Splenomegaly reduces blood counts through sequestration, marginalization, and destruction of healthy blood cells inside the spleen.Hairy cells are nearly mature B cells, which are activated clonal cells with signs of VH gene differentiation. They may be related to pre-plasma marginal zone B cells or memory cells. Cytokine production is disturbed in HCL. Hairy cells produce and thrive on TNF-alpha. This cytokine also suppresses normal production of healthy blood cells in the bone marrow.Unlike healthy B cells, hairy cells express and secrete an immune system protein called interleukin-2 receptor (IL-2R). In HCL-V, only part of this receptor is expressed. As a result, disease status can be monitored by measuring changes in the amount of IL-2R in the blood serum. The level increases as hairy cells proliferate, and decreases when they are killed. Although uncommonly used in North America and Northern Europe, this test correlates better with disease status and predicts relapse more accurately than any other test. Hairy cells respond to normal production of some cytokines by T cells with increased growth. Treatment with interferon-alpha suppresses the production of this pro-growth cytokine from T cells. A low level of T cells, which is commonly seen after treatment with cladribine or pentostatin, and the consequent reduction of these cytokines, is also associated with reduced levels of hairy cells. In June 2011, E Tiacci et al discovered that 100% of HCL samples analysed had the oncogenic BRAF mutation V600E, and proposed that this is the diseases driver mutation.
Toxicity
Azacitidine causes anemia (low red blood cell counts), neutropenia (low white blood cell counts), and thrombocytopenia (low platelet counts), and patients should have frequent monitoring of their complete blood counts, at least prior to each dosing cycle. The dose may have to be adjusted based on nadir counts and hematologic response.It can also be hepatotoxic in patients with severe liver impairment, and patients with extensive liver tumors due to metastatic disease have developed progressive hepatic coma and death during azacitidine treatment, especially when their albumin levels are less than 30 g/L. It is contraindicated in patients with advanced malignant hepatic tumors.Kidney toxicity, ranging from elevated serum creatinine to kidney failure and death, have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for conditions other than myelodysplastic syndrome. Renal tubular acidosis developed in five patients with chronic myelogenous leukemia (an unapproved use) treated with azacitidine and etoposide, and patients with renal impairment may be at increased risk for renal toxicity. Azacitidine and its metabolites are primarily excreted by the kidneys, so patients with chronic kidney disease should be closely monitored for other side effects, since their levels of azacitidine may progressively increase.Based on animal studies and its mechanism of action, azacitidine can cause severe fetal damage.