NF1-associated juvenile myelomonocytic leukemia (NF1-JMML) is a rare blood cancer that happens in young children who already have neurofibromatosis type 1 (NF1). In this disease, early white blood cells called monocytes and myelomonocytic cells grow in an uncontrolled way in the bone marrow and blood. In NF1-JMML, the child is born with a change (mutation) in the NF1 gene, which normally makes a protein called neurofibromin. Neurofibromin helps keep a control “brake” on a growth signal inside the cell called the RAS pathway. When NF1 does not work, this brake is weak, the RAS pathway becomes overactive, and bone-marrow cells can grow too fast and form leukemia.
NF1-associated juvenile myelomonocytic leukemia (JMML) is a rare blood cancer that happens in young children who already have neurofibromatosis type 1 (NF1), a genetic condition caused by changes in the NF1 gene. NF1 normally helps control a growth pathway in cells called the RAS–MAPK pathway; when NF1 does not work properly, this pathway is over-active and blood stem cells in the bone marrow grow and survive too much.
JMML itself is a myelodysplastic/myeloproliferative disease, meaning the bone marrow both makes too many immature white blood cells (especially monocytes and granulocytes) and also fails to make normal, healthy blood cells. Children often have high white blood cell counts, anemia, low platelets, big spleen and liver, and symptoms like fever, infections, bleeding, poor growth, and tiredness.
About 10–15% of children with JMML are clinically diagnosed with NF1, and NF1 mutations are found in up to about one-third of cases. Children with NF1 have a very high (hundreds-fold) increased risk of JMML compared with children without NF1.
JMML, including NF1-associated JMML, is driven in almost all patients by changes in genes that turn on the RAS–MAPK pathway (for example NF1, NRAS, KRAS, PTPN11, CBL). This over-signaling pushes myeloid cells to grow and divide when they should stop. Because of this biology, the main curative treatment is usually early allogeneic hematopoietic stem cell transplantation (HSCT), often recommended quickly (“swift HSCT”) in children with NF1-associated disease.
NF1-JMML usually appears in babies and very young children under 4 years of age. Many children have a very large spleen, a large liver, anemia, high white blood cell count, and very high monocyte count in the blood. It is an aggressive disease and often needs a stem-cell (bone-marrow) transplant to give the child the best chance of cure.
Other names
Doctors may use several names or phrases for this condition. All of them describe the same or very closely related situations:
NF1-associated juvenile myelomonocytic leukemia
NF1-JMML
JMML in a child with neurofibromatosis type 1
NF1-related myeloproliferative / myelodysplastic disorder of childhood
RAS-pathway–driven JMML with germline NF1 mutation
More broadly, NF1-JMML belongs to the group called “juvenile myelomonocytic leukemia,” which itself is part of the World Health Organization (WHO) category “myelodysplastic/myeloproliferative neoplasms of childhood.”
Types
Doctors often group JMML into types based on which gene in the RAS pathway is changed. NF1-JMML is one of these genetic types:
PTPN11-mutated JMML – JMML where the main change is in the PTPN11 gene.
NRAS-mutated JMML – JMML driven mainly by changes in the NRAS gene.
KRAS-mutated JMML – JMML driven mainly by changes in the KRAS gene.
CBL-mutated JMML – JMML due to changes in the CBL gene.
NF1-associated JMML – JMML in a child with a germline NF1 mutation and additional hits in NF1 or related genes; this is the focus of this article.
These types all share common features, such as high monocyte count and big spleen, but NF1-JMML happens specifically in children who already have NF1, and they may also show typical NF1 skin and nerve signs.
Causes / Contributing factors
Here “cause” means any factor that can lead toward NF1-JMML in a child with NF1. The true main cause is gene and cell-signal changes, but many steps are involved.
