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

Introduction: Chimeric Antigen Receptor-T (CAR-T) cell therapy has revolutionized the treatment of hematological malignancies, particularly relapsed/refractory (R/R) B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). However, there are several challenges with CAR-T cell therapy, including severe cytopenias. Our systematic review and meta-analysis aimed to highlight this issue by identifying the incidence, onset, and severity of cytopenias associated with CD-19-targeted CAR-T cell therapy.

Methods: Our study adhered to the preferred reporting items for systemic reviews and meta-analysis (PRISMA) guidelines. We conducted a comprehensive literature search on four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov) using MeSH terms and keywords. After the primary and secondary screening, we included studies reporting cytopenia after CD-19-targeted CAR-T cell therapy. We calculated inter-study variance using the Der Simonian-Laird Estimator and performed a pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2). This rigorous methodology ensured the reliability of our findings.

Results: In this systematic review and meta-analysis, we included 26 randomized control trials (RCTs) and 38 observational studies to evaluate the incidence and severity of cytopenias in CD-19-targeted CAR-T cell therapy. 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. Among these, 34 studies (89%) were retrospective, with a median follow-up duration of 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 systematic review and meta-analysis highlight the common and often severe cytopenias following CAR-T cell therapy, a critical but frequently underestimated adverse effect. Our findings, which show that cytopenias, including neutropenia, thrombocytopenia, anemia, and lymphopenia, are prevalent among patients undergoing CD19-targeted CAR-T cell therapy, emphasize the urgent need for heightened awareness and proactive management strategies.

Lutfi:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ahmed:Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. McGuirk:CRISPR therapeutics: Consultancy; Envision: Consultancy; Sana technologies: Consultancy; Allo Vir: Consultancy; Caribou bio: Consultancy; Novartis: Consultancy; Legend biotech: Consultancy; BMS: Consultancy; Kite: Consultancy; NEKTAR therapeutics: Consultancy; Autolus: Consultancy. Mushtaq:Iovance Biotherapeutics: Research Funding.