bubble_chart Overview

Chronic myeloid leukemia (CML) is a clonal malignant proliferation of multipotent hematopoietic stem cells in the bone marrow. It has been established that the Philadelphia chromosome translocation, specifically t(9;22)(q34;q11.2), which forms the BCR/ABL fusion gene, serves as the molecular basis for the development of CML. The expression product of this gene, the p210 fusion protein, plays a significant role in the pathogenesis of CML. Recent studies have also identified the loss of imprinting of the insulin-like growth factor 2 gene as closely associated with the progression of CML from the chronic phase to the accelerated phase and blast crisis. Clinically, CML is characterized primarily by elevated white blood cell counts and splenomegaly, with acute leukemia-like manifestations appearing after blast transformation. The incidence of CML in children is approximately 2-7%, and it is classified into adult-type and juvenile-type. The clinical course of CML is divided into the chronic phase, accelerated phase, and blast crisis.

bubble_chart Diagnosis

(1) The adult-type chronic myeloid leukemia is more common in childhood.

1. Chronic phase

(1) Clinical manifestations

1) Onset is insidious, with no systemic symptoms, or may present with dizziness, lack of strength, poor appetite, weight loss, low-grade fever, etc.
2) Hepatomegaly, splenomegaly, and lymphadenopathy, with splenomegaly being predominant. In half of the cases, the spleen is grade II or larger, while the liver is only grade I enlarged.
3) Skin may show maculopapular rashes, nodules, or other changes.
4) Symptoms vary widely across systems and may include manifestations caused by compression from enlarged spleen or lymph nodes, such as cough, pulmonary rales, abdominal distension and fullness, abdominal pain, diarrhea, bone and joint symptoms, etc. Sudden severe pain in the splenic area, progressive splenomegaly with tenderness, friction rub over the spleen, bloody ascites, fever, profuse sweating, or even shock suggest concurrent splenic infarction.

(2) Laboratory findings

1) Peripheral blood shows normocytic normochromic anemia. White blood cell count is elevated (>30×10⁹/L, mostly between 100–150×10⁹

/L), with neutrophils constituting the vast majority. Immature granulocytes account for >10%, and blasts plus promyelocytes (blasts and early granulocytes) range from 5–10%. Most cells are neutrophilic myelocytes, metamyelocytes, and band forms, with possible increases in eosinophils and basophils. Platelet count is normal or grade I elevated in the initial stage [first stage], followed by significant elevation, potentially exceeding 1000×10⁹/L.
2) Bone marrow exhibits extreme hyperplasia, predominantly neutrophilic myelocytes, metamyelocytes, and band forms, with blasts (type I + II) < 10%,嗜酸及嗜鹼粒細胞增多，巨核細胞數增多，紅細胞系下降。
3) Cytogenetic and molecular studies: Most cases show the Philadelphia (Ph) chromosome in bone marrow and peripheral blood cell karyotyping. Molecular testing reveals the characteristic BCR/ABL fusion gene.
4) Others: Bone marrow CFU-GM culture shows significantly increased colony and cluster formation compared to normal. Neutrophil alkaline phosphatase score is decreased or absent. Serum lactate dehydrogenase is elevated.

(3) Exclusion of leukemoid reaction, other myeloproliferative disorders, and MDS.

2. Accelerated phase The presence of two or more of the following suggests this phase:
(1) Unexplained fever, worsening anemia, bleeding, and/or bone pain.
(2) Progressive splenomegaly.
(3) Platelet count progressively decreases or increases, unrelated to medication.
(4) Blasts in peripheral blood and/or bone marrow >10%.
(5) Peripheral blood basophils >20%.
(6) Significant collagen fibrosis in the bone marrow.
(7) Additional chromosomal abnormalities beyond the Ph chromosome.
(8) No response to conventional anti-CML therapy.
(9) CFU-GM proliferation and differentiation defects, with an increased cluster/colony ratio.

3. Blast crisis Diagnosis is made if any of the following is present:

(1) Blasts (type I + II) in peripheral blood or bone marrow ≥20%.
(2) Peripheral blood blasts plus promyelocytes ≥30%.
(3) Bone marrow blasts plus promyelocytes ≥50%.
(4) Extramedullary blast infiltration. Clinical symptoms and signs worsen compared to the accelerated phase, and CFU-GM culture shows small cluster growth or no growth.

(2) Infant-type chronic myeloid leukemia has an acute onset and short course, resembling acute leukemia. Differences from the adult-type are summarized in Table 7-4.

