1. Patients with a higher disease burden of acute lymphoblastic leukemia (ALL) treated with CD19-specific chimeric antigen receptor (CAR) T cell therapy experienced greater incidences of cytotoxic release syndrome and neurotoxicity compared to low disease burden patients.
2. Patients with high disease burden had shorter overall survival times compared to low disease burden patients.
Evidence Rating Level: 2 (Good)
Study Rundown: Relapsed and refractory ALL continues to be difficult to treat, with poor overall survival rates using standard chemotherapy and biologic regimens. CD19-CAR therapy has been investigated as a potential therapy for patients with refractory B-cell cancers, showing promise over limited periods of follow-up. This reports longer term follow-up of a phase 1 trial assessing safety and efficacy of CD19-CAR therapy in a cohort of adults with relapsed or refractory ALL. Safety outcomes of this study included incidences of cytotoxic release syndrome and neurotoxic adverse events, which occurred in the majority of patients and at a higher incidence in patients with higher disease burden. Secondary efficacy outcomes included overall survival rates and complete remission rates, which showed longer overall survival relative to many biologic therapy treated relapsed ALL patients. Overall survival was also greater in patients with lower ALL disease burden.
Strengths of the study include its extensive subgroup analysis by disease burden and extended follow-up for a novel treatment regiment, while its main limitation is the study size and power associated with the phase 1 design.
In-Depth [prospective cohort]: This phase 1 clinical trial enrolled 83 adult patients between 2010 and 2016 with either relapsed or refractory B-cell ALL. A total of 53 patients later received 19-28z CAR T-cell infusion therapy. Safety outcomes, incidence of cytotoxic release syndrome and neurotoxic effects, were both graded on a numeric scale and considered severe with a grade of 3 or higher. Efficacy outcomes included complete remission rates, defined as less than 5% bone marrow blasts or absence of blasts, and overall survival rates.
Severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15-40%), with 45 of 53 patients experiencing any grade of cytokine release syndrome (85%; 95%CI, 72-93%). One patient died from severe cytokine release syndrome. Grade three neurotoxicity occurred in 19 patients (36%) and 3 patients were noted to have grade 4 toxicity (6%). Patients with higher disease burden (defined as having five percent or greater bone marrow blasts or extramedullary disease) had higher rates of severe cytokine release syndrome (41 % for high burden vs 5% for low burden; p = 0.004) and neurotoxic effects (59 % for high burden vs 14% for low burden; p = 0.002) compared to patients with low disease burden. Median event-free survival among all patients was 6.1 months (95%CI, 5.0 to 11.5 months) after a median follow-up of 29 months. When stratified by disease burden, patients with low disease burden had significantly longer overall survival compared to patients with high disease burden (median overall survival 20.1 months vs 12.4 months; p = 0.02).
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