Enjaymo brings lasting gains for CAD patient misdiagnosed with cancer
Correctly identifying the autoimmune disease guided doctors to proper care
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A woman with cold agglutinin disease (CAD) who was misdiagnosed with and treated for a blood cancer achieved lasting health improvements once doctors switched her to Enjaymo (sutimlimab-jome), a case study shows.
The woman had initially received therapies for chronic lymphocytic leukemia (CLL). However, those treatments failed to stop the rapid destruction of her red blood cells, or hemolysis. Once she was correctly diagnosed with CAD, treatment with Enjaymo successfully halted this cell destruction and eliminated her need for frequent blood transfusions.
Enjaymo works by blocking the complement cascade, a part of the immune system that drives the red blood cell damage marking CAD. The therapy rapidly halted hemolysis and led to a sustained recovery after treatments targeting antibody-producing B-cells had failed. B-cells are immune cells that produce antibodies, including those that drive CAD.
“Early recognition of [CAD] enables prompt initiation of complement blockade, potentially avoiding unnecessary exposure to [chemotherapy] or targeted B-cell therapies and reducing transfusion requirements,” researchers wrote.
The case study, “A diagnostic pitfall in cold agglutinin disease: KMT2D-mutated CAD-associated lymphoproliferative disorder with a CLL-like immunophenotype,” was published in Oxford Medical Case Reports.
A case of mistaken disease identity
CAD is caused by cold agglutinins, or self-targeting antibodies that bind to red blood cells at low temperatures. Such attacks activate the complement cascade, leading to hemolysis and disease symptoms.
The disease may be primary when associated with the abnormal but slow multiplication of a single B-cell in the bone marrow, and is also known as a CAD-associated lymphoproliferative disorder (CAD-LPD). Secondary CAD occurs as a complication stemming from other conditions.
CAD-LPD differs from B-cell-related blood cancers such as CLL, and distinguishing the conditions is critical because therapeutic strategies are distinct.
In the report, a team of researchers in Japan described the case of a woman initially diagnosed with and treated for CLL who was eventually diagnosed with CAD and successfully treated with Enjaymo. Administered directly into the bloodstream, Enjaymo is a complement-suppressor therapy approved to reduce red blood cell destruction in adults with CAD.
The woman, in her 50s, had experienced progressive fatigue and yellowing of the skin and whites of the eyes during colder seasons for about three years.
A physical examination detected enlargement of the spleen and lymph nodes, as well as cold-induced Raynaud’s phenomenon, a common CAD symptom in which extremities become cold, numb, and painful, and turn white or blue.
Blood tests showed low hemoglobin (the protein that carries oxygen in red blood cells), an elevated number of immature red blood cells, and high levels of lactate dehydrogenase and bilirubin — all signs of hemolysis.
The Coombs test, which detects antibodies and/or complement proteins bound to red blood cells, came back positive for the complement protein C3d, a hallmark of CAD. The woman also had high levels of cold agglutinins.
However, analysis of bone marrow revealed a small clonal B-cell population and molecular markers consistent with a CLL-like profile. Even though there were no other hallmarks of CLL, the woman was experiencing severe hemolysis that required frequent blood transfusions, prompting the doctors to start treatment with ibrutinib (sold as Imbruvica), which is approved for CLL.
The treatment failed to reduce hemolysis, as well as subsequent treatment with venetoclax (sold as Venclexta and Venclyxto) plus rituximab (sold as Rituxan and others, with biosimilars available) — a combination approved for CLL.
Genetic tests on bone marrow cells identified a mutation in the KMT2D gene, which is involved in B-cell growth and maturation. Mutations in this gene have been associated with CAD.
Based on these findings, the presence of complement-mediated hemolysis, and resistance to B-cell target therapies, “the diagnosis was revised to CAD-LPD,” the researchers wrote.
The woman was switched to Enjaymo, which gradually increased her hemoglobin levels and normalized levels of hemolysis markers, without adverse events. After one year, the woman remained stable on Enjaymo.
“This case illustrates a common diagnostic pitfall in CAD: minimal bone marrow involvement by a clonal B-cell population with a CLL-like [profile] can lead to misclassification as CLL,” the researchers wrote. It also “underscores the value of molecular profiling in guiding appropriate therapy.”
