Can rituximab (rituximab) cause anemia in patients, especially those with a history of cancer or autoimmune disorders?

Can Rituximab Cause Anemia?

Yes, rituximab can cause anemia through multiple mechanisms, including direct cytopenias (occurring in 3% of patients as Grade 3-4 anemia), hemolytic anemia (including pure red cell aplasia), and prolonged/late-onset neutropenia leading to secondary complications. 1

Mechanisms of Rituximab-Associated Anemia

Direct Hematologic Toxicity

• Grade 3-4 anemia occurs in 3% of patients receiving rituximab monotherapy for non-Hodgkin lymphoma, with cytopenias reported in 48% of patients overall 1
• Pure red cell aplasia (PRCA) has been documented as a rare but serious complication, requiring bone marrow evaluation and consideration of treatments including corticosteroids, IVIG, cyclosporin A, or eltrombopag 2
• Transient aplastic anemia has been reported in single-arm studies of rituximab 1

Hemolytic Anemia

• Two occurrences of hemolytic anemia following rituximab therapy were documented in clinical trials 1
• The NCCN guidelines specifically note that autoimmune hemolytic anemia (AIHA) should not preclude the use of combination therapy containing fludarabine, though patients should be observed carefully 2
• Paradoxically, rituximab is also used to treat autoimmune hemolytic anemia, with response rates of 70-80% in steroid-refractory cases 3

Bone Marrow Suppression and Neutropenia-Related Complications

• In CLL patients treated with rituximab plus fludarabine-cyclophosphamide (R-FC), prolonged neutropenia occurred in 8.5-24.8% and late-onset neutropenia in 14.8-38.7%, significantly higher than chemotherapy alone 1
• Prolonged neutropenia (Grade 3-4 lasting 24-42 days after last dose) and late-onset neutropenia (starting ≥42 days after treatment) can lead to infectious complications and secondary anemia 1

Clinical Context and Risk Factors

High-Risk Populations

• Patients with chronic lymphocytic leukemia receiving R-FC combinations face the highest risk, with prolonged neutropenia rates of 24.8% in previously treated patients 1
• Pediatric patients with mature B-cell NHL/B-AL experienced serious infections in 32% of cases when receiving rituximab with chemotherapy 1
• Patients with high tumor burden or lymphocyte counts >25 × 10⁹/L require reduced infusion rates and closer monitoring 4

Monitoring Requirements

• The American Society of Clinical Oncology recommends obtaining daily CBC during therapy initiation, then periodically based on clinical response 4
• Hemoglobin levels should be monitored weekly until steroid tapering is complete in patients being treated for autoimmune conditions 3
• The American Journal of Hematology recommends monitoring serum immunoglobulin levels before and periodically after rituximab, as hypogammaglobulinemia risk increases with multiple courses 4

Important Clinical Distinctions

Rituximab as Treatment vs. Cause of Anemia

• Rituximab is paradoxically both a cause and treatment of hemolytic anemia, depending on the clinical context 3, 5, 6, 7, 8, 9
• When used to treat autoimmune hemolytic anemia, rituximab (375 mg/m² weekly for 4 weeks) achieves complete response in many steroid-refractory cases, with median hemoglobin increases from 7.7 g/dL to 11.8 g/dL 9
• However, rituximab can also trigger new-onset hemolytic anemia as an adverse effect 1

Combination Therapy Considerations

• The risk of cytopenias is substantially higher when rituximab is combined with chemotherapy, particularly fludarabine-based regimens 1
• In patients with sickle cell disease at risk for hemolytic transfusion reactions, rituximab may be used as immunosuppression, though reports include deaths attributed to severe anemia (hemoglobin 2 g/dL) despite treatment 2

Management Approach

Prevention and Supportive Care

• Folic acid supplementation (1 mg daily) should be administered to support increased erythropoiesis in patients at risk 3
• Blood product support should be transfused according to institutional standards, with all blood products irradiated to avoid transfusion-associated GVHD 2
• For immune thrombocytopenia purpura (ITP) developing during treatment, bone marrow evaluation is required to determine the cause of low platelets 2

When to Suspect Rituximab-Induced Anemia

• New-onset anemia developing during or within months after rituximab treatment, particularly if accompanied by reticulocytosis or other signs of hemolysis 1
• Persistent or worsening cytopenias beyond expected chemotherapy-related nadirs 1
• Late-onset neutropenia (≥42 days post-treatment) with secondary complications 1