| disease | Chronic Lymphocytic Leukemia |
| alias | Chronic Lymphocytic Leukemia, Slow Drip, CLL |
Chronic lymphocytic leukemia (CLL) is a clonal malignant disorder of B lymphocytes (rarely T lymphocytes). This disease is typically indolent, characterized by the progressive accumulation of immunologically dysfunctional, mature small lymphocytes that exhibit a diminished response to antigenic stimulation. The immune dysfunction is associated with abnormal B cells producing inappropriate antibodies, which can suppress the body's immune function. In advanced stages, CLL can lead to bone marrow failure and direct infiltration of tissues and organs.
bubble_chart Clinical Manifestations
Symptoms and signs often appear later than the significant changes in blood tests. Chronic lymphocytic leukemia (CLL) is a disease that primarily affects middle-aged and older individuals, with about 90% of patients being over 50 years old and an average age of 65. Many patients are incidentally found to have lymphocytosis. The earliest symptoms often include lack of strength, fatigue, and reduced physical activity during seasonal epidemics. Enlarged superficial lymph nodes, especially in the neck, are usually the first to draw the patient's attention. In advanced stages, these lymph nodes may cluster together, reaching diameters of 2–3 cm, and are typically painless, firm, and movable. Enlarged mesenteric or retroperitoneal lymph nodes can cause abdominal or urinary symptoms. The spleen may be mildly to moderately enlarged (grade II), and the liver may also enlarge, though not as prominently as in chronic myeloid leukemia. Later symptoms may include loss of appetite, weight loss, low-grade fever, night sweats, and anemia. About 10% or more of patients may develop autoimmune hemolytic anemia, which can lead to severe anemia and jaundice. In advanced stages, skin purpura and bleeding tendencies may occur, along with increased susceptibility to infections, particularly respiratory infections—this is linked to reduced production of normal immunoglobulins and may become a direct cause of death. Additionally, varying degrees of damage may occur in the gastrointestinal or skeletal systems. Some patients experience cutaneous pruritus. Rarely, leukemic skin infiltration may manifest as purplish-red or brownish-red nodules or thickened skin. Generalized skin redness may occur, and the tonsils, salivary glands, or lacrimal glands may also enlarge.
bubble_chart Auxiliary ExaminationAn increase in white blood cells in the blood picture is a characteristic of this disease. The most prominent finding is an increase in small lymphocytes, with white blood cell counts mostly ranging from 15 to 50×109/L, and a few cases exceeding 100×109/L. In the early stage, small lymphocytes account for 65–75% of white blood cells, while in the advanced stage, they account for 90–98%, and their morphology is difficult to distinguish from normal small lymphocytes. Neutrophils and other normal white blood cells are significantly reduced. In the early stage, anemia may be absent but gradually worsens later. In the advanced stage, anemia can be severe, with increased reticulocytes and elevated serum bilirubin. In the advanced stage, platelet counts are often reduced. Bone marrow findings: In the early stage, leukemia cells appear only in a few bone marrow cavities, so the early bone marrow picture may show no significant changes. In the advanced stage, normal bone marrow cells are almost entirely replaced by mature small lymphocytes, with primitive lymphocytes and immature lymphocytes accounting for only 5–10%. Additionally, 50% of cases exhibit reduced gamma globulin; 10–20% of patients have autoantibodies; and 30% of patients have hyperuricemia.
(1) Medical history and symptoms
(1) History inquiry: The onset is slow, and patients often have no obvious symptoms. Inquiry should focus on whether there are manifestations such as low-grade fever, night sweating, and susceptibility to infections.
(2) Clinical symptoms: lack of strength, weight loss, poor appetite, night sweating, decreased physical stamina, fever, and occasionally cutaneous pruritus.
Generalized lymphadenopathy, with nodes of medium hardness and mobility; in advanced stages, they may adhere and fuse together. Hepatosplenomegaly (grade I), with significant splenomegaly in advanced stages. Bone pain is not obvious. In advanced stages, petechiae may be visible on the skin.
(3) Auxiliary examinations
1. Blood test: Normocytic normochromic anemia. White blood cell count >10×109/L, with lymphocytes >50% and an absolute count >5.0×109/L; predominantly mature lymphocytes, with occasional immature or atypical lymphocytes. Platelet count may be normal or reduced.
