The Safety of Repurposing Daratumumab for Relapsed or Refractory Autoimmune Antibody Mediated Hemolytic Anemia

Autoimmune Hemolytic Anemia (AIHA) is a hematologic disorder in which the red blood cells are targeted and destroyed by autoantibodies produced by the immune system, specifically B-cells and plasma cells. It can be either idiopathic, or secondary to other autoimmune conditions, but is commonly related to lymphoproliferative disorders such as CLL or indolent lymphomas. It is a rather uncommon condition, which affects an estimated 17 people per 100,000 in their lifetime.

Unfortunately, AIHA is often difficult to treat. The goal of treatment is to achieve and maintain a Hemoglobin concentration of above 10 g/dL. Treatment historically involves the use of relatively high doses of steroids (i.e. 1 mg/kg), followed by a prolonged taper. According to a review article, 80% of patients initially respond to corticosteroid therapy, but steroids alone do not frequently "cure" the disorder, as steroids do not eliminate the anti-RBC antibody producing clone. In fact, only 20% of patients treated with first line steroid therapy are cured, and 15-20% of patients require maintenance Prednisone doses above 15 mg per day. This puts patients at risk of long-term steroid side effects, including infections, osteoporosis, aseptic joint necrosis, diabetes and hypertension.

The discovery of rituximab improved outcomes for AIHA. Rituximab is a monoclonal antibody against CD20, a marker for B-cells, that is now approved in both the first-line setting as well as relapsed/ refractory AIHA. It works by depleting CD20-positive B-cells that produce the autoantibody.

Early studies have shown that adding rituximab to steroids as first line treatment improved outcomes compared to steroids alone. In one study, a similar number of patients responded to rituximab and steroid, compared to steroid alone, but the length of response was significantly improved for the rituximab arm. Among responders, at 36 months, 70% vs 45% of patients treated in the combination arm vs steroids alone were still in remission.

However, despite these advances, some patients either fail to respond to the rituximab (20-30%), or have to remain on unacceptably high doses of steroid to control their hemolysis. In addition, many relapse after rituximab therapy. At that point, splenectomy is commonly recommended, but this only has a cure rate of 20%, is invasive, and comes with long-term sequelae of risks of clots and infection. After splenectomy, patients are left with a host of other immunosuppressants, such as azathioprine, mycophenolate, cyclosporine, or cyclophosphamide, but these typically require long term usage, and have poor side effect profiles (infection, liver toxicity, renal toxicity, lymphoma, etc), and are often ineffective.