| disease | Chronic Myeloid Leukemia |
| alias | Slow Grain, Chronic Myelogenous Leukemia |
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by excessive production of granulocytes (including both mature and immature stages). In the early stages of the disease, these cells retain their ability to differentiate, and bone marrow function remains normal. The condition typically remains stable for several years before eventually progressing to a more aggressive form of the disease. Most patients with CML are between 30 and 40 years old, and cases in individuals under 20 are rare.
bubble_chart Diagnosis
1. Clinical manifestations and symptoms: The onset is insidious, and there may be no symptoms in the early stages. The earliest subjective symptoms are often manifestations of hypermetabolism such as lack of strength, low-grade fever, profuse sweating or night sweats, and weight loss. Splenomegaly can cause a feeling of heaviness or discomfort in the left hypochondrium or upper left abdomen, as well as postprandial fullness. Due to the slow progression of symptoms, patients often seek medical attention months after the onset of the disease. Less common symptoms include back pain or limb pain, and severe pain in the upper left abdomen or lower left chest due to splenic infarction. In the advanced stage, when thrombocytopenia occurs, the skin and gums may bleed easily, and women may experience hypermenorrhea. In patients with excessive white blood cells, symptoms induced by "blockage" or embolism of white blood cells in blood vessels may sometimes be observed, such as blurred vision, respiratory distress, and priapism. In these cases, the white blood cell count is often far higher than 500×109/L. The most prominent sign is splenomegaly. By the time patients first seek medical attention, the spleen is often already palpable below the level of the umbilicus, firm and non-tender, but if there is a recent splenic infarction, there may be obvious localized tenderness and a friction rub may be heard. When chronic myeloid leukemia presents with anemia and splenomegaly, it must be differentiated from cirrhosis, schistosomiasis, and Hodgkin's disease. The liver is often grade II enlarged, but not as significantly as the spleen. The skin and mucous membranes are grade II pale. Superficial lymph nodes are usually not enlarged. There is often mild to grade II tenderness in the lower sternum. In the advanced stage, petechiae may appear on the skin and mucous membranes. Venous congestion and white-centered spots may be seen in the fundus. Painless masses (chloromas) may appear in the orbits, skull, breasts, and other soft tissues.
2. Laboratory testsBlood picture: The white blood cell count is high, often above 100×109/L. The blood smear mostly shows neutrophilic band cells and late myelocytes, with the remainder being segmented neutrophils, myelocytes, promyelocytes, and a few blast cells. Eosinophils and basophils are also increased. In the early stages, hemoglobin and red blood cells are grade I reduced, while platelets are normal or increased. In the advanced stage, red blood cells and platelets decrease. The blood picture must be differentiated from a leukemoid reaction.
Bone marrow findings: The bone marrow shows marked to extreme hyperplasia, with cell classification similar to that in the peripheral blood. In the bone marrow smear, granulocytes at all stages can be seen, with myelocytes and late myelocytes predominating. Myeloblasts and promyelocytes are increased compared to normal but generally do not exceed 5–10%. Eosinophils and/or basophils are increased, while the erythroid series is relatively reduced, with a granulocyte-to-erythroid ratio of about 10–50:1. Erythroblasts and megakaryocytes are often increased in the early stages but decrease in the advanced stage. In 90% of patients, the alkaline phosphatase activity of mature neutrophils is significantly reduced.
Chromosomal analysis: The Ph’ chromosome is found in over 90% of patients with chronic myeloid leukemia. The Ph’ chromosome is considered a neoplastic marker of the pluripotent stem cells in chronic myeloid leukemia. A small number of patients with chronic myeloid leukemia are Ph’ chromosome-negative. Based on the presence or absence of the Ph’ chromosome, chronic myeloid leukemia can be divided into two major categories: Ph’-positive and Ph’-negative, with the former having a better prognosis than the latter.
Blood biochemistry: A significant increase in serum vitamin B12 concentration and vitamin B12 binding capacity is one of the characteristics of this disease. The extent of the increase is proportional to the degree of leukocytosis. The reason for the increase is that a large number of normal and leukemic granulocytes produce excessive transcobalamin I, which transports vitamin B12. Serum uric acid concentration may also increase, especially during chemotherapy.bubble_chart Treatment Measures
1. Treatment Principles: There is no need to rush the treatment of chronic myeloid leukemia (CML). Patients with a white blood cell (WBC) count below 100×109/L do not require immediate treatment, as the circulating cells are primarily mature granulocytes, which are smaller in size than blast cells and have better deformability. For patients with a WBC count above 200×109/L, aggressive treatment measures should be taken. Currently, chemotherapy with cytotoxic drugs is the mainstay of treatment. For symptoms caused by extreme leukocytosis, such as priapism, respiratory distress, blurred vision, or psychological abnormalities, acute leukapheresis should be performed in combination with myelosuppressive agents.
