Juvenile Myelomonocytic Leukemia
Disease Details
Family Health Simplified
- Description
- Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive form of leukemia that affects young children, characterized by the overproduction of myelomonocytic cells in the bone marrow.
- Type
- Juvenile myelomonocytic leukemia (JMML) is a type of pediatric leukemia characterized by the overproduction of myelomonocytic cells. It is typically associated with genetic conditions and mutations, including those in the PTPN11, NRAS, KRAS, CBL, and NF1 genes. The genetic transmission of JMML can be autosomal dominant, particularly when associated with inherited genetic syndromes like Noonan syndrome or neurofibromatosis type 1. However, it can also occur sporadically without a clear familial pattern.
- Signs And Symptoms
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The following symptoms are typical ones that lead to testing for JMML, though children with JMML may exhibit any combination of them:
pallor
fever
infection
bleeding
cough
poor weight gain
a maculopapular rash (discolored but not raised, or small and raised but not containing pus)
lymphadenopathy
moderate hepatomegaly
marked splenomegaly
leukocytosis
absolute monocytosis
anemia
thrombocytopeniaMost of these conditions show common nonspecific signs and symptoms.
Children with JMML and neurofibromatosis 1 (NF1) (about 14% of children with JMML are also clinically diagnosed with NF1, though up to 30% carry the NF1 gene mutation) may also exhibit any of the following symptoms associated with NF1 (in general, only young children with NF1 are at an increased risk of developing JMML):
6 or more café-au-lait (flat, coffee-colored) spots on the skin
2 or more neurofibromas (pea-size bumps that are noncancerous tumors) on or under the skin
Plexiform neurofibromas (larger areas on skin that appear swollen)
Optic glioma (a tumor on the optic nerve that affects vision)
Freckles under the arms or in the groin
2 or more Lisch nodules (tiny tan or brown-colored spots on the iris of the eye)
Various bone deformations including bowing of the legs below the knee, scoliosis, or thinning of the shin bone.Noonan syndrome (NS) may predispose to the development of JMML or a myeloproliferative disorder (MPD) associated with NS (MPD/NS), which resembles JMML in the first weeks of life. However, MPD/NS may resolve without treatment. Children with JMML and Noonan's syndrome may also exhibit any of the following most common symptoms associated with Noonan's syndrome:
Congenital heart defects, in particular, pulmonic stenosis (a narrowing of the valve from the heart to the lungs)
Undescended testicles in males
Excess skin and low hair line on back of neck
Widely set eyes
Diamond-shaped eyebrows
Ears that are low-set, backward-rotated, thick outer rim
Deeply grooved philtrum (upper lip line)
Learning delays - Prognosis
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Prognosis refers to how well a patient is expected to respond to treatment based on their individual characteristics at time of diagnosis. In JMML, three characteristic areas have been identified as significant in the prognosis of patients:
Without treatment, the survival rate of children under the age of five (5) of children with JMML is approximately 5%. Only Hematopoietic Stem Cell Transplantation (HSCT), commonly referred to as bone marrow or (umbilical) cord blood transplant, is successful in curing a child of JMML. With HSCT, recent research studies have found the survival rate to be approximately 50%. Relapse is a significant risk after HSCT for children with JMML. It is the most leading cause of death in JMML children who have had stem cell transplants. Relapse rate has been recorded as high as 50%. If the first treatment was not entirely successful, many children have been brought into remission after a doctor recommended second stem cell transplant.After bone marrow transplant, the relapse rate for children with JMML may be as high as 50%. Relapse often occurs within a few months after transplant, and the risk of relapse drops considerably at the one-year point after transplant. A significant number of JMML patients do achieve complete remission and long-term cure after a second bone marrow transplant, so this additional therapy should always be considered for children who relapse. - Onset
- Juvenile myelomonocytic leukemia (JMML) typically presents in early childhood, usually affecting children under the age of 4. It is a rare and aggressive form of leukemia characterized by the overproduction of myelomonocytic cells. Common symptoms at onset include pallor, fever, infection, easy bruising, enlargement of the spleen or liver, and skin rashes. Early diagnosis and intervention are critical for better outcomes.
- Prevalence
- Juvenile myelomonocytic leukemia (JMML) is a rare form of childhood leukemia. It affects approximately 1.2 cases per million children annually.
- Epidemiology
- Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive form of childhood leukemia. It predominantly affects children under the age of four, with a peak incidence in infants and toddlers. JMML is more common in boys than in girls with a male-to-female ratio of approximately 2:1. This rare disease accounts for about 1-2% of all childhood leukemias. There is a higher incidence of JMML in children with certain genetic conditions, such as Noonan syndrome and neurofibromatosis type 1.
