Combination therapy brings durable remission in severe AIHA case series
Two had cold agglutinin syndrome; 2 stopped Enjaymo without recurrence
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Combining a complement inhibitor with rituximab was found to rapidly control severe autoimmune hemolytic anemia (AIHA), including in two patients with cold agglutinin syndrome, a condition related to cold agglutinin disease. In two of the three patients in the series, the complement inhibitor Enjaymo (sutimlimab) was later stopped without recurrence to date.
Researchers at the University of Freiburg Medical Center in Germany described this series of patients in “Combination therapy of sutimlimab and rituximab can lead to stable remission in autoimmune hemolytic anemia: a case series,” which was published in the Annals of Hematology.
“This highly informative case series reports on an innovative therapeutic concept and may form the basis for further clinical studies in AIHA,” they wrote. “Combination therapy with [Enjaymo] and rituximab in AIHA is a promising therapeutic approach, but the efficacy and safety must certainly be evaluated in further clinical trials,” the researchers added.
Complement plays a central role in autoimmune hemolysis
AIHA occurs when antibodies target red blood cells, causing their destruction, or hemolysis. In many cases, the complement system, a part of the immune system, contributes to this process, particularly in cold AIHA. In cold agglutinin disease, antibodies are most active at lower temperatures, while in warm AIHA, they are most active at warmer temperatures. Blocking complement proteins can help reduce hemolysis.
Enjaymo, approved to reduce hemolysis in adults with cold agglutinin disease, targets a specific complement protein, C1s. However, it normally requires regular infusions. In this series of three patients, doctors combined Enjaymo with rituximab, which depletes B-cells, immune cells involved in producing antibodies, including the self-reactive antibodies that drive AIHA.
Of the three patients, two had cold agglutinin syndrome and one had primary warm AIHA. All three received four weekly doses of rituximab, which is marketed as Rituxan in the U.S. and Mabthera in Europe. While rituximab is not approved for cold agglutinin disease, it is considered a first-line option for patients who require medication.
Because Enjaymo was not immediately available, each patient first received one dose of eculizumab, another complement inhibitor marketed as Soliris. They then switched to a weight-based regimen of Enjaymo, given weekly for the first two doses and then every two weeks. Because the combination suppresses immune defenses in different ways, the patients received the antibiotic azithromycin to help prevent bacterial infections.
First 2 patients improved after combination therapy
The first patient, a 54-year-old woman, was admitted with severe anemia — her hemoglobin, the oxygen-carrying protein in red blood cells, was very low. Testing showed antibodies on her red blood cells and the presence of cold agglutinins, antibodies that can cause red blood cells to clump at low temperatures.
Corticosteroids did not help, so she received blood transfusions followed by eculizumab, rituximab, and Enjaymo. Her hemoglobin gradually improved. She was later hospitalized with severe neutropenia, meaning a very low number of neutrophils, a type of white blood cell, and an infection. She recovered with antibiotics and G-CSF, which stimulates the production of white blood cells.
Three months after diagnosis, her hemoglobin had improved, and other markers of hemolysis had normalized. Enjaymo was stopped after six doses because of joint pain and low white blood cell counts. Six months after diagnosis, her hemoglobin was normal despite being off treatment.
The second patient, a 58-year-old woman, developed severe hemolysis and anemia. She had recently been treated for immune thrombocytopenia, which occurs when the immune system destroys platelets, blood cells that help with clotting.
Blood testing found both warm- and cold-reactive antibodies. The doctors considered warm AIHA with possible complement system activation most likely. She received corticosteroids, a blood transfusion, eculizumab, rituximab, and then Enjaymo. Her hemoglobin improved. After six doses, she chose to stop Enjaymo. At the latest follow-up seven months after diagnosis, her hemoglobin had continued to improve despite being off treatment.
Third patient remained on Enjaymo after recovery
The third patient, a 23-year-old man, developed cold agglutinin syndrome, also known as secondary cold agglutinin disease, shortly after a respiratory infection. His hemoglobin was very low, and he became less alert and developed low blood pressure requiring vasopressors, which are medications that increase blood pressure.
The man also received corticosteroids and plasmapheresis, a procedure that removes antibody-containing plasma, the liquid part of blood, and replaces it with fresh plasma or another replacement fluid. He then received eculizumab and rituximab, plus four units of red blood cells. After stabilization, he continued with rituximab and Enjaymo.
His hemoglobin gradually increased, and he no longer needed transfusions three weeks after admission. He was briefly readmitted with abdominal pain and abnormal liver tests, but his hemoglobin remained stable. Imaging showed fatty liver and gallbladder sludge without clear blockage, and there was no evidence of infectious hepatitis. The episode resolved without additional treatment.
“We report on a novel combination therapy of [Enjaymo] and rituximab, which led to rapid and durable remission in three patients,” the researchers wrote. “In two of these patients, treatment with [Enjaymo] could be discontinued without any recurrence to date. The other patient is also in remission but with ongoing therapy,” they added.
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