Woman develops cold agglutinin disease secondary to blood cancer
Case study highlights association between CAD, aggressive lymphomas
A 79-year-old woman developed cold agglutinin disease (CAD) secondary to a rare, aggressive type of blood cancer called intravascular large B-cell lymphoma (IVLBCL), a case study reports.
B-cell lymphomas are a form of blood cancer that affects B-cells, the type of white blood cell that produces antibodies, including those that cause CAD and other autoimmune conditions. A treatment regimen for the woman’s underlying cancer successfully treated CAD and improved her condition.
“This case highlights that cold agglutinin syndrome can be associated with aggressive lymphomas, including IVLBCL,” researchers wrote. Cold agglutinin syndrome is another name for secondary CAD, a form of the disease caused by an underlying condition, including infections, other autoimmune diseases, or cancers.
The case study, “Intervascular Large B-cell Lymphoma with Severe Anemia and A High-titer of Cold Agglutinin,” was published in Internal Medicine.
Secondary cold agglutinin disease rarely linked to aggressive lymphomas
CAD is caused by a specific type of self-reactive antibodies, called cold agglutinins, which bind to red blood cells at low temperatures, causing them to clump together and be marked for destruction (hemolysis).
This results in anemia, or a lack of red blood cells to transport oxygen to all tissues in the body, and symptoms such as fatigue, pale skin, and circulatory problems.
Secondary CAD “is most commonly associated with [slow-growing] B-cell lymphomas … but it is rarely linked to aggressive lymphomas,” the researchers wrote.
In this case study, researchers at Japan’s National Hospital Organization Kyoto Medical Center described the case of a woman who developed CAD secondary to IVLBCL.
She was admitted to the hospital with a fever that persisted for a month, general malaise (general feeling of discomfort or being unwell), and severe anemia. She had high blood pressure and normal heart and breathing rates.
Blood work revealed she had low levels of red blood cells and hemoglobin, the protein that carries oxygen in red blood cells, and elevated levels of reticulocytes (immature red blood cells) and the lactate dehydrogenase (LDH) enzyme — two hemolysis markers. Her levels of C-reactive protein, a marker of inflammation, were also higher than normal.
The woman also had high levels of cold agglutinins. A blood smear to check how cells looked under a microscope revealed clumps of red blood cells, strongly suggesting the presence of CAD. She received several blood transfusions for her severe anemia, without major improvements.
Therapeutic regimen for B-cell lymphoma plays pivotal role
Whole-body CT scans revealed no signs of infection, as well as no enlargement of lymph nodes (immune structures) or of the spleen, which can occur with infections or blood cancers.
Still, “given her persistent fever, we initially speculated an infectious cause for her cold agglutinin-mediated hemolysis,” the researchers wrote. Antibiotics failed to improve her condition.
This, along with the fact that she had high blood levels of soluble interleukin-2 receptor (sIL-2R), a marker of lymphoma, prompted the researchers to conduct analyses of bone marrow and skin tissue, which confirmed an IVLBCL diagnosis.
This rare and aggressive form of B-cell lymphoma can result in a fever of unknown cause, neurological and skin symptoms, and a decreased number of blood cells. A brain MRI revealed the presence of multiple cerebral infarctions, when blood flow to certain brain regions is disrupted, causing nerve cell death.
In CAS [cold agglutinin syndrome], it is crucial to address the underlying disease.
A therapeutic regimen for B-cell lymphoma called Pola-R-CHP was begun. It includes the immunotherapy polatuzumab vedotin to deliver chemotherapy to B-cells, rituximab (a B-cell-depleting medication also used off-label in CAD), two chemotherapy drugs, and prednisolone (a corticosteroid).
“This promptly resolved the fever and malaise,” the researchers wrote.
The woman no longer needed blood transfusions, and reductions in markers of hemolysis and lymphoma were detected as early as after the first treatment course. Two months after completing six therapy cycles, her hemoglobin, LDH, and cold agglutinin levels had normalized, and her sIL-2R levels showed an even greater drop.
“In CAS [cold agglutinin syndrome], it is crucial to address the underlying disease,” the researchers wrote. “For curable malignancies, such as aggressive lymphomas, achieving complete remission is typically accompanied by the resolution of hemolytic anemia, whereas a delayed diagnosis often leads to fatal outcomes.”
The researchers also conducted a literature review, identifying 14 reported cases of cold agglutinin syndrome associated with large B-cell lymphoma, with only one being IVLBCL. Most cases had bone marrow involvement and lesions outside lymph nodes (extranodal), but no lymph node involvement.
“These findings suggest that most lymphomas associated with CAS predominantly present with bone marrow and extranodal lesions without lymph node involvement, which complicates the diagnostic process,” the researchers wrote.
Overall, this case “highlights the need to consider aggressive lymphomas, such as IVLBCL, along with [slow-growing] lymphomas in cases of CAS,” they concluded.
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