Juvenile granulomonocytic leukemia

Summarize

1. General

OVERVIEW: Juvenile granulomonocytic leukemia is a rare myelodysplastic syndrome/myeloproliferative neoplasm that occurs in early childhood and is characterized by abnormal proliferation and differentiation of granulomonocytes and organ infiltration.

Performance: The most typical symptoms of juvenile granulomonocytic leukemia are granulomonocytic infiltration and skin damage, anemia, fever, hemorrhage, hepatosplenomegaly and other symptoms are mainly common.

Treatment: Juvenile granulocytic mononucleosis is a heterogeneous group of leukemias, the severity of the disease varies greatly, and chemotherapy is generally ineffective; the most effective treatment is allogeneic hematopoietic stem cell transplantation. The most effective treatment is allogeneic hematopoietic stem cell transplantation. However, some children are treated with demethylating drugs with remarkable effects, and a small number of children with very mild disease even have the possibility of recovering on their own without treatment.

Prognosis: The prognosis for juvenile granulomonocytic leukemia is mostly less than ideal. Long-term survival with conventional chemotherapy alone is only 10%. Allogeneic hematopoietic stem cell transplantation can achieve an overall survival rate of more than 60%. Recent studies have found that combined treatment with demethylating drugs can improve outcomes. A small percentage of children with specific gene mutations can heal on their own or survive for a longer period of time without transplantation.

2. Definition of disease

Juvenile myelomonocytic leukemia (JMML), once known as chronic granulomonocytic leukemia, juvenile chronic granulocytic leukemia, and infantile chromosome 7 monosomy. It is a rare myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) that occurs in early childhood and is not an acute or chronic leukemia. Juvenile granulomonocytic leukemia is characterized by abnormal proliferation and differentiation of granulomonocytes and organ infiltration.

Epidemiological

epidemiological

Juvenile granulomonocytic leukemia accounts for 1-2% of all childhood leukemias, with an annual incidence of 0.12-0.30 cases per 100,000 population reported abroad, and there is no definitive epidemiological information available in China.

Juvenile granulomonocytic leukemia occurs most often in infants and young children; 50% are diagnosed before the age of 2 years, and the incidence is significantly higher in boys than in girls.

Etiolog & Risk factors

1. General

The cause of juvenile granulomonocytic leukemia is associated with chromosomal and genetic variations, but it is not a hereditary disease, and the associated variations are basically due to abnormalities in development. However, genetic disorders involving related genes increase the risk of developing juvenile granulomonocytic leukemia.

2. Underlying causes

The main cause of juvenile granulomonocytic leukemia is a genetic mutation in hematopoietic cells, which leads to the uncontrolled proliferation of granulomonocytes, crowding out the living space of normal cells and enabling them to rapidly overflow into the bloodstream and reach other parts of the body through the bloodstream such as lymph nodes, the spleen, the liver, or other organs, forming an infiltration that interferes with the normal functioning of the other cells, leading to various juvenile granulomonocytic leukemia Symptoms.

Ninety percent of juvenile granulomonocytic leukemia involves mutations in genes in the RAS signaling pathway, such as PTPN11, N-RAS, K-RAS, NF1, etc. The CBL, SPRED, and transcriptional intermediate factor γ1 genes have also been associated with the development of juvenile granulomonocytic leukemia. About 35% of these children carry a non-hereditary mutation in the PTPN-11 gene, and 20-25% carry a mutation in the K-RAS or N-RAS genes. Mutations in children with juvenile granulomonocytic leukemia are usually systemic, i.e., nongenetic mutations that occur later in life, but a small number of them are germline mutations that are hereditary.

3. Predisposing factors

Children with neurofibromatosis type 1 have an increased risk of developing juvenile granulomonocytic leukemia because the mutation in the gene that causes neurofibromatosis type 1 is associated with juvenile granulomonocytic leukemia. Approximately 11% of children with juvenile granulomonocytic leukemia also have neurofibromatosis type 1.

Classification & Stage

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Clinical manifestations

1. General

The most typical symptoms of juvenile granulomonocytic leukemia are granulomonocytic infiltration and skin lesions, hepatosplenomegaly, and anemia, fever, and bleeding are also more common.

2. Typical symptoms

Granulomonocytic infiltration: this is the most common symptom of juvenile granulomonocytic leukemia, which is usually manifested by enlarged lymph nodes in different parts of the body and/or enlarged liver and spleen, and respiratory distress. Hepatosplenomegaly is the most common symptom, present in about 97% of children at first diagnosis; lymph node enlargement is present in 75% of children.

