Distinguishing between primary and secondary cold agglutinin disease (CAD), as well as understanding if cancer is the underlying cause of secondary CAD, is critical to ensure patients get the right treatment, according to a recent review study.
Primary CAD — sometimes known simply as CAD — is not associated with an underlying condition, while secondary CAD, also called cold agglutinin syndrome (CAS), arises due to another health condition, such as cancer, infections, or other autoimmune diseases.
Treating the underlying cancer emerges as the critical therapeutic strategy for managing these CAS cases, whereas primary CAD is treated with other types of therapies, the study noted.
“The distinction between CAD and CAS has essential therapeutic consequences, as has the presence of any underlying [cancer] in CAS,” the researcher wrote, adding that, therefore, “appropriate diagnostic workup is critical for therapy” in this patient population.
The review study, “Cold-antibody Autoimmune Hemolytic Anemia: its Association with Neoplastic Disease and Impact on Therapy,” was published in Current Oncology Reports.
Autoimmune hemolytic anemia (AIHA) is an umbrella term for disorders in which the body’s immune system produces self-reactive antibodies that wrongly attack red blood cells. This marks the cells to destruction, causing symptoms of anemia (too few red blood cells).
In cold AIHA, or cAIHA, these abnormal antibodies bind to red blood cells at temperatures below around 37 degrees Celsius (around 98.6 F) and are called cold agglutinins. cAIHA can be divvied into two main types: primary and secondary CAD.
In the review, a researcher in Norway discussed differences between cAIHA types, particularly their relationship to cancer, and how they’re treated.
Previous research has shown the underlying cause of primary CAD is a clonal B-cell lymphoproliferative disease (LPD) in the bone marrow. Simply, this means that a single B-cell, the immune cells responsible for producing antibodies, multiplies excessively for an unknown reason.
Their excess multiplication in primary CAD is what causes the elevated production of cold agglutinins that in turn activate the immune system against red blood cells. While uncontrolled cell growth is also a hallmark of cancer, this CAD-causing LPD is not malignant and very rarely leads to B-cell lymphoma, a type of blood cancer.
CAS is very similar to CAD in terms of symptoms, but it develops in people who have other underlying health conditions. In cases caused by infections, CAS is usually temporary, while cases related to cancers, such as B-cell lymphoma, are usually chronic.
While the presence of malignancy, or cancer, may be used to distinguish primary CAD from CAS, making this distinction can actually be more complicated than that, the researcher noted.
For example, it is possible that a person assumed to have CAS actually has two separate disorders: primary CAD and cancer not related to B-cells. Moreover, while it is rare, the LPD that causes CAD could possibly become lymphoma later on.
Further complicating the matter is that CAD-associated LPD might sometimes get confused and misdiagnosed as a rare and slow-progressing type of B-cell lymphoma called Waldenström macroglobulinemia. This means that patients may be wrongfully categorized as having CAS.
Still, it is also possible for cAIHA patients to actually have Waldenström macroglobulinemia.
Importantly, underlying neoplastic disorders — benign or malignant conditions characterized by excessive cell growth — can influence treatment of these conditions.
“Not all patients with cAIHA need treatment, but on the background of several available therapies for CAD, patients should be treated if they have symptomatic anemia, significant fatigue, or bothersome circulatory symptoms,” the scientist wrote.
Primary CAD responds well to rituximab, an antibody therapy that depletes B-cells. Sometimes it’s combined with bendamustine, a chemotherapy agent, to help keep cell growth under control. Where there are possible signs of Waldenström macroglobulinemia, this approach could still be effective, the researcher noted.
People with primary CAD are also commonly given therapies, such as Enjaymo (sutimlimab), that target the immune complement cascade, which mediates cold agglutinin-induced red blood cell destruction.
Still, “complement-directed therapies cannot be expected to relieve the cold-induced circulatory symptoms, which are not complement-mediated,” the researcher wrote.
In addition, this approach is not as well-established if Waldenström macroglobulinemia or overt B-cell lymphoma is present.
CAS is often treated similarly to primary CAD, but whenever overt lymphoma is the cause, “treatment of the underlying malignancy remains the best-documented approach,” the researcher wrote.
