Incidence and Severity of Cytopenias Secondary to CD19-Targeted CAR-T Cell Therapy: A Systemic Review and Meta-Analysis

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Introduction This systematic review and meta-analysis aimed to identify cytopenias' incidence, onset, and severity associated with CD-19-targeted Chimeric Antigen Receptor T (CAR-T) cell therapy. Methods Following PRISMA guidelines, we conducted a comprehensive literature search across PubMed, Embase, Cochrane, and Clinicaltrials.gov using relevant MeSH terms and keywords. A total of 26 randomized control trials (RCTs) and 38 observational studies reporting cytopenias after CD19-targeted CAR-T cell therapy were included. Inter-study variance was calculated using the Der Simonian-Laird Estimator, and pooled analysis was performed using the "meta" package in R (version 4.16-2). Results The 26 RCTs involved 1369 patients with a median age of 58 years (range 24-65), of which 59% were male. The studies comprised 46% Phase I trials, 11.5% Phase I/II, 19% Phase II, and 11.5% Phase III RCTs, while 11.5% RCTs did not specify the study phase. The median follow-up duration was 8.7 months (range 1-37.5). The median time to the onset of cytopenia was 18.5 days (range 7-90). The pooled incidence of neutropenia was 67% (95% CI, 0.57-0.77, I2=89%, p<0.01), with grade III-IV neutropenia at 54% (95% CI, 0.31-0.75, I2=93%, p<0.01). Thrombocytopenia incidence was 45% (95% CI, 0.33-0.58, I2=82%, p<0.01), with grade III-IV thrombocytopenia at 38% (95% CI, 0.23-0.56, I2=68%, p=0.03). Anemia was observed in 49% (95% CI, 0.39-0.60, I2=86%, p<0.01) of cases, with grade III-IV anemia at 30% (95% CI, 0.24-0.37, I2=26%, p=0.25). Lymphopenia was found in 40% (95% CI, 0.19-0.65, I2=95%, p<0.01) of patients, with grade III-IV lymphopenia at 37% (95% CI, 0.08-0.80, I2=90%, p<0.01). The median overall survival (OS) ranged from 13.4 to 42.8 months, and the median progression-free survival (PFS) ranged from 2.1 to 19.5 months. The 38 observational studies included 3672 patients with a median age range of 52 to 78 years, of which 61.7% were male. The median follow-up duration was 8.4 months (range 1-25). The median time to cytopenia onset was 28 days (range 5-30). The pooled incidence of neutropenia was 67% (95% CI, 0.47-0.82, I2=93%, p<0.01), lymphopenia was 84% (95% CI, 0.51-0.96, I2=87%, p<0.01), thrombocytopenia was 57% (95% CI, 0.44-0.69, I2=91%, p<0.01), and anemia was 46% (95% CI, 0.32-0.61, I2=89%, p<0.01). Growth factor was the most common treatment for neutropenia (reported in 10 studies), while transfusion support was done for severe thrombocytopenia and anemia. The median OS for these studies ranged from 11 to 24.1 months, while the median PFS ranged from 3.6 to 20 months. Conclusion This review highlights the high incidence of cytopenias, including neutropenia, thrombocytopenia, anemia, and lymphopenia, following CD19-targeted CAR-T therapy. These common and severe adverse effects emphasize the need for proactive management strategies to reduce their impact on patient outcomes.

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