OVERVIEW
Chronic granulocytic leukemia (CML), true erythrocytosis, primary thrombocythemia, and idiopathic myeloid metaplasia (AMM) were first proposed by Dameshek in 1951 as being associated with myeloproliferative syndromes. Although each disease has unique clinical manifestations, laboratory and biological features, the common denominator is polyclonal proliferation involving cells throughout the myeloid, suggesting that the disease occurs in the pluripotent hematopoietic stem cells.CML accounts for 15% to 20% of all leukemias, and in children, CML can present in two types: adult-onset chronic granulocytic leukemia (ACML) and juvenile myelomonocytic leukemia (JMML ).JMML is restricted to children and has a distinctive clinical presentation, laboratory and cytogenetic features. Pediatric adult-onset chronic granulocytic leukemia, with an age of onset of 5 years or older, is more common between 10 and 14 years of age, and is rarely seen in children under 3 years of age. The bone marrow is actively proliferative, with predominantly granulomatous hyperplasia, with <10% primitive granulocytes, mostly intermediate and late juvenile granulocytes and rod-shaped nucleated cells. Bone marrow megakaryocytes are significantly increased, with mature megakaryocytes predominating.
Etiology
The etiology of most children is unknown, and ionizing radiation is the only clear risk factor for adult-type chronic granulocytic leukemia.CML is a malignant tumor involving the hematopoietic stem cell lineage, and it is now believed that CML is mainly caused by inhibition of apoptosis.
Symptoms
1. Adult CML
It is the main presenting type of CML in children, Ph chromosome positive, adult-type CML (adult-type CML) accounts for 3% of leukemia in children under the age of 15 years, and about 10% of all CML. The age of onset is rare in children under 5 years old, and it is more common in children aged 10 to 12 years old. Its clinical manifestations are very similar to those of adult CML, and it can also be divided into chronic, accelerated, and acute phases. The onset of the disease is slower, but it is more urgent than adult CML; the initial symptoms are mild, mostly manifested as lethargy, weight loss, bone and joint pain and green tumor. Splenomegaly is moderate to severe, liver is large, and lymph nodes may be enlarged. Clinical manifestations such as intracranial hemorrhage and optic papillary edema due to significant leukocytosis/leukocyte stasis may also occur. Cytogenetically, it has been shown that pediatric adult CML is the same disease as adult CML. In terms of clinical manifestations, pediatric adult CML is less responsive to conventional chemotherapeutic agents (e.g., hydroxyurea, etc.) than adult CML, and has a tendency to undergo acute changes more quickly.
2. Juvenile CML
Different from adult type, it accounts for about 1.5%~2% of childhood leukemia, most common in infants and young children under 4 years old, which has the following characteristics: ① bleeding phenomenon and thrombocytopenia in the early stage of the disease, hemorrhage is common, which is manifested as skin purpura, rhinorrhea, visceral or intracranial hemorrhage; ② recurrent infections are prone to occur, and there are often fever and other symptoms; enlarged lymph nodes are common, and they may be generalized or limited, and the cervical lymph nodes often have a tendency to become suppurative, and the liver and spleen often have a tendency to become suppurative. Lymph node enlargement is common, which can be generalized or limited, and the lymph nodes in the neck often have a purulent tendency, and the liver and spleen are often enlarged and hard, but not as significant as the adult type; (3) the face and limbs often have corn-like papules, eczematous rashes, or hemorrhagic plasmodial herpes; (4) the therapeutic effect is poor, and the drug reactivity is insensitive; (5) the survival is shorter, and the median survival is less than 2 years. Some scholars have suggested that children with Ph-negative chromosomes are not true CML, but an atypical acute granulomonocytic leukemia or subacute juvenile granulomonocytic leukemia, but this viewpoint is still controversial and has not been universally recognized.
3. Familial CML
It is a granulocytic proliferative disease, characterized by the fact that it often occurs in close relatives. The clinical symptoms are similar to those of the juvenile type, but there is a certain gap between the laboratory tests and those of the juvenile type of CML.
4. Other
In addition, most children with adult-type CML are in the chronic phase at the time of diagnosis, with a slow onset and mild onset of symptoms and signs. Common symptoms include general malaise, malaise, weight loss, fever, and bone and joint pain. A small number of children are asymptomatic and are diagnosed only when a high white blood cell count is found during routine blood tests. Severe bone and joint pain, bleeding and unexplained high fever or extramedullary infiltration are mostly seen in the acute stage.
5. Physical signs
(1) Enlarged liver, spleen, lymph nodes, giant spleen, enlarged liver, mildly enlarged lymph nodes, fullness in the epigastrium or a mass in the left upper abdomen. Most of the children have enlarged spleens of varying degrees, which are accessible under the ribs, and in the case of giant spleens, they are hard and often have cut marks. In the case of giant spleen, it is hard and often has cut marks. Sharp pain in the splenic region or friction sound in the splenic region is a sign of splenic infarction. Half of the children have mild to moderate hepatomegaly. Lymph node enlargement is rare.
(2) Central nervous system involvement Retinopathy, optic disc edema etc.
(3) Skin A few children have skin infiltration and develop skin nodules.
(4) Others: Pulmonary dysfunction and arthritis, abnormal penile erection. A small number of children are prone to ulcerative disease, mostly caused by basophilia. Leukocytosis due to high primitive cell count is common in children with ACML, but the symptoms are mild.
