Review Addresses Rituxan and Bendamustine as First-line Treatment for CAD

First-line treatment of cold agglutinin disease (CAD) should employ a combination of Rituxan (rituximab) and bendamustine, according to a review study. The scientists also highlight the potential of therapies targeting the complement system, which are undergoing clinical trials.

The research, “Cold agglutinin disease: current challenges and future prospects,” appeared in the Journal of Blood Medicine.

In CAD, autoantibodies known as cold agglutinins bind to red blood cells when they pass through the cooler parts of the peripheral circulation, ultimately causing activation of the complement system — a set of over 20 blood proteins that form part of the body’s immune defenses — and hemolysis (the destruction of red blood cells).

Although largely based on clinical experience, protecting against exposure to cold — in particular the head, face and extremities — and avoiding cold infusions are well-known recommendations for these patients. Bacterial infections should be treated promptly to prevent exacerbation of hemolysis, while, in the case of blood transfusions, the patient and the extremity used for infusion must be kept warm.

Pharmacological treatment has been increasingly used in patients with symptomatic anemia, severe cold-induced circulatory symptoms, and thrombosis, or blood clots. Based on their poor efficacy and excessive doses, corticosteroids are widely viewed as not adequate for CAD, while immunosuppression with azathioprine or interferon-alpha have not provided benefits.

Rituximab — sold in the U.S. by Genentech and Biogen as Rituxan and MabThera in Europe (by Roche) — was the first therapy showing efficacy in CAD, as assessed by a significant proportion of patients responding to the treatment and its low toxicity. Recently, its combination with the chemotherapy medication bendamustine led to a higher efficacy and a more sustained response, while toxicity data was favorable as compared to rituximab with fludarabine.

In turn, bortezomib, also a therapy targeting immune B-cells and sold under the brand name Velcade (by Takeda Oncology), showed efficacy in a Phase 2 trial, suggesting further benefits if given for longer periods or as combination treatment.

Complement-directed therapies are more recent. One such medication is Soliris (eculizumab, by Alexion), an anti-C5 protein antibody, which showed the ability to block hemolysis and as a rescue therapy for severe CAD.

An ongoing Phase 1b trial (NCT02502903) showed that Bioverativ Therapeutics’ sutimlimab, an antibody against complement C1, increased the levels of hemoglobin — the protein in red blood cells that transports oxygen throughout the body — eliminated hemolysis outside blood vessels and enabled six previous transfusion-dependent patients to become transfusion-free.

Sutimlimab is being tested in Phase 3 trials in patients with CAD (NCT03347396 and NCT03347422 — the latter is still recruiting participants; find more information here).

Other approaches under development include Annexon Biosciences’ C1q protein inhibitor ANX005 and the C3 blocker APL-2, with results of Phase 1 and Phase 2 trials — NCT03010046 and NCT03226678 — being expected.

Looking ahead, the team from Germany, Norway, and Austria mentioned the need for consensus-based clinical definitions, increased awareness to prevent misdiagnosis and improve treatment, and the need to establish an international CAD patient registry to overcome inconsistent data. Also, multi-center, international studies would help define accurate treatment recommendations, the investigators said.

Overall, they recommend Rituxan plus bendamustine as the first-line option for severely affected patients without major comorbidities, and standalone Rituxan in other cases. Still, scientists should aim at developing less toxic and more efficacious therapies, the team said, including combination strategies with a type of medication called proteasome inhibitors (such as Velcade).

As for complement modulators, they present limitations, such as not being able to lessen cold-induced circulatory symptoms, a likely high cost, and the potential of requiring treatments of indefinite duration.

“Patients with CAD requiring treatment should be included in prospective trials whenever possible,” the researchers said.

The study’s authors received support from, were paid by, or consulted for Alexion, Bioverativ, and Roche, all unrelated to this work.