Dual therapy benefits man with aHUS, Castleman disease
Case report highlights use of iptacopan and Sylvant in Pakistani man
A 21-year-old man with atypical hemolytic uremic syndrome (aHUS) associated with Castleman disease improved after receiving treatment with iptacopan and Sylvant (siltuximab), according to a case report.
Castleman disease presents symptoms that mimic aHUS due to the overgrowth of lymph nodes.
Iptacopan is marketed as Fabhalta for diseases driven by abnormal activation of the complement system. The therapy is currently being tested for aHUS in the Phase 3 APPELHUS trial (NCT04889430). Sylvant is an antibody-based therapy approved to treat Castleman disease.
The findings were detailed in the case study, “Iptacopan in C5 blockade refractory atypical hemolytic uremic syndrome with associated Castleman’s disease: case report,” published in BMC Nephrology.
Understanding aHUS and its connection to Castleman disease
aHUS is caused by abnormal activity of the complement cascade that leads to the formation of blood clots in small vessels, known as thrombotic microangiopathy (TMA). The most common symptoms are red blood cell destruction (hemolysis), low platelet levels, and kidney failure.
Here, researchers at the University of California Irvine described the case of a Pakistani man with a history of aHUS who later developed Castleman disease.
He first sought medical care due to weakness, fatigue, and shortness of breath. Tests showed low hemoglobin — the protein that carries oxygen in red blood cells — and elevated levels of lactate dehydrogenase, a marker of hemolysis. His platelet levels were low, and both D-dimer and fibrinogen were elevated, indicating an increased risk for blood clots.
He also had elevated creatinine and uric acid, signs of potential kidney damage. A kidney biopsy showed signs of tissue damage and TMA. Because of bleeding and kidney complications after the biopsy, he was transferred to UCI Medical Center for further care.
After other types of TMA were ruled out, the man was diagnosed with aHUS, and started on eculizumab (available as Soliris and as biosimilars). He showed partial improvement but remained on dialysis, a kidney replacement therapy. After switching to Ultomiris (ravulizumab), there was a rapid improvement in blood parameters, and three months later, the man was off dialysis.
Two years after the initial presentation, he went to the emergency department with fatigue, increased creatinine, and reductions in hemoglobin and platelet levels. According to the researchers, “the patient’s sudden cessation of an effective and complete TMA response was not previously seen in the adult literature with compliant patients.”
Genetic testing showed a deletion, or loss, of a copy of a gene coding for complement system proteins. Deletion in both gene copies has been associated with aHUS. The man then began taking iptacopan at 200 mg twice daily.
“Iptacopan emerged as a candidate due to its recent positive data in [certain] patients with paroxysmal nocturnal hemoglobinuria,” the scientists wrote. “This agent was thus selected as a possible candidate for FDA emergency compassionate use authorization in an attempt to save the patient’s life.”
Treatment response and later complications
Although his condition initially improved — with hemoglobin and creatinine levels returning to normal — 10 months later he went to the emergency room with increasing abdominal distension and pain. At evaluation, he had low hemoglobin and platelet levels again and kidney function worsening.
He also had an enlarged spleen and fluid buildup in the abdomen. He was ultimately diagnosed with TAFRO syndrome, a subtype of Castleman disease. At that point, doctors started him on a combination therapy with eculizumab and iptacopan for aHUS, along with Sylvant for TAFRO.
After two months, eculizumab was discontinued. He continued treatment with iptacopan and Sylvant, along with outpatient dialysis and regular monitoring.
At the last follow-up, three months later, his condition had improved, and he remained on the same treatment plan, together with once-weekly dialysis.
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