot R, et al: Earlier steroid use with axicabtagene ciloleucel in patients with relapsed/refractory large B cell lymphoma. 2019 ASH Annual Meeting & Exposition. Abstract 243. Presented December 7, 2019.
2. Topp MS, van Meerten T, Wermke M, et al: Preliminary results of earlier steroid use with axicabtagene ciloleucel in patients with relapsed/refractory large B-cell lymphoma. 2019 ASCO Annual Meeting. Abstract 7558. Presented June 3, 2019.
3. Locke FL, Ghobadi A, Jacobson CA, et al: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. Lancet Oncol 20:31-42, 2019.
