CAD, wAIHA Patients May Benefit from Different Rituxan Doses, Study Suggests

Treatment with low-dose Rituxan can effectively treat patients with warm autoimmune hemolytic anemia (wAIHA) but higher doses may be more beneficial for patients with cold agglutinin disease (CAD), results from a 10-year retrospective study suggest.

The study, “Low dose rituximab in autoimmune hemolytic anemia: ten years after,” was published in the journal Blood.

Rituxan (rituximab, marketed by Genentech) is an engineered antibody that was designed to target both healthy and cancerous immune B cells. By promoting the depletion of B cells, this treatment  can also prevent the overproduction of potentially harmful antibodies that can attack the host’s own tissues and organs (autoimmune diseases).

Given its demonstrated potential, Rituxan has become the preferred second-line choice for off-label treatment of steroid-refractory (resistant) wAIHA and the first-line treatment for CAD.

However, it is expensive, not available worldwide and not reimbursable in many countries. This highlights the need to fully recognize Rituxan’s effectiveness for the treatment of these rare autoimmune diseases.

Results from a previous pilot clinical study (NCT01345708) showed that treatment with low-dose Rituxan could promote a positive response in about 80% and 60% of patients with primary wAIHA and CAD, respectively. Also, this treatment strategy could reduce by about 50% the use of steroid-based therapies in these populations.

Researchers have now evaluated the long-term impact of treatment with Rituxan in 20 of the patients who originally participated in the clinical trial. They also assessed an additional group of 34 patients with wAIHA, CAD, mixed, and atypical cases, who followed the same treatment protocol between 2012 and 2018.

The patients received weekly administrations of 100 mg of Rituxan for four weeks combined with a short course of prednisone, starting at 1 mg/kg per day with subsequent tapering and stop within three months.

Patients were followed for a median of 53 months, with more than 80% of treated patients showing a positive response within the first three years. The rate of disease remission increased from 46% upon at least two months of treatment to more than 60% at six months and thereafter.

This amelioration of response over time “is in line with the immune-modulating effect of [Rituxan] that may emerge beyond the well-known B-cell depleting activity,” researchers said. “The progressive increase of response rates further suggests that [Rituxan] takes a while to work.”

A more detailed analysis showed that the response rate to Rituxan treatment was better among patients with wAIHA than other disease forms, including CAD, mixed, and atypical cases.

The median duration of response was one year and three months, and 62% of cases relapsed. These patients were then treated with various strategies, including steroids, immune suppressors such as azathioprine (sold under the brand names Imuran and Azasan) and Cytoxan (cyclophosphamide), surgical removal of the spleen, Velcade (bortezomib), and additional administration of Rituxan at standard doses.

Disease relapse was found to be significantly correlated with AIHA type. The relapse-free survival time was longer in wAIHA compared to other cases — 64 months versus 25 months. Patients with mixed and atypical AIHA cases experienced a particularly short time of relapse-free survival — six months.

“The analysis of these … data confirm the efficacy of low-dose [Rituxan] in primary AIHA, both as short-term response as well as long-term outcomes,” researchers said.

Still, these findings also showed that low-dose Rituxan “has a better efficacy and induces sustained responses in warm cases compared to CAD.”

The team thinks that patients with CAD would benefit from using a higher dose of Rituxan given the greater burden of B cells involved in the underlying mechanisms of this specific type of autoimmune anemia.

In general, low-dose Rituxan treatment was shown to be safe and well-tolerated by the patients with no significant changes in patients’ blood balance one year after treatment. Also, the therapy was found to be safely re-administrated, with efficacy in up to 60% of cases.

“These findings suggest that re-treatment with low-dose [Rituxan] seems more appropriate to gain a fine-tuning of the autoimmune reactivity, at variance with the massive B-cell depletion obtained with standard doses,” they stated.

Collectively, the data demonstrated that one-seventh the standard dose of Rituxan can effectively be used as early second-line treatment in wAIHA while reducing associated costs. Still, standard doses should be used in patients with cold, mixed, and atypical AIHA cases.