- Intractability
- Juvenile myelomonocytic leukemia (JMML) is often considered challenging to treat due to its aggressive nature. Standard chemotherapy often has limited effectiveness, and the disease can be resistant to treatment. The preferred treatment is hematopoietic stem cell transplantation (HSCT), which offers the best chance for a cure. However, the outcomes can vary, and there is a risk of relapse even after HSCT. So, while it is not completely intractable, it is difficult to manage and requires specialized care.
- Disease Severity
- Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive form of childhood leukemia that affects young children, typically under the age of 4. The severity of JMML is significant as it progresses rapidly without treatment. Symptoms may include fever, rash, an enlarged spleen, liver, and lymph nodes, as well as anemia and high white blood cell counts. Treatment often involves hematopoietic stem cell transplantation (HSCT), but the prognosis can vary based on several factors, including age at diagnosis, genetic mutations, and response to initial treatment. Due to its aggressive nature, close monitoring and prompt, intensive treatment are crucial.
- Healthcare Professionals
- Disease Ontology ID - DOID:0050458
- Pathophysiology
- Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive myeloproliferative/myelodysplastic disorder that affects young children. The pathophysiology of JMML involves the uncontrolled proliferation of myelomonocytic cells. This condition is often associated with mutations in genes that regulate the RAS/MAPK signaling pathway, including PTPN11, NF1, NRAS, KRAS, and CBL. These genetic mutations lead to abnormal cell signaling, driving excessive growth and proliferation of immature myeloid cells and monocytes. The accumulation of these cells disrupts normal hematopoiesis, leading to symptoms such as anemia, thrombocytopenia, and organ infiltration.
- Carrier Status
- Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive form of leukemia that primarily affects young children. Carrier status is not generally a relevant concept for JMML because it is not typically inherited in a classic carrier sense. JMML often arises due to somatic mutations that occur in myeloid progenitor cells, and these mutations are not passed down from parents in a carrier state. However, certain genetic mutations or syndromes, such as neurofibromatosis type 1 (NF1) or Noonan syndrome, can increase the risk of developing JMML and might be inherited.
- Mechanism
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Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive form of leukemia that primarily affects young children. Here are the key details regarding its mechanism and molecular mechanisms:
### Mechanism:
JMML is characterized by the overproduction of myelomonocytic cells, a type of white blood cell, due to the dysregulation of signaling pathways that control cell growth and differentiation. This causes an excessive proliferation of these cells in the bone marrow, leading to their accumulation in various tissues and organs.
### Molecular Mechanisms:
1. **RAS Pathway Mutations**: Many cases of JMML involve mutations in genes that are part of the RAS signaling pathway, which regulates cell growth and survival. Common mutations include those in the **NRAS**, **KRAS**, and **PTPN11** genes, as well as the **NF1** gene which is involved in neurofibromatosis type 1.
2. **PTPN11 Mutations**: PTPN11 is the gene encoding for the protein tyrosine phosphatase SHP-2, which plays a role in cell signaling. Mutations in PTPN11 lead to increased and prolonged RAS/MAPK signaling, promoting uncontrolled cell proliferation.
3. **GM-CSF Hypersensitivity**: Cells from JMML patients often show hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that promotes the survival and proliferation of myeloid cells. This hypersensitivity is linked to the downstream effects of the molecular mutations in the RAS pathway.
4. **Epigenetic Alterations**: DNA methylation changes and other epigenetic modifications have also been observed in JMML, contributing to the dysregulated expression of genes involved in cell cycle control and apoptosis.
5. **Other Genetic Mutations**: Additional mutations may occur in other components of the RAS signaling pathway and related pathways, including **CBL**, **JAK3**, and **SETBP1**.
Understanding these molecular mechanisms is crucial for developing targeted therapies and improving the prognosis for children affected by JMML. - Treatment
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There are two widely used JMML treatment protocols: stem cell transplantation and drug therapy. There are four common subtypes of internationally accepted treatment protocols, which are based and clinically tested in the geographical location of the patient:
North America: the Children's Oncology Group (COG) JMML study
Europe: the European Working Group for Myelodysplastic Syndromes (EWOG-MDS) JMML studyThe following procedures are used in one or both of the current clinical approaches listed above: - Compassionate Use Treatment
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Juvenile Myelomonocytic Leukemia (JMML) is a rare and serious childhood leukemia.
**Compassionate Use Treatment:**
Compassionate use, also known as expanded access, allows for the use of investigational drugs outside of clinical trials. In JMML, compassionate use might include access to newly developed targeted therapies or immune-based treatments that are still under investigation.