Germline NF1 mutation (inherited)
Many children with NF1-JMML inherit a faulty NF1 gene from a parent. NF1 is an autosomal-dominant disorder, so only one changed copy is enough to cause NF1. This built-in gene error sets the stage for leukemia if extra changes later happen in bone-marrow cells.New (de novo) NF1 mutation in the child
Some children develop NF1 even though neither parent has NF1. In these cases, the NF1 mutation appears for the first time in the child (de novo). These children still carry the same high leukemia risk as those who inherit NF1.Loss of the second NF1 copy in bone-marrow cells (biallelic inactivation)
NF1 patients are born with one normal and one faulty NF1 copy. If a bone-marrow cell later loses or damages the remaining good NF1 copy (through events like mitotic recombination), that cell is left with no working NF1. This “second hit” greatly increases the chance that the cell will grow in an uncontrolled way and form JMML.RAS-MAPK pathway over-activation
Without enough neurofibromin, the RAS-MAPK signaling pathway is stuck in a more “on” state. This pathway controls growth and survival of blood-forming cells. When it is over-active for a long time, myelomonocytic cells can grow too much and ignore normal stop signals, leading to JMML.Abnormal sensitivity to GM-CSF (growth factor)
JMML cells often show strong, abnormal response to a growth factor called granulocyte-macrophage colony-stimulating factor (GM-CSF). With NF1 loss, myeloid progenitor cells can become hypersensitive to GM-CSF, so even normal levels of this signal cause extra growth, helping leukemia to develop.Extra somatic mutations in RAS genes (KRAS or NRAS)
Some JMML cases acquire new (somatic) mutations in KRAS or NRAS inside bone-marrow cells. These changes keep RAS switched on. In rare situations, children with NF1 may also gain such RAS mutations in their leukemia cells, further driving disease.Somatic mutations in PTPN11 or CBL
PTPN11 and CBL are other genes in the same signaling network as NF1. Changes in these genes can also activate RAS signaling. While mutations in NF1, RAS, PTPN11, or CBL are usually mutually exclusive in classic JMML, the same pathways are involved; their disruption is a core cause of the disease.Monosomy 7 (loss of one copy of chromosome 7)
Many children with JMML have loss of one whole copy of chromosome 7 (monosomy 7) or other changes in this chromosome. Chromosome 7 contains several genes important for normal blood-cell control. When one copy is missing in a child with NF1, it can help push bone-marrow cells toward leukemia.Other clonal chromosome abnormalities
JMML cells may also show other stable chromosome changes, such as translocations or extra copies of certain chromosomes. These changes can disrupt genes that control cell growth and death and add to the effect of the NF1 mutation.Clonal expansion of myelomonocytic stem cells
In NF1-JMML, one early blood-forming stem cell that has multiple hits (NF1 plus other changes) begins to copy itself more than normal. All daughter cells carry the same gene errors, creating a “clone” that fills the bone marrow and blood with abnormal myelomonocytic cells.Very young age and developing bone marrow
JMML usually appears in babies or toddlers under 4 years old. Their bone marrow and immune systems are still developing and may be more vulnerable to the effects of NF1 and RAS-pathway activation, which may make it easier for leukemia to emerge.Overall increased risk of leukemia in NF1
Children with NF1 have a much higher risk of JMML and other myeloid cancers compared with the general population. Studies suggest a several-hundred-fold increased risk of JMML in NF1, showing that the NF1 mutation itself is a strong cause.Family history and genetic background
A child whose parent has NF1 may inherit both the NF1 mutation and other subtle gene differences that affect how cells respond to growth signals or repair DNA damage. These background factors may slightly change the risk or behavior of NF1-JMML.Large NF1 microdeletions
Some people have large deletions that remove not only NF1 but also nearby genes on chromosome 17. These “microdeletions” are linked with more severe NF1 and higher tumor risk, and may also increase the chance that JMML will develop.Chronic inflammatory signals in NF1
NF1-related tumors and tissue changes can release inflammatory molecules and growth factors into the blood. These signals may act on bone-marrow cells that already lack NF1, promoting their survival and growth and helping a leukemic clone to expand.Immune system dysregulation
NF1 is associated with subtle immune changes and increased risk of infections and tumors. An immune system that does not control abnormal cells well may allow early leukemic cells to survive longer and build up in the marrow.Second primary tumors and treatment stress
Some NF1 children develop other tumors (like optic gliomas or nerve-sheath tumors) and may need chemotherapy or radiotherapy. Treatments that damage DNA can add extra stress to bone-marrow cells and may contribute to leukemia development in a child whose cells already lack full NF1 protection.Random DNA errors during cell division
Bone-marrow stem cells divide many times. Each division carries a small chance of extra DNA errors. In a background of NF1 haploinsufficiency, these random mutations are more likely to create a harmful combination that leads to JMML.Unknown modifier genes
Research suggests there may be other genes, not yet fully known, that change how strongly NF1 mutations affect the RAS pathway and tumor risk. These “modifier” genes may help explain why only a small part of NF1 children develop JMML.Still-unknown environmental or biological factors
For many NF1-JMML cases, no clear trigger other than the NF1 and RAS-pathway changes is found. Doctors believe that additional, still-unknown internal or environmental factors may play a smaller role, but current evidence points mainly to genetic and cell-signal causes.
Symptoms
Below are common symptoms seen in JMML, including NF1-associated cases. A child may have some or many of them.
