A Phase 2 clinical trial investigating very low doses of rituximab in patients with cold agglutinin disease (CAD) and other forms of autoimmune hemolytic anemia (AIHA) has revealed limitations in maintaining sustained B-cell suppression, despite showing initial promise in rapid B-cell depletion.
The European Union-based pilot study (EudraCT 2016-002478-11), which included seven adults with CAD among its participants, aimed to evaluate whether doses lower than those currently approved for other conditions could effectively treat AIHA. The trial's findings suggest that while immediate B-cell reduction was achieved, the sustained therapeutic effect remained inconsistent across patients.
Study Design and Patient Demographics
The trial enrolled ten AIHA patients in total, comprising six women and four men, with a mean age of 68 years. All participants had received prior treatments before entering the study. The researchers implemented various dosing regimens, starting with the lowest doses and escalating based on response:
- Three patients received 5 mg per square meter every three weeks
- Three patients received 20 mg every four weeks
- Three patients received 50 mg every three months
- One patient received 100 mg every three months
Key Findings and Clinical Outcomes
The initial results showed promising rapid B-cell depletion within the first 24 hours of treatment in most patients. However, the study revealed significant variability in maintaining these reduced B-cell levels. Researchers observed that B-cell suppression occurred consistently when rituximab concentrations exceeded 0.4 micrograms per milliliter in the bloodstream.
During the treatment period, six participants demonstrated ongoing red blood cell destruction, indicating continued disease activity. Two patients required blood transfusions as emergency interventions, and one received Enjaymo (sutimlimab-jome), the only approved CAD therapy.
Safety and Adverse Events
The safety profile raised some concerns, with one CAD patient who received the 100 mg dose developing inflammation of the heart lining approximately 7.5 months into treatment. This was classified as a serious adverse event with potential links to the treatment.
Study Limitations and Future Implications
The trial faced several significant limitations:
- Early termination due to COVID-19-related recruitment challenges
- Small patient population
- Relatively short duration of follow-up
"The current data do not provide sufficient evidence to treat patients with low-dose rituximab regimens and future clinical trials are necessary to investigate their clinical efficacy," the researchers concluded in their report published in Frontiers in Medicine.
The findings highlight the need for more extensive clinical studies to determine optimal dosing strategies for rituximab in autoimmune conditions. While the study demonstrated that very low doses can achieve initial B-cell depletion, the lack of sustained response suggests that current low-dose approaches may need refinement before clinical implementation.