Skin lesions: Skin lesions are an important feature of juvenile granulomonocytic leukemia and are characterized by maculopapular rash (40%-50% of children have this symptom), discoloration of folds of the skin (e.g., groin and armpits), yellow tumors, green tumors, and milky café au lait spots.

Anemia: is one of the earlier symptoms and worsens with the progression of the disease. It usually occurs gradually and is characterized by pallor, weakness, shortness of breath after activity, drowsiness, etc. The nails and the conjunctiva of the eyelids may also appear to varying degrees of pallor.

Fever: The fever is mainly due to the juvenile granulomonocytic leukemia itself, which is usually low to moderate, around 38°C, and does not respond to antibiotic treatment, but resolves within 72 hours of induction therapy. It may also be accompanied by infections due to the immunocompromised nature of the child due to the reduced number of leukocytes and their abnormal functioning, especially the low neutrophil count. The most common infections of the respiratory tract are tonsillitis and bronchitis, which occur in 50% of children. The source of the infection may be almost any pathogen and is prone to co-infections.

Bleeding: Most of the time, bleeding or ecchymosis of the skin and mucous membranes (e.g., bruising of the skin) is present, as well as unexplained nosebleeds or bleeding gums. Some children may have gastrointestinal bleeding or hematuria, but this is very rare.

Pulmonary infiltrates: respiratory symptoms are frequent in juvenile granulomonocytic leukemia, and shadows are common on lung imaging, which is often considered a pulmonary infection, but in reality pulmonary infiltrates are so common that they are often mistakenly treated as a pulmonary infection and remain untreated.

Clinical Department

1. General

The diagnosis of juvenile granulomonocytic leukemia is based on clinical symptoms, signs and symptoms, blood tests, peripheral blood smears, bone marrow cytology, immunophenotyping, cytogenetic features, and genetic testing. At the same time, the doctor will also conduct other auxiliary tests, such as ultrasound, chest X-ray, blood biochemistry, etc., to assess the physical condition of the child and the specific disease.

2. Consultation room

Hematology, Pediatrics, Hematology-Oncology

Examination & Diagnosis

1. Diagnostic basis

According to the criteria set by the World Health Organization (WHO) in 2016, the diagnostic criteria for juvenile granulomonocytic leukemia are as follows:

I. All of the following criteria must be met simultaneously:

●BCR-ABL fusion gene negative

● Absolute peripheral blood mononuclear cell count ≥1.0×109 /L

●Splenomegaly

:: Bone marrow or peripheral blood naïve cell ratio <20%

II. At least one of the following must be met:

● Presence of somatic mutations in the RAS or PTPN11 genes

● Meets diagnostic criteria for neurofibromatosis type 1 or has a mutation in the NF1 gene

●CBL gene germline mutation with heterozygous deletion of the CBL gene

III. If at least one of the criteria in II is met, this part of the criteria need not be taken into account; if the criteria in II are not met, the following criteria need to be met:

● Monosomy of chromosome 7 (normal individuals have 2 chromosome 7s), or the presence of clonal cytogenetic inheritance other than monosomy of chromosome 7, or at least 2 of the following criteria are met:

● Fetal hemoglobin higher than normal for age

:: The presence of myeloid naïve cells in peripheral blood

●=

● Granulocyte-macrophage colony-stimulating factor hypersensitivity

●Highly phosphorylated STAT5

2. Relevant inspections

1) Routine physical examination and history taking

Routine physical examination including physical condition, manifestations of disease, other abnormal signs like painless lumps. The doctor will also ask about the history of previous illnesses, family history and treatment.

2) Blood tests

● Routine blood tests: counts of all types of white blood cells, hemoglobin levels, platelet counts,. In addition to automated routine blood tests, a blood smear should be done for manual classification. General leukocytosis, anemia, thrombocytopenia, and a marked increase in the absolute number of monocytes, greater than 1x109/L are typical laboratory features of this disease, and naïve cells are common in the peripheral blood.

● Blood biochemistry tests: routine blood biochemistry indicators are checked to determine if any are outside the normal range. Liver and kidney function, lactate dehydrogenase levels, and electrolytes are mandatory. Patients with a high white blood cell load may have increased blood uric acid and lactate dehydrogenase levels.