Examination
1. Peripheral blood picture
Mainly leukocyte counts are increased, with 80% of children with adult-type CML above 100 × 109/L. Hematocrit is around 80g/L. Thrombocytosis. Classification of visible granulocytosis, including eosinophilic and basophilic granulocytosis. Primitive granulocytosis is not obvious, with predominance of intermediate, late juvenile and mature granulocytes.
2. Blood tests
Leukocyte alkaline phosphatase is decreased. Fetal hemoglobin (HbF) is not increased in adult-onset CML. Serum immunoglobulins are not elevated. Serum and urinary lysozyme are not elevated, but vitamin B12 and vitamin B12 transporter protein are elevated.
3. Bone marrow examination
Proliferation is active, with predominantly granulomatous proliferation, with <10% of primitive granulocytes, mostly middle and late granulocytes and rod-shaped nucleated cells, and granulocyte:red is 10-50:1. Some patients can see myelofibrosis. Bone marrow megakaryocytes increased significantly, with mature megakaryocytes predominating. Bone marrow culture colonies and clusters are increased.
4. Other auxiliary examinations
Chest X-ray, ultrasound, electrocardiogram are routinely performed, and others are selected according to clinical needs.
Diagnosis
1. Positive Ph1 chromosome and/or positive bcr-abl fusion gene.
About half of children with CML are Ph-positive and the other half are Ph-negative; the majority of children over 5 years of age are Ph-positive, i.e., there are occasional infants who are Ph-positive, and the clinical manifestations and laboratory tests of these children are similar to those of adults with CML; therefore, the diagnosis of pediatric adult CML should still be made.
Ph1 chromosome positivity and/or bcr-abl fusion gene positivity with any of the following is diagnostic.
(1) Elevated peripheral blood leukocyte count Neutrophils predominate, immature granulocytes >10%, and primitive granulocytes <10%.
(2) Highly proliferative granulopoiesis in the bone marrow, with predominantly neutrophils, late granulocytes, increased rod-shaped granulocytes, and <10% of primitive cells (type I+II).
2. Ph1 chromosome positive and/or bcr-abl fusion gene negative.
Ph1 chromosome positivity and/or bcr-abl fusion gene negativity can be diagnosed only if three of the following (1) to (4) plus (5) are present.
(1) Splenomegaly.
(2) Persistently elevated peripheral blood leukocyte count >30×109/L, with predominantly neutrophils, >10% immature granulocytes, basophils, and <10% primitive cells (type I+II).
(3) The proliferation of bone marrow image is obvious to extremely active, with predominantly neutral neutrophils, late juvenile granulocytes, increased rod granulocytes, and primitive cells (type I+II) <10%.
(4) Neutrophil phosphatase (NAP) score is decreased.
(5) The ability to exclude leukemia-like reactions, JMML or other types of myelodysplastic syndromes (MDS), other types of myeloproliferative diseases.
3. Other
In juvenile CML, a significant increase in fetal hemoglobin with disease progression can be considered one of the main features of juvenile CML.
Differential diagnosis
1. Leukemia-like reaction
The leukemia-like reaction in children is characterized by: the presence of a clear underlying disease leading to leukemia-like reaction, such as infection, tuberculosis, etc.; no leukemia cell infiltration in the spleen and organs; increased or normal leukocyte alkaline phosphatase activity; platelet count does not decrease; granulocytes can be seen as poisoned granules and vacuoles; and the blood picture will return to normal after the underlying disease is controlled.
2. Juvenile Myelomonocytic Leukemia (JMML)
WHO classifies JMML as myelodysplastic/myeloproliferative disease (tumor) (MDS/MPN), which is a myeloid tumor. It occurs in young children or infants under 4 years of age and accounts for about 1.5% of childhood leukemias, with 20% of children having mutations in the RAS gene.
The diagnostic criteria are:
(1) Peripheral blood mononucleosis > 1X109/L;
(2) Primary cells (including primary and young monocytes) less than 20% of peripheral blood leukocytes or bone marrow nucleated cells;
(3) Ph negative and BCR/ABL negative;
(4) Plus any two of the following three: (1) fetal hemoglobin (HbF) higher than the value expected for age, (2) immature cells in peripheral blood (PB), (3) WBC>10X109/L, clonal chromosomal abnormality (often monosomy 7);
(5) Granulosa monophyletic progenitor cells are highly sensitive to GM-CSF in in vitro culture. Since JMML and juvenile CML are quite similar in terms of onset, clinical manifestations, laboratory tests and prognosis, there are different opinions in the academic community as to whether JMML and juvenile CML are the same disease or similar manifestations of different diseases. Some scholars believe that JMML has more similarities with adult subacute or chronic granulomonocytic leukemia.
3. Familial myeloproliferative disorders
This disease is clinically and laboratory similar to CML, with increased leukocytes, hepatosplenomegaly, anemia, thrombocytopenia, etc. However, there is a family history of this disease, and the liver and spleen may be enlarged. However, there is a family history of this disease, liver and spleen biopsy shows extramedullary hematopoiesis without infiltration of leukemia cells, Ph chromosome is negative, fetal hemoglobin is normal; anti-leukemia treatment is ineffective, and splenectomy can sometimes correct hyper-splenism, which can be relieved by itself in some cases.
Treatment
1. Drug therapy
Hydroxyurea, interferon and Gleevec can be used according to the specific conditions of the children. For Ph chromosome-positive pediatric adult CML, Gleevec is preferred.
2. Bone marrow transplantation
Allogeneic bone marrow transplantation.