Myeloid leukemia turns up as hidden cause of CAD: Case study
Woman's cancer discovered when anemia worsened despite CAD treatment
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A 78-year-old woman with cold agglutinin disease (CAD) was later found to have acute myeloid leukemia (AML), a type of blood cancer, which likely caused the disease, according to a case study from the U.S.
Doctors discovered the woman’s AML after her anemia continued to worsen despite signs that her CAD was responding to therapy. CAD-mediated red blood cell destruction, or hemolysis, “may be the presenting manifestation of an occult myeloid [cancer],” the researchers wrote.
One previous study had reported a case of CAD “as the initial manifestation of AML,” the researchers wrote, adding that “clearly documented published AML cases with [CAD-mediated] hemolytic anemia remain exceedingly rare.”
The new case study, “Cold Agglutinin-Mediated Hemolytic Anemia Preceding the Diagnosis of Acute Myeloid Leukemia: A Case Report and Literature Review,” was published in Cureus.
In CAD, the immune system produces self-reactive antibodies, called cold agglutinins, that attack red blood cells at cooler temperatures, causing them to clump together and break down. This leads to anemia, or low levels of red blood cells or hemoglobin, the protein in red blood cells that carries oxygen.
A rare case
There are two main types of CAD. Primary CAD occurs without an identifiable cause, while secondary CAD, also known as cold agglutinin syndrome (CAS), results from another condition, such as an infection or underlying blood cancer.
Still, CAD “is only rarely linked to acute myeloid leukemia (AML),” the researchers wrote. “Because cold agglutinin-mediated hemolysis is not typically associated with AML, the initial hemolytic diagnosis may narrow the differential diagnosis and delay recognition of underlying [bone marrow disease].”
The woman in the case study had a history of breast cancer and had been on hormone therapy for four years after surgery.
Until she arrived at the researchers’ medical center complaining of fatigue, her hemoglobin levels had been stable at about 12 g/dL (normal range 12 to 16 g/dL). However, new blood tests revealed lower-than-normal hemoglobin (8.1 g/dL) and a lower-than-normal percentage of red blood cells, as well as larger-than-normal red blood cells (macrocytosis). She also had high immune cell counts and low platelets (the cell fragments that help blood clot).
A Coombs test, which detects antibodies and/or immune complement proteins attached to red blood cells, was positive for the complement protein C3, a hallmark of CAD. In addition, she had high levels of cold agglutinins.
These findings, along with negative tests for infections, other autoimmune diseases, or recurrent breast cancer, supported a CAD diagnosis.
Doctors treated the woman with rituximab, a medication that depletes B-cells (the immune cells that produce antibodies), including those that drive the disease. Despite treatment, her anemia worsened, with her hemoglobin levels falling to 6.5 g/dL. However, her cold agglutinin levels declined, indicating that her CAD was responding to rituximab.
Further blood tests showed a shift toward more immature white blood cells (myeloid cells) and blood cell progenitors (blasts) than normal.
The woman received a warmed blood transfusion to manage her CAD, but “given the discordance between improving [blood] markers and worsening blood counts, she underwent a bone marrow biopsy to evaluate for an underlying marrow process,” the researchers wrote.
The results of examination of her bone marrow, where all blood cells are produced, were consistent with AML. Genetic tests identified several mutations, including in the U2AF1 gene, which has been implicated in the rapid progression of AML.
A high-risk AML was therefore considered to be the cause of her CAD. And in secondary CAD, also known as cold agglutinin syndrome (CAS), treating the underlying disease is the only effective approach.
The woman was enrolled in a clinical trial testing an investigational anti-cancer regimen. After two treatment cycles, she developed severe septic shock, a life-threatening infection complication, and died despite supportive care.
“The coexistence of immune hemolysis and [bone] marrow [abnormalities] presents a diagnostic challenge, particularly in older adults with new-onset macrocytic anemia,” the researchers wrote. “Clinicians should pursue marrow evaluation when presumed immune hemolysis is accompanied by worsening [blood cell counts], persistent macrocytosis, or evolving [circulating] blasts.”