● Coagulation tests: including prothrombin time (PT), activated partial thromboplastin time (APTT), prothrombin time (TT), fibrinogen (FIB), D-dimer (DD), fibrin degradation products (FDP). The onset of juvenile granulomonocytic leukemia can result in a decrease in prothrombin and fibrinogen, which can lead to prolonged prothrombin time and bleeding.

3) Bone marrow examination

4) Cytomorphologic examination: common hyperplasia is markedly active, with an increase in myeloid naïve cells, but not more than 20%. Immunophenotyping: the type of cells is analyzed by immunological markers on the cell surface.

● Cytogenetic and molecular biological analysis: chromosomal examination of the cells in the sample, -7 and -7q are the most common karyotypic abnormalities, which can account for about 25% of the children, and some literature suggests that having a -7 abnormality has a poor prognosis, but most of the literature suggests that it is not associated with prognosis.

5) Genetic testing

As juvenile granulomonocytic leukemia often has mutations in related genes, somatic mutations in NF1, NRS, KRAS, PTPN11, CBL genes in the Ras pathway can be detected in 90% of children, and secondary mutations in SETBP1 and JAK3 can be detected in some JMML, which often suggests a poor prognosis. Therefore, the detection of such mutations can help diagnose and differential diagnosis of juvenile granulomonocytic leukemia and determine the prognosis, and has become an important diagnostic value. Peripheral blood and bone marrow have the same diagnostic value.

In addition to blood or bone marrow tests, hair follicles, fingernails, or oral mucous membranes are also taken and tested for genes to help determine whether a germline mutation or a somatic mutation is present in order to determine the severity of the disease.

In recent years methylation testing has shown a close correlation with disease severity and can help determine the severity of the disease and the significance of methylation therapy. In addition to the relevant mutations in the RAS gene, the concomitant secondary mutations in SETBP1 and JAK3 suggest a poor prognosis and therefore also require attention to testing.

6) Bone marrow biopsy

Doctors will perform a bone marrow aspiration, which is a puncture using a special hollow needle in the iliac or femur area to extract a small amount of bone specimen to be sent for testing. The importance of bone marrow biopsy has diminished with the development of genetic testing techniques.

7) Imaging

Chest X-rays, abdominal ultrasound, and, depending on the condition, ultrasound (in order to understand cardiac function and abdominal organs), CT (to assess for head or chest and abdominal occupations, bleeding, or inflammation), or Magnetic Resonance Imaging (MRI, to assess for occupations and bleeding and vascularity).

3. Differential diagnosis

Juvenile granulomonocytic leukemia is easily confused with other types of myelodysplastic syndromes/myeloproliferative neoplasms. However, juvenile granulomonocytic leukemia usually occurs under the age of 5 years. Disease-associated genetic abnormalities are specific and often help in differentiation.

Infectious mononucleosis due to EBV infection also has liver and spleen lymph node enlargement, fever and other manifestations, and blood leukemia is significantly increased, with similarities to juvenile granulomonocytic leukemia, peripheral blood smear whether there is a heterogeneous lymphocyte increase in conjunction with viral serological examination of the family to help identify.

Juvenile granulomonocytic leukemia is more easily confused with chronic granulocytic leukemia. Both are chronic leukemias, both are characterized by hepatosplenomegaly, both have markedly elevated peripheral blood cells, and both are frequently accompanied by increased peripheral blood naïve granulocytes. However, the former is usually thrombocytopenic, while the latter is often thrombocytopenic in the chronic phase, with markedly elevated anterior peripheral mononuclear cells. The presence or absence of the BCR/ABL fusion gene is an important basis for identifying chronic granulocytic leukemia.

Clinical Management

1. General

Conventional chemotherapy is ineffective in most juvenile granulomonocytic leukemias, and some children show some efficacy with demethylating drugs, with allogeneic hematopoietic stem cell transplantation being the most effective tool at present.

2. Chemotherapy

Conventional chemotherapy is not effective in juvenile-type granulomonocytic leukemia. However, before undergoing allogeneic hematopoietic stem cell transplantation, some children may receive chemotherapy with antimetabolic chemotherapeutic agents (e.g., 6-mercaptopurine) or demethylating agents to reduce the number of leukemic cells.

3. Allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation is a method of transplanting hematopoietic stem cells from other normal individuals (not identical twins) into an affected child to perform normal hematopoietic and immune functions.

