Immunochemotherapy can help control CAD but it carries safety risks
While effective, treatment led to serious side effects for 1 in 4 patients
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A combination of chemotherapy and immune-targeting medications may provide long-lasting relief for people with cold agglutinin disease (CAD), though the treatment often comes with a high risk of serious side effects, according to real-world patient data.
These “immunochemotherapy” (ICT) regimens, specifically those using R-bendamustine, have shown significant success in normalizing hemoglobin levels and halting the destruction of red blood cells.
Researchers found that while two standard ICT regimens helped manage the autoimmune disorder, R-bendamustine (a combination of rituximab and the chemotherapy bendamustine) tended to be more effective and offer longer-lasting results than R-cyclophosphamide, which is a combination of rituximab (sold as Rituxan and others) and cyclophosphamide. However, the study also underscored a significant trade-off: approximately one in four patients experienced severe safety complications, and many required dose adjustments to handle the treatment’s toxicity.
The study, “Real-world efficacy and safety of immunochemotherapy in cold agglutinin-mediated autoimmune haemolytic anaemia,” was published as a research letter in the British Journal of Haematology.
Understanding CAD and the role of B-cells
CAD is an autoimmune disorder characterized by self-reactive antibodies that target red blood cells at low temperatures, resulting in symptoms such as anemia, pain, and skin discoloration in response to cold exposure. Anemia refers to a condition characterized by low counts of red blood cells or low levels of hemoglobin, the protein in red blood cells that carries oxygen in the bloodstream.
Primary CAD is thought to arise from the non-cancerous growth of antibody-producing immune B-cells. In contrast, secondary CAD develops as a complication of an underlying disorder, such as cancer or an infection.
“Several treatment options exist for CAD, each with advantages and limitations, but [there’s] no consensus on the optimal strategy,” the researchers wrote.
Rituximab, which works by killing B-cells, is a first-line CAD therapy. However, about half of treated patients still experience relapses, and the median response duration is less than one year.
ICT, which ultimately aims to destroy B-cells, has been explored as a treatment for primary CAD, as well as secondary CAD related to blood cancers, where these immune cells grow uncontrolled. “However, evidence on their efficacy … remains limited,” the researchers wrote.
Now, a team of researchers in the Netherlands has retrospectively analyzed outcomes from 34 CAD patients who received at least one ICT cycle between 2000 and 2024 at 20 Dutch centers.
“We present the first real-world experience of ICT in [CAD] in a relatively large Dutch [group of patients],” the team wrote.
Approximately half of the patients were women, and the average age at diagnosis was 62 years. Most had evidence of abnormal immune cell growth; 13 (46%) had secondary CAD related to an overt B-cell cancer. Patients were followed for a median of more than two years.
Comparing R-cyclophosphamide and R-bendamustine
A total of 17 patients were given ICT regimens based on R-cyclophosphamide. Eleven (73.3%) of the 15 patients with anemia before ICT experienced an increase in hemoglobin levels, including six who showed normalization of their hemoglobin levels. The median time to the first hemoglobin response was 1.4 months. Red blood cell destruction, or hemolysis, resolved in 45% of the patients who showed anemia lessening after ICT.
Of the 12 patients (71%) who experienced bothersome cold-induced symptoms before ICT, 58% reported clinical improvement, with complete resolution of these symptoms in 25% of the 12 patients.
Median event-free survival, defined as the time from ICT initiation to death or subsequent treatment (for CAD or underlying disease), was 28 months (little over two years), with 28% of patients estimated to remain free from events at five years.
The other half of the 34 patients were given ICT regimens based on R-bendamustine. Results were generally a bit better with these regimens, the researchers noted.
Of the 10 people with anemia, nine showed an increase in hemoglobin levels after ICT, with eight achieving normalization. The median time to the first hemoglobin response was 6.8 months. Hemolysis was resolved in 78% of hemoglobin responders.
Most (83%) of the 12 patients with cold-induced symptoms reported that these symptoms eased after ICT, including complete resolution in five patients.
Median event-free survival was not reached, indicating that more than half of the patients remained free from events at the last follow-up. The estimated five-year event-free survival was 83%.
Overall, the combined response rate in terms of hemoglobin and cold-induced symptoms was 56% for individuals receiving R-cyclophosphamide-based ICT and 88% for those receiving R-bendamustine-based ICT.
Navigating the risks of intensive treatment
“While this retrospective study is neither designed nor suitable for a head-to-head comparison, R-bendamustine seemed associated with better response rates and a trend towards longer duration of response,” the researchers wrote.
They highlighted that this difference was seen even though patients given R-bendamustine had generally received more prior therapies, implying they’d had more difficulty controlling their disease in the past.
With both regimens, around one in four patients reported serious safety complications during treatment. Additionally, 29% of patients on R-cyclophosphamide and 53% of those on R-bendamustine required dose adjustments due to tolerability issues.
“Our findings support ICT, particularly R-bendamustine, as a valid fixed-duration treatment option offering durable symptom relief for both anaemia and [cold-induced symptoms],” the researchers concluded. However, they added that “Disadvantages remain the relatively long time to response and unfavourable toxicity profile.”