2. Bone marrow examination: Hypercellular to markedly hypercellular, with prominent mature lymphocyte proliferation (>40%), and presence of primitive and immature lymphocytes. <10%。紅系、粒系相對減少，巨核細胞正常或減少。
3. Reduced serum immunoglobulins; or monoclonal immunoglobulin elevation, mostly IgM type. Positive for κ or λ light chain detection.
(4) CLL clinical staging and differential diagnosis
1. Staging: Stage I: Lymphocytosis, possibly accompanied by lymphadenopathy.
Stage II: Stage I + hepatomegaly or splenomegaly. Stage III: Stage I or II + anemia (hemoglobin <100 g/L or <6.2 mmol/L).
2. Differential diagnosis: Should be distinguished from subcutaneous nodular lymphadenitis, lymphoma, infectious mononucleosis, hairy cell leukemia, and prolymphocytic leukemia. {|118|}
bubble_chart Treatment Measures
Clinical Staging The purpose of staging chronic lymphocytic leukemia (CLL) is to guide clinical treatment and estimate prognosis. The currently accepted international clinical staging criteria are as follows:
Stage A: Lymphocytes in blood ≥15×109/L, lymphocytes in bone marrow ≥40%. No anemia or thrombocytopenia. Lymphadenopathy involves fewer than 3 regions (lymph nodes in the neck, axilla, or abdomen, whether unilateral or bilateral, count as one region each; liver and spleen each count as one region).
Stage C: Blood and bone marrow lymphocyte counts same as above, but with anemia (hemoglobin <110g/L in males, <100g/L in females) or thrombocytopenia (<100×109/L). The extent of lymph node involvement is not considered.
Treatment Patients with Stage A do not require treatment but should be monitored regularly for disease progression. Patients with Stage B and C require treatment. 1. Chemotherapy: Chlorambucil (CLB) is the most widely used. Dosage regimens include: - ① 0.1–0.2 mg/kg/day orally for 6–12 days, reduced to 2–4 mg/day after 2 weeks for long-term maintenance. - ② Intermittent therapy: 0.2 mg/kg/day orally for 10–14 days, followed by a 2-week break before repeating. Combination chemotherapy may also be used, such as CLB + prednisone (PDN): CLB 0.1–0.2 mg/kg/day and PDN 10–20 mg/day for 4 days, repeated every 3 weeks. Alternatively, the M2 protocol may be used: - Day 1: Carmustine (BCNU) 0.5–1 mg/kg IV. - Day 2: Cyclophosphamide (CTX) 10 mg/kg IV. - Days 1–14: Melphalan (L-PAM) 0.25 mg/kg/day orally. - Day 21: Vincristine (VCR) 0.03 mg/kg IV. - Days 1–14: Prednisone (PDN) 1 mg/kg/day orally. Treatment may be repeated after a 4-week break.
Advanced-stage cases may be treated with a combination of VCR + CTX + CLB + PDN. Most patients experience symptom relief, reduction in lymphadenopathy and splenomegaly, and a decrease in white blood cell count. However, even if the white blood cell count normalizes, the percentage of lymphocytes in blood and bone marrow remains elevated, serum globulin decreases, and lymphadenopathy and splenomegaly (Grade I) often persist. Patients who relapse within weeks of stopping treatment require continuous therapy.
2. Radiotherapy: Mainly used for superficial or deep lymphadenopathy or splenomegaly that shows inadequate response to chemotherapy. Local radiotherapy is also effective for relieving compression or obstruction symptoms. Whole-body irradiation with 60Co can induce remission in some patients, though it is rarely used clinically today.
3. Other treatments: - For concurrent autoimmune anemia or thrombocytopenia, glucocorticoids may be used with good efficacy. - If splenic radiotherapy fails, splenectomy may be considered. Postoperatively, lymphocyte counts may not change significantly, but hemoglobin and platelet counts often improve. - For recurrent or severe infections, antibiotics may be administered. - Patients with hypogammaglobulinemia may receive regular gamma globulin infusions. - Additionally, the Chinese patent drug *Miraculous Pill of Six Ingredients* has shown some efficacy. - Furthermore, fludarabine is a new experimental agent that may be tried in cases resistant to other treatments.
The duration of the disease varies greatly, ranging from 1-2 years to over 10 years, with an average of about 3-4 years (calculated from the time of diagnosis). The main causes of death are severe anemia, bleeding, or infections caused by bone marrow failure, with pulmonary infections being the most common.