Most individuals with CBL germ cell mutations, with or without concomitant heterozygous deletion of hematopoietic cell genes (LOH, loss of heterozygosity), are self-healing, and therefore close follow-up is recommended and immediate transplantation is not required unless chromosomal abnormalities or disease progression occurs. Some children with low HbF expression and high platelet counts who are positive for somatic mutations in the N-RAS and K-RAS genes (e.g., NRASG12S and KRASG12V) with juvenile-type granulomonocytic disease can survive longer without transplantation.

4. Drug treatment

Recent studies have found that the combination of demethylating drugs in the treatment of juvenile granulomonocytic leukemia can improve the efficacy of treatment, and the efficacy of some children is significant. Commonly used demethylating drugs include azacitidine and decitabine.

5. Cutting-edge treatment

Since mutations in the RAS signaling pathway are present in 90% of juvenile granulomonocytic leukemias, targeted agents against the RAS signaling pathway, such as the MEK1/2 inhibitor trametinib, may improve the prognosis of juvenile granulomonocytic leukemia. Currently, there are clinical trials in the United States that are investigating the use of trametinib in the treatment of refractory and relapsed juvenile granulomonocytic leukemia.

Prognosis

1. General

Conventional chemotherapy for juvenile granulomonocytic leukemia is unsatisfactory, with a long-term survival rate of only 10%. Allogeneic hematopoietic stem cell transplantation can achieve an overall survival rate of more than 60%.

However, the majority of those with CBL germ cell mutations resolve spontaneously and usually have a favorable prognosis. Also, some children with low HbF expression and high platelet counts who are positive for somatic mutations in the N-RAS and K-RAS genes (e.g., NRASG12S and KRASG12V) with juvenile-type granulocytic mononuclear cells can survive for a longer period of time without transplantation.

Follow-up & Review

1. Review

Mildly ill patients can be left untreated and simply followed up for observation, or given a small dose of chemotherapy to follow up whether the disease is progressing or not, these children need lifelong follow-up to prevent the disease from progressing sharply. At present, the post-transplantation review and follow-up program adopted by most hospitals in China is:

● For 1 year after stopping the drug: review every 3 months or so.

● Years 2 to 3 after stopping the drug: review every 6 months or so.

● After 3 years of discontinuation: annual review.

Usually, the review after the end of transplantation includes a comprehensive general physical examination, laboratory tests, and disease-related genetic testing is an important monitoring indicator. In addition, follow-up of organ function and endocrine function is the main observation for children with long-term transplant survival.

2. Recurrence

Juvenile granulomonocytic leukemia is more prone to relapse, with a 30% relapse rate even after hematopoietic stem cell transplantation.

Routine

1. General

Complete the treatment as prescribed by the doctor, maintain good living habits and a clean living environment, and take care to prevent infection. Regular follow-ups should be conducted after completion of treatment to monitor recurrence and long-term adverse effects. Meanwhile, in daily life, children should be provided with a nutritionally balanced diet and encouraged to have moderate activities.

2. Home care

Since children under treatment often have reduced immunity, care should be taken to prevent infection. Pay attention to washing hands frequently, keeping food and drinking water clean and hygienic, and good living hygiene habits. Keep the living environment neat and clean, open windows regularly to maintain air circulation. Do not put fresh flowers and potted flowers indoors for the time being. Garbage cans should be covered and garbage should not be stored for more than 2 hours. At the same time, the contact between the child and the infected patient should be reduced, and the infection of the accompanying staff should also be noted. If someone in the family has a cold, contact with the child should be avoided as much as possible; if contact with the child is necessary, hand washing (with soap or hand sanitizer), wearing a mask and other protective measures must be done. At the same time, parents should pay attention to daily observation of the child's condition and seek medical attention as soon as possible if there are signs of infection or fever.

3. Management of daily life

1) Diet

Both during and after treatment, it is recommended to provide children with a nutritious and balanced diet, guaranteeing the intake of high-quality proteins (e.g., meat, eggs, milk, poultry, fish and shrimp, soybeans and soybean products, etc.), as well as more grains and cereals, vegetables and fruits, and moderate consumption of dairy products and nuts to ensure the intake of other nutrients. At the same time should eat less refined rice and white flour, deep-processed snacks and processed meats, control oil and salt.

In addition, during the treatment period, the child's immunity will be reduced and expired, spoiled, unclean and potentially food-safe foods should be avoided. Specific dietary advice can be obtained from the dietitian at your hospital.

2) Movement

If the physical condition of the child allows, you can encourage and assist the child to do some activities. Moderate exercise is helpful in preventing muscle atrophy, increasing physical strength and endurance, and promoting appetite.