Pale skin (pallor)
Low red blood cells (anemia) make the child look pale or “washed out,” especially on the face, lips, and inside the eyelids. This happens because the bone marrow is busy making abnormal white cells instead of healthy red cells.Tiredness and weakness (fatigue)
Anemia and active disease make children feel very tired, weak, or less active than usual. They may want to sleep more, play less, or become easily out of breath when moving.Fever
Many children with JMML have repeated or long-lasting fever. Fever can come from infections because immunity is weak, or from the leukemia itself, which releases inflammatory chemicals.Frequent or severe infections
Because abnormal leukemia cells crowd out healthy white blood cells, the body cannot fight germs well. The child may have repeated coughs, chest infections, ear infections, or other illnesses that are slow to recover.Easy bruising or bleeding
Low platelet counts make bruises appear easily, even after small bumps. There may be nosebleeds, gum bleeding, or tiny red or purple spots on the skin (petechiae).Cough and breathing problems
Very large spleen or liver and high white cell counts can affect breathing. Some children get cough, fast breathing, or chest discomfort, especially if there is lung infection or enlarged lymph nodes inside the chest.Poor weight gain or weight loss
JMML often causes poor appetite, early feeling of fullness (because of big spleen), and increased body energy use. Children may not gain weight as expected or may even lose weight.Skin rash
A flat or small raised red rash can appear on the body. This rash is often due to leukemia cells entering the skin, a feature seen in many JMML patients.Enlarged spleen (splenomegaly)
A very large spleen is one of the most important signs of JMML. The spleen can grow so big that it fills much of the left side of the child’s abdomen and can be easily felt by the doctor. It often causes a tight, swollen belly and discomfort.Enlarged liver (hepatomegaly)
Many children also have a bigger liver. This adds to abdominal swelling and may cause pain in the upper right side of the belly.Swollen lymph nodes (lymphadenopathy)
Lymph nodes in the neck, armpits, or groin may become enlarged, soft, and rubbery. This can be from leukemia cells or from repeated infections.Bone or joint pain
Some children complain of aches in bones or joints. This can be due to crowded bone marrow or to inflammation in the tissues around the joints.Irritability and fussiness
Constant tiredness, discomfort from enlarged organs, and feeling unwell can make babies and toddlers more irritable, crying more than usual or not wanting to be held.Typical NF1 skin signs
Because these children have NF1, they often have café-au-lait spots (light brown flat patches) and sometimes soft skin tumors called neurofibromas. These are not caused by leukemia but help doctors suspect NF1-JMML when blood changes appear.Large belly and poor comfort when eating
A very large spleen and liver push on the stomach and intestines. The child may feel full after only a few bites and may complain of tummy pain or look uncomfortable when lying on the stomach.
Diagnostic tests
Doctors use many tests together to diagnose NF1-JMML, to rule out other diseases, and to plan treatment. There are no home tests; all must be done by health professionals.
Physical examination tests
Full physical examination
The doctor carefully checks the child’s general health. They look at the color of the skin, breathing pattern, heart rate, temperature, and overall activity. This helps detect pallor, fever, and signs of infection or bleeding that suggest leukemia.Abdominal exam for spleen and liver size
By gently feeling (palpating) and tapping (percussing) the abdomen, the doctor checks how far the spleen and liver extend below the ribs. A big spleen is required for the diagnosis of JMML and is a key sign of NF1-JMML.Skin and mucous-membrane exam
The doctor looks for bruises, tiny red spots, rashes, and gum or nose bleeding. They also check for café-au-lait spots and neurofibromas that show NF1. These findings link the blood problem to NF1 and support the diagnosis of NF1-JMML.Lymph-node and general exam
Lumps in the neck, armpits, or groin are checked by touch. The doctor also listens to the chest and heart and checks for signs of chest infection or heart strain, which can occur in advanced leukemia.
Manual (bedside) tests
Manual spleen size follow-up
Over time, doctors repeatedly feel the spleen to see if it is growing or shrinking. This simple bedside test helps tell whether the disease is getting better or worse with treatment.Manual growth and nutrition assessment
Weight, height, and head size are measured and plotted on growth charts. Slow growth or weight loss shows the long-term impact of the disease and helps guide nutrition support.Manual vital-sign checks (pulse, breathing, blood pressure)
Regular bedside checks of heart rate, breathing rate, and blood pressure show how the child is coping. Very fast heart rate or breathing can suggest severe anemia, infection, or pain.Simple neurologic exam
Because NF1 can affect the brain and nerves, doctors check movement, strength, reflexes, and coordination. This exam helps detect other NF1-related problems and establishes a baseline before treatments like chemotherapy.
