A systematic review and meta-analysis has uncovered significant discrepancies between reported efficacy rates in chimeric antigen receptor (CAR) T-cell therapy clinical trials, revealing potential selection bias that may overestimate treatment benefits for patients with hematologic malignancies.
The research, conducted by Mohyuddin et al., examined both CD19 and B-cell maturation antigen (BCMA) targeting CAR T-cell therapy trials, finding consistent differences between efficacy reported in modified intent-to-treat (mITT) populations versus true intent-to-treat (ITT) analyses that included all enrolled patients.
Selection Bias in CAR T-Cell Therapy Reporting
Despite the revolutionary impact of CAR T-cell therapy in treating relapsed/refractory hematologic malignancies, the meta-analysis identified concerning patterns in efficacy reporting. Researchers found that many patients who enrolled in clinical trials never received the therapy or were excluded from efficacy analyses, creating a selection bias that favors patients with less aggressive disease.
The analysis revealed that differences in response rates between mITT and ITT analyses ranged from 8-12%, suggesting that current reporting practices may overestimate the real-world effectiveness of these therapies.
"Even if a patient is fortunate enough to have access to CAR T-cell therapy, there are often delays in collection and production during which disease progression can occur," the researchers noted. These patients are frequently excluded from efficacy analyses, skewing results toward more favorable outcomes.
BCMA CAR T-Cell Therapy in Multiple Myeloma
The review identified 28 BCMA CAR T-cell therapy clinical trials for multiple myeloma (MM) patients, with only ten reporting both enrollment and treatment numbers. Among these studies:
- The pooled overall response rate (ORR) in the mITT population was 78.0% (95% CI, 67.0–89.0%)
- The pooled ORR in the ITT population was significantly lower at 70% (95% CI, 59.0–80.0%)
- 46 patients did not receive CAR T-cell therapy after enrolling
- For 86.9% of these patients, reasons for not receiving therapy were not reported
Additionally, 47 patients who did receive CAR T-cell therapy were excluded from efficacy analyses, primarily due to insufficient follow-up (97.8%) or early death from infection (2.2%).
CD19 CAR T-Cell Therapy Studies
The analysis examined 74 CD19 CAR T-cell therapy studies, with 52 reporting complete enrollment and treatment data. These studies showed similar patterns of selection bias:
- For leukemia-specific studies, the mITT response rate was 87.2% compared to 74.9% in ITT analyses
- For lymphoma-specific studies, the mITT response rate was 70.7% versus 58.7% in ITT analyses
- Across all CD19 studies, the pooled ORR was 79.0% for mITT versus 68.1% for ITT populations
Among the 52 CD19 studies with complete reporting, 266 enrolled patients never received CAR T-cell therapy, and 113 patients were excluded from efficacy analyses despite receiving treatment.
Barriers to CAR T-Cell Therapy Access
The research highlighted several challenges that contribute to the gap between enrollment and treatment:
- Limited availability at specialized cancer centers
- Inpatient administration requirements
- High treatment costs
- Manufacturing delays
- Rapid disease progression during production wait times
Dr. Mohyuddin's team emphasized that these barriers create a significant selection bias that must be considered when interpreting clinical trial results.
Clinical Implications and Recommendations
While acknowledging CAR T-cell therapy's transformative impact on hematologic malignancy treatment, the researchers stressed the importance of more transparent reporting practices. The meta-analysis recommends:
- Prospective collection of real-world data
- Transparent reporting of patients unable to receive therapy after enrollment
- Clear documentation of reasons for exclusion from efficacy analyses
- Consistent use of ITT analyses alongside mITT results
"This meta-analysis shows that CAR T-cell therapy trials are indeed susceptible to selection bias," the researchers concluded. "Transparent reporting is essential to understand the true efficacy of CAR T-cell therapy and correctly identify patients who are eligible for and will benefit from this therapy."
Study Limitations
The researchers acknowledged several limitations to their analysis, including small sample sizes in many included studies and significant heterogeneity between trials. The heterogeneity was notably higher in ITT analyses compared to mITT analyses, further highlighting the impact of selection bias on reported outcomes.
Despite these limitations, the findings provide important context for clinicians and patients considering CAR T-cell therapy, emphasizing the need for realistic expectations about treatment accessibility and outcomes in real-world settings.