Appropriate regular exercise is recommended after the child has finished treatment. If available, consider 30-60 minutes of moderate-intensity exercise per day (e.g., brisk walking, bicycling, yoga, table tennis, etc.) or a moderate amount of high-intensity exercise per week (e.g., running, swimming, jumping rope, aerobics, basketball, etc.).

3) Lifestyle

The patient needs to be guaranteed a sleep schedule. Regular and quality sleep is helpful for recovery and immunity. A suitable sleep environment (usually dimly lit, quiet, and at the right temperature) may be helpful in improving the patient's quality of sleep.

Studies have shown that children with leukemia have a higher risk of cardiovascular disease, metabolic disease, and secondary cancer in the long term than the general population. A healthy lifestyle, such as a balanced diet and moderate exercise, is the most important and effective means of preventing these diseases. Children are also advised to pay attention to weight control, as being overweight may increase the risk of developing cancer (e.g., breast, pancreatic, rectal, endometrial, etc.) later in life.

4. Daily condition monitoring

Side effects caused by radiotherapy (e.g., hair loss, fatigue, vomiting, etc.), recurrence of leukemia metastasis, and growth restriction need to be attended to. Consult your doctor when fever, worsening symptoms, new symptoms, and treatment-induced side effects occur.

5. Special Considerations

If the child's platelets are too low (usually less than 20x109 /L), care needs to be taken to avoid bleeding, to stay away from sharp, prickly toys and objects, and to avoid all impact sports (such as bouncing, soccer, basketball, etc.). When eating, avoid bones and other foods that tend to poke the mouth, and use a soft-bristled brush when brushing teeth. At the same time, for younger children, should try to avoid violent crying to avoid intracranial hemorrhage. In addition, take care to keep the child's bowels clear, and do not self-administer anal suppositories or measure anal temperature to avoid rectal bleeding. Do not give your child medications that tend to cause bleeding, such as aspirin or ibuprofen, unless your doctor recommends it. Some over-the-counter cold medicines may have ingredients such as ibuprofen that require special attention.

6. Prevention

Currently, there is no definitive prevention for juvenile granulomonocytic leukemia. If a child has a genetic disorder associated with juvenile granulomonocytic leukemia (e.g. neurofibromatosis type 1), he/she should be screened for juvenile granulomonocytic leukemia. In addition, parents should be aware of the early signs and symptoms of juvenile granulocytic leukemia and seek early medical attention for early detection and treatment in order to achieve the best possible outcome.

Cutting-edge Therapeutic & Clinical Research

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References

1. arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016. 127(20): 2391-2405.

2. Wan Z, Gao J. Pathogenesis and diagnostic criteria of juvenile granulomonocytic leukemia. Chinese Clinical Journal of Practical Pediatrics. 2013. 28(3): 229-230.

3. Gao J, Liu XL. Progress in the diagnosis and treatment of juvenile granulomonocytic leukemia. Chinese Journal of Maternal and Child Clinical Medicine. 2012. 8(5): 557-559.

4. Franco Locatelli, Charlotte M. Niemeyer; How I treat juvenile myelomonocytic leukemia. Blood 2015; 125 (7): 1083-1090. doi: https:// doi.org/10.1182/blood-2014-08-550483

5. Salem, CB et al. Acute lung injury and acute respiratory distress syndrome. Lancet. 2007. 370(9585): 383.

6. Lee-Chiong Jr, T, Matthay RA. Drug-induced pulmonary edema and acute respiratory distress syndrome. Clin Chest Med. 2004. 25: 95-104.

7. Manabe A, Okamura J, Yumura-Yagi K, et al.: Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the International JMML Working Group. Leukemia 16 (4): 645-9, 2002. leukemia diagnosed based on the criteria of the International JMML Working Group. Leukemia 16 (4): 645-9, 2002.

8. Niemeyer CM, Fenu S, Hasle H, et al.: Response: differentiating myelomonocytic leukemia from infectious disease. Blood 91(1): 365-367.

9. Vardiman JW, Pierre R, Imbert M, et al.: Juvenile myelomonocytic leukaemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Pathology and Genetics of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 55-7.

10. Emanuel PD: Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 22 (7): 1335-42, 2008.

11. Luna-Fineman S, Shannon KM, Atwater SK, et al.: Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood 93 (2) : 459-66, 1999. : 459-66, 1999.

12. Niemeyer CM, Arico M, Basso G, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood 89 (10): 3534-43, 1997.