CAD May Be Related to Marginal Zone Lymphoma, Study Says

People with cold agglutinin disease (CAD) have genetic alterations previously reported in patients with marginal zone lymphoma (MZL), suggesting the disorders might be related, study reports.

The study, “Cold agglutinin–associated B-cell lymphoproliferative disease shows highly recurrent gains of chromosome 3 and 12 or 18,” was published in the journal Blood Advances.

CAD is a form of autoimmune hemolytic anemia (AIHA), in which self-directed antibodies (cold agglutinins) attack and destroy red blood cells at low body temperatures. The disorder is thought to be associated with a specific type of B-cell lymphoproliferative disease, in which malignant B-cells start accumulating in the bone marrow. (B-cells are immune cells responsible for the production of antibodies.)

Some studies have suggested that copy number variations (CNVs) — when specific DNA segments within a chromosome are repeated countless times, varying among different individuals — associated with chromosome instability are one of the features of CAD or CAD-associated malignant lymphoproliferative disorders.

Chromosome instability occurs when a portion or even an entire chromosome is duplicated or lost. It is seen frequently in many types of cancer.

To explore the possible association between CNVs and CAD, researchers in Norway and Canada used advanced gene sequencing to analyze the exome (all protein-coding regions in the DNA) in samples from 15 CAD patients, along with microarray analysis to identify CNVs.

Most samples (13) were obtained from patients participating in a previous Phase 2 trial (NCT02689986) investigating the safety and effectiveness of a combination therapy of bendamustine and rituximab for CAD. These samples were used for both exome sequencing and a technique called microarray analysis, while the two remaining samples were used only for exome sequencing.

A complete or partial gain in chromosome 3 was detected in 14 samples. In addition, analyses revealed that more than half of the samples (11) had gains in either chromosome 12 or 18.

Investigators also found smaller regions in other chromosomes in which recurrent genetic gains or losses were identified. Yet, some of these smaller CNVs detected by microarray analysis could not be confirmed by exome sequencing. According to the team, this likely is due to the limited material available.

The scientists also found that major CNVs had a copy number around 3, while the smaller CNVs had a copy number of approximately 2.5, suggesting that the smaller CNVs were present only in a subset of patient cells.

“We conclude that gain of chromosome 3 is a highly recurrent finding in CAD-associated lymphoproliferative disease. Further gain of chromosomes 12 and 18 might be predictors of therapy outcome,” they wrote.

“These genetic findings are similar to what has previously been demonstrated in nodal and extranodal MZL, suggesting that CAD-associated lymphoproliferative disease, a disease of the bone marrow, might be related to MZL,” they added.

While nodal MZL occurs within the lymph nodes, extranodal NZL (the most common subtype) is seen in places such as the stomach, small intestine, salivary glands, thyroid, eyes, and lungs.