Rituximab is a U. S. Food and Drug Administration (FDA)-approved medication for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.

Rituximab is also used as first-line therapy for cold agglutinin disease (CAD). When not effective alone, rituximab may be combined with a chemotherapeutic or an immunosuppressive agent.

The medication is marketed under the name Rituxan in the U.S. (by Genentech and Biogen), and as MabThera in Europe (by Roche).

How rituximab works

Rituximab is an antibody that targets antibody-producing immune cells (called B-cells). B-cells can go wrong and produce autoantibodies, or proteins that mistakenly target a person’s own tissues or organs. In CAD, these antibodies bind to red blood cells (RBCs) at cold temperatures, causing these blood cells to clump together. The immune system views the clumps as a threat, and attacks and destroys the RBCs, leading to anemia.

By lowering the number of autoantibody-producing B-cells, rituximab works to reduce the binding that causes red blood cells to clump and the anemia that results.

Rituximab in clinical trials

Rituximab was tested in a Phase 2 clinical trial that enrolled 27 CAD patients in Norway with a mean age of 71. All received 375 mg/m2 of rituximab as an infusion into the bloodstream on days 1, 8, 15, and 22. A complete responder was defined as someone with no anemia, no signs of hemolysis (destruction of red blood cells), no clinical CAD symptoms, and no other biochemical signs of CAD in the blood. Partial responders were those with a stable increase in hemoglobin levels of at least 20 g per L, a reduction in IgM concentration by at least 50 percent in the blood (most autoantibodies produced in CAD are of the IgM type), an improvement in clinical symptoms, and independence from blood transfusions. Patients who did not respond to rituximab treatment within three months or had relapses during the study period were offered re-treatment with rituximab in combination with IFN, an immunomodulating agent.

More than half of the patients (14 out of of 27, or 52%) responded to the first course of rituximab (one complete response and 13 partial responses), results published in 2003 showed. The median time to response was 1.5 months, and the median response duration was 11 months. Two of the 13 non-responders were given rituximab in combination with IFN, as were a few others who relapsed after treatment. But the number here was too small to judge for efficacy. Still, trial researchers found rituximab to be well-tolerated by patients, “effective in primary CAD,” and that re-treatment was possible.

Another Phase 2 clinical trial included 20 CAD patients. They again received 375 mg/m2 of rituximab as an infusion on days 1, 8, 15, and 22. Nine of the 16 patients who completed the study (45%) responded to the treatment. One had a complete response, and eight a partial response. The median time to maximal response was three months, and the median duration of response was 6.5 months. The researchers concluded that, while rituximab treatment had a “favourable effect … few patients will obtain CR and, in most patients, the effect will be transient.”

Another Phase 2 clinical trial (NCT00373594), also in Norway, assessed the efficacy of rituximab treatment in combination with fludarabine, a chemotherapeutic agent, in 29 adults with CAD. Fifteen patients had been treated with rituximab before; 10 of them had not responded to the therapy.

All received 375 mg/m2 of rituximab as an infusion into the bloodstream on days 1, 29, 57, and 85, and 40 mg/m2 of oral fludarabine on days 1 to 5, 29 to 34, 57 to 61, and 85, to 89. A total of 22 patients (76%) responded. Of these, six (21%) had a complete response and 16 (55%) a partial response. Among the 10 nonresponsive to rituximab as a monotherapy, one patient achieved a complete response and six a partial response to the combo. The median time to response was four months, and the estimated median response duration was more than 66 months.

Side effects like toxicity are a limiting factor in this treatment combination, the researchers wrote. Two participants, ages 76 and 77, died seven and nine months after therapy started due to stroke and pneumonia. Cytopenia (reduction in the number of mature blood cells) was observed in 76% of patients. Hematologic toxicity (a decrease in the bone marrow and blood cells) occurred in 22% of patients.

A separate Phase 2 clinical trial (NCT02689986) assessed the efficacy of rituximab treatment in combination with bendamustine, also a chemotherapeutic agent, in 45 CAD patients. All were treated with 375 mg/m2 of rituximab as an intravenous infusion on day 1, and 90 mg/m2 of bendamustine on days 1 and 2, for four cycles at a 28-day interval. A total of 32 people (71%) responded, with 18 (40%) having a complete response, and 14 (31%) a partial response. The median time to response was 1.9 months, and the median response duration was 32 months. “[B]endamustine-rituximab combination therapy is highly efficient, sufficiently safe, and may be considered in first line for patients with CAD requiring therapy,” the researchers concluded.

A Phase 2 clinical trial (NCT01345708) in Italy assessed 23 patients with primary autoimmune hemolytic anemia (AIHA), of which nine had CAD. All received a low dose (100 mg) of rituximab for four weekly infusions, and 1 mg/kg of prednisone on days 1 to 30, after which the steroid’s dose was slowly tapered. After two months, the overall response rate was 55.6% in CAD patients, with a sustained response rate of 77.7% after six months and 66.7% after 12 months. The relapse rates were 11.1% at six months and 33.3% at 12 months. The median time to response was 19 days. At two years after treatment start, 40% of the CAD patients were relapse-free. This low-dose combination treatment was well-tolerated, the researchers wrote, with no adverse events recorded.

Additional information

Rituximab-associated side effects can include infusion-related reactions, fever, cough, headache, nausea, diarrhea, shivering, dizziness, and low blood pressure.

In patients with a previous hepatitis B infection, rituximab treatment may cause the condition to come back.


Last updated: Aug. 16, 2019


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