Iptacopan rapidly stops red blood cell damage in rare CAD case
Case study shows fast recovery in CAD linked to lymphoma after oral therapy
A 44-year-old man with cold agglutinin disease (CAD) secondary to lymphoplasmacytic lymphoma, a type of blood cancer, recovered quickly after starting iptacopan, an oral therapy that targets the complement system, together with lymphoma treatment, a study showed.
The complement cascade is a part of the immune system that contributes to the hemolysis, or red blood cell destruction, that marks CAD.
Iptacopan — marketed as Fabhalta and approved for certain blood and complement-related conditions — rapidly stopped the man’s hemolysis and eliminated his need for blood transfusions after standard therapies failed.
“These findings suggest that iptacopan can rapidly ameliorate hemolysis in CAD, warranting further investigation into its therapeutic potential,” the researchers wrote.
The case, “Iptacopan for cold agglutinin disease: a case report with literature review,” was published in Frontiers in Immunology.
How cold agglutinin disease causes red blood cell destruction
CAD occurs when self-reactive antibodies, called cold agglutinins, bind to red blood cells at low temperatures. This causes the cells to clump together and activates the complement cascade, coating the cells with a complement protein called C3b, tagging them for destruction.
Common symptoms of CAD include anemia (low red blood cell counts), dizziness, fatigue, shortness of breath, and jaundice — a yellowing of the skin and the whites of the eyes.
The condition is considered primary when it develops without a known cause, and secondary when it occurs due to another condition, most often infections or blood cancers.
First-line treatment for CAD often involves the off-label use of rituximab (sold as Rituxan and MabThera, with biosimilars available), an antibody-based therapy that targets B-cells, the immune cells that produce antibodies.
Rituximab alone can ease CAD symptoms, but relapses are common. Combining it with other medications, such as the chemotherapy bendamustine, may improve response rates but can raise the risk of infections and other complications.
Enjaymo (sutimlimab-jome), the only CAD-approved therapy to date, works by blocking the complement cascade. It is cleared for use in the U.S. and other parts of the world, but not in China, according to the researchers.
Blocking complement activity may help prevent further damage
Iptacopan works by suppressing complement factor B, which helps prevent the formation of C3b. By blocking this step, it can also prevent hemolysis, or red blood cell destruction. This mechanism may also benefit people with CAD, particularly in regions where Enjaymo is not yet available.
Here, researchers in China described the case of a 44-year-old man with CAD secondary to lymphoplasmacytic lymphoma — a type of blood cancer that starts in B-cells — whose condition did not respond to standard therapies but improved quickly with iptacopan.
He was admitted to the hospital after a year of sporadic dizziness and generalized weakness, along with shortness of breath and chest discomfort during physical activity. On examination, he appeared pale and jaundiced, with a high heart rate and an enlarged spleen.
“Both his personal and family medical histories were unremarkable,” the researchers wrote.
Blood tests showed anemia, with low blood levels of hemoglobin — the protein in red blood cells that carries oxygen. He also had high blood levels of hemolysis markers, including bilirubin and lactate dehydrogenase.
Further testing detected elevated levels of cold agglutinins and revealed C3d, a complement protein, bound to the surface of red blood cells, confirming the presence of CAD.
Excess B-cells in the bone marrow and negative genetic tests for common B-cell lymphoma mutations confirmed a diagnosis of CAD secondary to lymphoplasmacytic lymphoma.
Patient improved quickly after switching to iptacopan
The man first began treatment with rituximab plus bendamustine, but he developed extensive blistering and skin infections on his feet and legs, which forced doctors to discontinue the therapy.
He was then switched to zanubrutinib (sold as Brukinsa for treating certain B-cell cancers), but his hemolysis persisted, and he required weekly blood transfusions to manage his anemia.
Treatment was then changed to iptacopan (200 mg) twice daily, together with standard lymphoma treatment comprised of cyclophosphamide and dexamethasone. Within one week, his hemoglobin levels began to rise, and he no longer needed blood transfusions.
After seven weeks, hemoglobin levels continued to increase, bilirubin had returned to normal, and levels of C3d bound to red blood cells decreased. The regimen was then reduced to alternate-day dosing of iptacopan and low-dose cyclophosphamide, while dexamethasone was discontinued.
Over four months of follow-up, his condition remained stable, with no recurrence of hemolysis or treatment-related adverse events.
“This case demonstrates that selective C3b [suppression] (via factor B blockade) can overcome resistance to anti-B cell therapies, which proposes a feasible regimen for regions lacking access to newer complement [blockers],” the team wrote.
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