**Off-label or Experimental Treatments:**
1. **Azacitidine:** While primarily approved for myelodysplastic syndromes, it has been used off-label in JMML to promote differentiation of the abnormal cells.
2. **Farnesyltransferase Inhibitors (e.g., Tipifarnib):** These inhibitors are used experimentally to target specific genetic mutations associated with JMML.
3. **MEK Inhibitors:** Such as trametinib, have shown promise in targeting specific pathways involved in JMML.
Participation in clinical trials might provide access to new treatments that are being actively studied in JMML.
Treatment options should always be discussed with a qualified healthcare provider to consider the benefits and risks and align with the child's specific medical condition. - Lifestyle Recommendations
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Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive form of childhood leukemia. Lifestyle recommendations for children with JMML primarily focus on supporting overall health and well-being during and after treatment. Consider the following:
1. **Balanced Diet**: Ensure a nutritious diet rich in fruits, vegetables, whole grains, and lean proteins. This helps maintain strength and supports the immune system.
2. **Physical Activity**: Encourage light to moderate physical activity as tolerated. Activities like walking, playing, and light exercise can improve mood and overall fitness, but always follow the healthcare provider’s guidelines.
3. **Adequate Rest**: Ensure the child gets plenty of rest. Fatigue is common due to the disease and its treatment.
4. **Infection Prevention**: Maintain good hygiene practices and avoid exposure to infections. Frequent hand washing and avoiding crowds during high-risk periods can help.
5. **Emotional Support**: Provide emotional and psychological support. Consider counseling services or support groups for coping with the stress and emotional challenges.
6. **Follow Medical Advice**: Adhere strictly to the treatment plan and follow-up appointments advised by the healthcare team.
7. **Hydration**: Keep the child well-hydrated to help their body manage treatment side effects.
These recommendations aim to improve the quality of life and support the child’s body in coping with the disease and its treatments. Always consult with the healthcare team for personalized advice. - Medication
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For juvenile myelomonocytic leukemia (JMML), medication options are generally limited, as this type of leukemia is often more resistant to standard chemotherapy than other forms of leukemia. However, some treatments used include:
1. **Azacitidine and Decitabine:** These are hypomethylating agents that can be used to manage symptoms and control the progression of the disease in some patients.
2. **Hydroxyurea:** This medication may help to reduce white blood cell counts and control disease symptoms.
3. **Stem Cell Transplantation:** While not a medication, allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective treatment for achieving long-term remission in JMML.
Research is ongoing to find more effective targeted therapies for JMML. Early consultation with a pediatric oncologist is crucial for the management of this condition. - Repurposable Drugs
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Juvenile Myelomonocytic Leukemia (JMML) is a rare and aggressive form of leukemia that primarily affects young children. While standard treatments typically involve hematopoietic stem cell transplantation, various drugs have been explored for repurposing to treat JMML. These include:
1. **Azacitidine** - An epigenetic modifier that has shown promise in treating JMML by targeting the abnormal methylation patterns in leukemia cells.
2. **Sorafenib** - A kinase inhibitor that targets multiple pathways often dysregulated in JMML, including the RAS/RAF/MEK/ERK pathway.
3. **Trametinib** - Another kinase inhibitor focusing on MEK, which is part of the MAPK pathway commonly mutated in JMML.
4. **Selumetinib** - Similar to trametinib, it targets the MEK pathway and has been investigated for its efficacy in JMML treatment.
When considering these repurposable drugs, patient-specific factors such as genetic mutations and overall health must be taken into account to optimize treatment outcomes. - Metabolites
- Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive form of leukemia that affects young children. It involves the overproduction of myelomonocytic cells, a type of white blood cell. In diagnosing and monitoring the disease, certain metabolites and metabolic pathways may be of interest, though specific metabolites unique to JMML are not well-defined in current medical literature. Further research is necessary to identify specific metabolic markers that are directly associated with JMML.
- Nutraceuticals
- There is no well-established evidence or consensus to support the use of nutraceuticals (food products that provide health benefits) for treating juvenile myelomonocytic leukemia (JMML). JMML is a rare and aggressive form of leukemia that primarily affects young children. Standard treatments generally include hematopoietic stem cell transplantation. Nutraceuticals should not replace conventional medical treatments and any supplementary therapies should be discussed with a healthcare provider.
- Peptides
- For juvenile myelomonocytic leukemia (JMML), treatment options primarily include hematopoietic stem cell transplantation (HSCT). Research into peptides and nanoparticles (nan) is ongoing, exploring their potential roles in targeted therapies and drug delivery systems. However, as of now, these advanced treatments are not standard care for JMML but may hold promise for future therapeutic developments.