Table 7-4 Comparison of Infantile and Adult Chronic Myeloid Leukemia

Item                      Infantile Type                      Adult Type  
Age                       Below 4 years, mostly 1-2 years old    Above 4 years, mostly 10-12 years old  
Onset                     Relatively acute                      Relatively slow  
Anemia                    Moderate                             Grade I  
Hemorrhage                Frequent                             Occasional  
Splenomegaly              Mild, grade II enlargement           Markedly enlarged  
Lymphadenopathy           Common                               Present  
Skin rash                 Often facial, eczema-like            Rare  
WBC count                 Mostly below 100,000, median 30,000  Often above 100,000, median 250,000  
Platelet count            Reduced or normal, median 30,000     Normal or increased, median 950,000  
Bone marrow megakaryocytes Reduced                              Normal or increased  
Myeloid:erythroid ratio in bone marrow 2:1～5:1                10:1～50:1  
Ph chromosome             Negative                             Positive  
Fetal hemoglobin          Increased to 15%～50%                Normal  
Splenic Malpighian corpuscles Present, unaffected              Infiltrated by leukemic cells  
Treatment response        Poor                                 Better response to busulfan  
Median survival           Shorter, often death within months   Around 3 years  

bubble_chart Treatment Measures

(1) Chronic phase chemotherapy

1. Single-agent therapy

(1) Busulfan: Can inhibit DNA synthesis and mitosis. The conventional dose selectively acts on granulocytes, with a remission rate (CR) of up to 90% for chronic myeloid leukemia (CML) and a 5-year survival rate of over 30%, but the 10-year survival rate is less than 10%. The initial dose is 4–8 mg/(m²·d), administered orally. When the white blood cell count drops to 50% of the original level, the dose is reduced. Treatment is discontinued when the white blood cell count falls to 15 ×10⁹/L, or when it drops to 20 ×10⁹/L, the dose is adjusted to 2 mg every other day for maintenance therapy, aiming to keep the white blood cell count around 10×10⁹/L. The main side effect is bone marrow suppression.

(2) Hydroxyurea: A ribonucleotide reductase inhibitor that acts on the S phase and has good antiproliferative effects against CML. The dose is 20–40 mg/(kg·d), administered orally. It is commonly used clinically for patients resistant to busulfan or those with thrombocytopenia and is currently considered the first-line drug. The main side effects are bone marrow suppression and gastrointestinal reactions.
(3) Interferon-α (IFN-α): 3 million U/(m²·dose), 3–4 times per week, can delay the onset of blast crisis. When used in the early chronic phase, it can achieve a CR rate of 60–80%, with a median survival of 66 months. Combined use with hydroxyurea and other drugs can reduce the required dose of chemotherapy drugs, thereby lowering toxicity. After achieving CR, IFN-α alone is effective for maintenance therapy.
(4) 6MP: For patients unresponsive to busulfan, this drug can be tried at 2.5–3 mg/(kg·d). Treatment is discontinued when the white blood cell count drops to 15×10⁹/L.

2. Combination chemotherapy

Due to the limitations of busulfan therapy, intensive chemotherapy can be used for the chronic phase of CML, achieving some success in reducing blast crisis and prolonging the stage of remission. Reports indicate that regimens such as IFN plus low-dose Ara-C, hydroxyurea, COAP, and DOAP yield better results than single-agent therapy.

3. Bone marrow transplantation

To date, allogeneic bone marrow transplantation is considered the only curative method for CML. Transplantation can convert the Ph'-positive clone of CML into a Ph'-negative clone, enabling long-term disease-free survival. The 5-year survival rate for transplantation during the chronic phase is about 53%, while outcomes are poorer during the accelerated and blast crisis phases. Recent studies on autologous bone marrow transplantation for chronic-phase patients have shown promising results, with reports indicating that 60% of cases post-transplantation can convert Ph'-positive clones to normal hematopoiesis, achieving a 3-year survival rate of 70%, of which 10% show complete absence of Ph'-positive clones. Currently, for treating CML in the chronic phase, when no suitable allogeneic bone marrow donor is available, the preferred options include hydroxyurea plus IFN-α, matched unrelated donor bone marrow transplantation, or autologous bone marrow transplantation with effective ex vivo purging.

4. Other treatments

Splenic irradiation can reduce spleen size and lower granulocyte levels in the blood.

(2) Treatment for blast crisis phase

There is no satisfactory treatment for CML blast crisis. Current approaches often use chemotherapy regimens for acute leukemia, such as COAP and DOAP. The prognosis is poor (refer to the "Acute Leukemia" section). In recent years, research has focused on treatments targeting the disease mechanism, such as using ex vivo antisense oligonucleotide technology to inhibit BCR/ABL expression, suppress abnormal proliferation of hematopoietic stem cells, and promote apoptosis of CML cells, opening new avenues for CML treatment.