What are the causes of anemia in Chronic Lymphocytic Leukemia (CLL)?

From the Guidelines

Anemia in chronic lymphocytic leukemia (CLL) is primarily caused by bone marrow infiltration, autoimmune hemolytic anemia (AIHA), and hypersplenism, with AIHA occurring in 5-10% of CLL patients, as reported in the 2011 ESMO clinical practice guidelines for diagnosis, treatment, and follow-up of CLL 1. The causes of anemia in CLL are multifactorial and can be attributed to various mechanisms.

• Bone marrow infiltration by leukemic cells disrupts normal hematopoiesis, leading to reduced red blood cell production.
• Autoimmune hemolytic anemia (AIHA) is a significant cause, occurring in 5-10% of CLL patients, where antibodies produced by the abnormal lymphocytes attack red blood cells 1.
• Hypersplenism can contribute to anemia through increased destruction of red blood cells in an enlarged spleen.
• Chemotherapy-induced myelosuppression during treatment can also lead to anemia.
• Bleeding complications from thrombocytopenia can result in blood loss anemia.
• Some patients develop pure red cell aplasia, where red blood cell precursors are specifically targeted.
• Nutritional deficiencies, particularly of iron, folate, or vitamin B12, can exacerbate anemia in these patients.
• Anemia of chronic disease plays a role through inflammatory cytokines that interfere with iron utilization and erythropoietin production. Management of anemia in CLL depends on identifying the specific cause and may include blood transfusions, erythropoiesis-stimulating agents, corticosteroids for autoimmune hemolytic anemia, or adjusting CLL treatment regimens, as suggested by the 2013 ESMO guidelines consensus conference on malignant lymphoma 1. The 2008 guidelines for the diagnosis and treatment of chronic lymphocytic leukemia also emphasize the importance of assessing disease progression and symptoms in determining treatment decisions, including the management of anemia 1. However, the most recent and highest quality study, the 2011 ESMO clinical practice guidelines, recommends that treatment of autoimmune cytopenia, including AIHA, should be based on the specific cause and may include corticosteroids, splenectomy, or monoclonal antibodies 1.

From the FDA Drug Label

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of CLL patients treated with Fludarabine Phosphate for Injection Life-threatening and sometimes fatal autoimmune phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur in patients receiving Fludarabine Phosphate for Injection

The causes of anemia in Chronic Lymphocytic Leukemia (CLL) include:

• Myelosuppression: a common adverse event associated with Fludarabine Phosphate for Injection treatment, which can lead to anemia 2
• Autoimmune phenomena: such as hemolytic anemia, which can be life-threatening and sometimes fatal 2

From the Research

Causes of Anemia in Chronic Lymphocytic Leukemia (CLL)

• Autoimmune cytopenias, including autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (AIT), autoimmune neutropenia (AIN), and pure red cell aplasia (PRCA) are common causes of anemia in CLL patients 3, 4, 5.
• The pathogenesis of AIHA in CLL is multifactorial, involving humoral, cellular, and innate immunity, with CLL B-cells acting as antigen-presenting cells and inducing T-cell subsets imbalance, favoring autoreactive B-cells that produce anti-red blood cells autoantibodies 4.
• T cell defect and inversion of the CD4/CD8 ratio are also characteristic of CLL, contributing to the development of autoimmune complications 3.
• Non-hematologic autoimmune complications, such as cold agglutinin disease (CAD), paraneoplastic pemphigus (PNP), acquired angioedema, and anti-myelin associated globulin, are rare but can also occur in CLL patients 3.
• Treatment with certain drugs, such as venetoclax, can also cause AIHA in CLL patients, although the exact mechanism is not fully understood 6.

Types of Autoimmune Cytopenias in CLL

• AIHA is the most common autoimmune complication of CLL, occurring in 7-25% of patients 3, 4.
• AIT is the second most common complication, reported in 2-3% of patients 3.
• AIN and PRCA are rare complications of CLL, and may actually belong to large granular lymphocytic leukemia (LGL) in some cases 3.
• Cold agglutinin disease (CAD) is a rare non-hematologic autoimmune complication of CLL, which can cause AIHA 4, 6.

Treatment-Related Causes of Anemia in CLL

• Monotherapy with purine analogues and alkylating agents should be avoided, as it may increase CLL-associated autoimmune complications 3.
• Venetoclax, a second-generation BH3 mimetic compound, can cause AIHA in some CLL patients, highlighting the need for careful monitoring and management of autoimmune complications during treatment 6.
• Alemtuzumab, a humanized CD52 monoclonal antibody, has been shown to be effective in treating severe refractory AIHA in CLL patients who have not responded to conventional therapy 7.