2. Chemotherapy: Effective drugs include BUS (busulfan), HU (hydroxyurea), CTX (cyclophosphamide), CLB (chlorambucil), 6-MP (6-mercaptopurine), and MMC (mitomycin). Among these, BUS is the first-line drug, followed by HU. BUS is currently the most effective drug, with a remission rate exceeding 95%, and its ease of administration is an advantage. The dosage is 2 mg three times daily until the WBC count drops below 14×109/L, after which the drug can be discontinued or given intermittently. Generally, symptoms improve within 1–2 weeks of treatment, with significant improvement observed in 4–6 weeks. When the WBC count decreases to 10×109
/L, the dose should be reduced to 1–2 mg/day and maintained for 2–3 months. After discontinuation, if the WBC fluctuates between 10–50×109/L, a low maintenance dose may be considered for over a year. The drug should only be discontinued if the WBC count drops to 5–10×109/L, platelets fall below 100×109/L, or there is a tendency for CML to progress to blast crisis. The main side effects of busulfan are bone marrow suppression, particularly thrombocytopenia. Some patients may develop pancytopenia even with low doses, and recovery is slow. Long-term use can lead to pulmonary fibrosis, skin pigmentation, symptoms resembling chronic adrenal insufficiency, azoospermia, or amenorrhea.HU is initially administered at a dose of 3 g daily orally. The WBC count drops rapidly after administration. When it falls to around 20×109/L, the dose is halved; when it decreases to 10×109/L, the dose is further reduced. The maintenance dose is approximately 0.5–1.0 g daily. Complete discontinuation is generally avoided because the WBC count rises quickly after stopping the drug. The advantages of HU are its rapid action, quick rebound of WBC count if it drops too low, and minimal side effects. The drawback is the need for frequent blood tests to guide treatment. Additionally, α-IFN (alpha-interferon) can be combined with HU for CML treatment.
Method: Administer HU orally at 2.0–6.0 g/day while simultaneously injecting α-IFN subcutaneously at 3 million units intravenously (IV) three times a week for 8–32 weeks. When the WBC count drops to 10×109/L, reduce the HU dose and continue for 1–2 weeks, then discontinue or adjust to a low dose as needed. The maintenance dose of HU is 0.5–1.0 g/day, and it may be continued if conditions permit. α-IFN is administered at 3 million units IV once weekly. During treatment, blood tests should be performed twice weekly, and bone marrow examinations should be conducted every four weeks.
3. Radiotherapy: Deep X-ray therapy is used to irradiate the whole body, the hepatic and splenic regions, and infiltrated areas. The initial dose for splenic irradiation is 50cGy, followed by 100-200cGy daily or every other day. Treatment is discontinued when the white blood cell count drops to 20×109/L. Radiotherapy can be employed for cases with poor response to chemotherapy or relapse, and its efficacy is reported to be no less than that of BUS. Radioisotope 32P therapy is only used for patients who respond poorly to BUS and splenic irradiation. The 32P dose is determined by the degree of leukocytosis. If the total white blood cell count exceeds 50×109/L, the initial 32P dose is 1-2.5mCi, administered intravenously. After 2 weeks, an additional 1-1.5mCi is given, followed by the same dose every 2 weeks until the white blood cell count decreases to 20×109/L. During the stage of remission, patients are monitored every 1-3 months. When the white blood cell count exceeds 25×109/L, another 1-1.5mCi may be administered.
4. Splenectomy: The spleen may be the primary site of blast crisis in chronic myeloid leukemia (CML), and splenectomy may delay the onset of blast crisis and prolong patient survival. Indications for splenectomy include: ①Confirmed diagnosis of CML; ②Good response to chemotherapy; ③Age below 65 with no contraindications for major surgery. Blast crisis is a contraindication for surgery.
5. Bone Marrow Transplantation: For patients aged 45–50 in the chronic phase, allogeneic bone marrow transplantation from HLA-matched siblings is performed. Successful transplantation generally leads to long-term survival or cure.
6. Other Treatments: If the white blood cell (WBC) count exceeds 500×109/L before chemotherapy, leukapheresis using a cell separator may be performed first to rapidly reduce the WBC count and avoid the risk of microvascular occlusion leading to cerebrovascular accidents. At the start of chemotherapy, especially when using hydroxyurea (Hu), allopurinol 0.1g three times daily should be administered concurrently to prevent hyperuricemic nephropathy due to rapid and excessive cell destruction.
7. Treatment of Blast Crisis: Treating blast crisis in CML is more challenging than treating acute leukemia, with a complete remission rate of only 10.7%. The current treatment regimen for blast crisis is as follows: Ara-C (cytarabine) 100mg/m²·d, days 1–14; ADM (doxorubicin) 30mg/m2·d, days 1–3; VCR 2mg, day 1; the above drugs are administered sequentially via intravenous infusion. PDN (prednisone) 40mg/m2·d, given orally in divided doses, days 1–7.
The median survival time for untreated patients is approximately 3.1 years. Whether treated with chemotherapy or radiotherapy, the initial treatment effect is very significant, with symptoms and signs completely disappearing, and blood and bone marrow findings returning to normal or near-normal. Before the onset of blast crisis, physical recovery and general health are often very good. However, the extension of life is limited, with a median survival time of about 3 to 4 years (range 1 to 10 years), and approximately 15% of patients can survive for 5 years or longer. Patients who are Ph chromosome-negative have a particularly poor prognosis. Once blast crisis occurs, most patients die within a few weeks to months. The impact of bone marrow transplantation on prognosis has been discussed earlier.