Newer cancer therapies improve outcomes in cancer-related CAD
Targeted treatments that control cancer help offset dual risks
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Certain types of blood cancer may increase the risk of cold agglutinin disease (CAD), and while the presence of both conditions has historically been associated with worse survival, a study suggests that modern, targeted cancer treatments have reduced this negative effect.
Because newer therapies are generally more effective at controlling cancer, the findings lend credence to the idea that the best way to manage cancer-related CAD is to effectively treat the underlying cancer.
“These findings support the concept that effective control of the [blood cell] clone is central to long-term control of [blood cancer-associated CAD] and provide real-world evidence supporting the use of targeted therapies in this setting,” the researchers wrote.
The study, “The prognostic implications of autoimmune hemolytic anemia in chronic lymphocytic leukemia across treatment eras,” was published in Haematologica.
CAD is an autoimmune disease in which self-reactive antibodies attack and destroy red blood cells at low temperatures. CAD is a rare form of autoimmune hemolytic anemia (AIHA), a broader term for disorders where self-targeting antibodies destroy red blood cells. AIHA is classified as CAD, warm AIHA, or mixed AIHA, depending on whether disease-driving antibodies attach to red blood cells at cold or warm temperatures, or a combination of both.
AIHA and CLL
Chronic lymphocytic leukemia (CLL) is a form of blood cancer marked by the uncontrolled growth of B-cells, the type of immune cell that produces antibodies, including those driving AIHA.
It’s well established that people with CLL and other types of cancers affecting B-cells are at elevated risk of developing AIHA. Studies suggest that as many as one in 10 CLL patients will develop AIHA, and historically, these patients have had worse outcomes.
But over the last decade or two, treatment for CLL has advanced considerably. Where this cancer used to be treated mainly with nontargeted approaches like chemotherapy, now it is more often managed using targeted therapies.
These include Bruton tyrosine kinase inhibitors and BCL2 inhibitors, which work by blocking specific signaling proteins that drive cancer cell growth and survival.
“Although AIHA has been regarded as a marker of adverse prognosis in CLL, its biological basis and prognostic significance in the era of targeted therapy remain incompletely understood,” the researchers wrote.
The team of scientists reviewed data from more than 1,400 people with CLL who were treated at a single center in China from 1994 to 2024. Participants were followed for a median of 45.5 months (nearly four years).
Similar to previous reports, about one in 10 patients (10.4%) developed AIHA. Nearly one-third of these patients (30.8%) had CAD specifically. Patients with AIHA were significantly more likely to be male and had a more advanced cancer profile.
Patients diagnosed with CLL and AIHA at the same time showed the poorest outcomes, including shorter time to first treatment and overall survival relative to those who developed AIHA after receiving a CLL diagnosis. Still, there was no significant difference in terms of survival without signs of cancer progression.
“No significant differences in survival were observed between patients with [warm AIHA] and [CAD],” the researchers wrote.
When looking at outcomes based on first-line treatment modality, the team found that AIHA was associated with shorter progression-free survival and overall survival in patients given older cancer treatments such as chemotherapy — consistent with historical data.
However, in patients given newer targeted therapies, none of these survival outcomes differed significantly based on AIHA status.
“Although AIHA was associated with inferior survival in the pre-targeted therapy era, this adverse prognostic effect appeared to be attenuated in patients treated with targeted therapies,” the team wrote.
Further analyses showed a close link between the effectiveness of cancer treatment and the control of AIHA, and that “targeted therapy-based regimens were associated with the most favorable control of AIHA, followed by chemoimmunotherapy, whereas chemotherapy-based regimens showed the least favorable outcomes,” the researchers wrote.
“These findings support the preferential use of targeted therapies in CLL patients with AIHA and highlight the need for routine AIHA screening in high-risk populations,” they added.
The researchers noted that their study is one of the first on AIHA in CLL to be conducted in Asia. This is especially noteworthy because, compared with western populations, Asian CLL patients more often have cancers with a mutation in the MYD88 gene.
In statistical analyses, the researchers found that this genetic mutation was significantly more common in CLL patients with CAD than among those with warm AIHA.
“Our findings raise the possibility that MYD88-mutant CLL may be associated with a more immunologically active [profile] that predisposes to [CAD],” the team concluded.
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