Laboratory and pathological tests
Complete blood count (CBC) with differential
CBC is a key test. It measures numbers of red cells, white cells, platelets, and types of white cells. In JMML there is high white cell count, high monocyte count (≥1×10⁹/L), anemia, and often low platelets. The pattern strongly suggests JMML when seen with big spleen and young age.Peripheral blood smear
A drop of blood is examined under the microscope. The lab doctor looks for immature myeloid cells, monocytes, and abnormal shapes. Seeing many myeloid precursors and monocytes helps confirm JMML and rules out other leukemias.Bone-marrow aspiration and biopsy
Bone marrow is taken, usually from the hip bone, using a needle. Under the microscope, doctors see increased myelomonocytic cells but less than 20% blast cells (immature blasts). This pattern, along with NF1 and blood findings, supports the diagnosis of JMML.Cytogenetic analysis and karyotyping
Chromosomes in the bone-marrow cells are studied to look for monosomy 7 or other clonal changes. Finding monosomy 7 or another stable abnormality is one of the important criteria for JMML and can also guide prognosis.Molecular testing for NF1 and RAS-pathway mutations
Advanced tests such as sequencing or targeted gene panels look for NF1 gene changes and other RAS-pathway mutations (KRAS, NRAS, PTPN11, CBL). In NF1-JMML, there is a germline NF1 mutation, and many cases show biallelic NF1 loss in leukemia cells. This confirms the NF1-associated subtype.Hemoglobin F (fetal hemoglobin) level
Many JMML children have higher than normal fetal hemoglobin for their age. Measuring HbF adds evidence when other major criteria are present and helps distinguish JMML from other blood problems.Basic blood chemistry and liver-function tests
Tests such as electrolytes, kidney-function, and liver-enzymes help show how organs are coping with the disease. They also provide a baseline before starting chemotherapy or a transplant.Coagulation (clotting) tests
Tests like prothrombin time and activated partial thromboplastin time can show if the blood is clotting normally. Serious clotting problems may appear in some advanced leukemia cases or with infection and are important to detect early.
Electrodiagnostic tests
Electrocardiogram (ECG)
An ECG records the electrical activity of the heart. Children with leukemia may receive drugs (such as anthracycline chemotherapy) that can stress the heart. An ECG, often together with an echocardiogram, gives a baseline and helps monitor for heart rhythm or function problems during and after treatment.Nerve-conduction studies (NCS) when needed
NF1 can be associated with peripheral neuropathy (nerve damage), and some treatments may also affect nerves. Nerve-conduction studies measure how fast and how well nerves carry signals. They are not routine for JMML diagnosis but may be used if the child has weakness, numbness, or other nerve symptoms.
Imaging tests
Abdominal ultrasound
Ultrasound uses sound waves to create pictures of the inside of the body. It is very useful to measure the size of the spleen and liver, to look for enlarged abdominal lymph nodes, and to follow changes over time during and after treatment.Chest X-ray or chest CT scan
Imaging of the chest can show lung infections, fluid around the lungs, and enlarged lymph nodes. This helps doctors evaluate breathing problems, plan treatment, and look for complications related to JMML and its therapy.
Non-pharmacological treatments (therapies and other approaches)
Care in a specialist JMML / NF1 center
Children with NF1-associated JMML benefit greatly from care in a pediatric center that has experience with both NF1 and JMML, because decisions about timing of HSCT, bridge therapy, and NF1-related complications are complex. A specialist team can coordinate oncology, hematology, NF1 experts, transplant, and supportive care in one place.Multidisciplinary team care
A full team usually includes pediatric oncologists, transplant specialists, neurologists and dermatologists for NF1, nurses, dietitians, physiotherapists, psychologists, and social workers. Working together, they build a single plan that covers leukemia control, NF1 monitoring, school life, and family support, reducing conflicting advice and missed problems.Close monitoring and early HSCT planning
In NF1-associated JMML, guidelines suggest not waiting too long, because the disease can progress quickly. Regular blood tests, spleen and liver checks, bone marrow tests, and genetic studies allow the team to judge the best moment for HSCT and to avoid both unnecessary delay and unsafe rush.Transfusion support (red cells and platelets)
Children often have anemia and low platelets. Red blood cell transfusions improve oxygen carrying capacity, reduce tiredness, and help growth, while platelet transfusions reduce bruising and bleeding risk, especially before procedures or when counts are very low. This does not cure JMML, but it stabilizes the child so that definitive treatments like HSCT are safer.Infection prevention and hygiene measures
Because JMML and its treatments weaken immunity, families are taught careful hand-washing, avoiding sick contacts, food safety (well-cooked foods, safe water), and early reporting of fever. In hospital, staff use protective isolation and infection-control policies to cut the chance of life-threatening infections before and after transplant.Central venous catheter care
Many children need a central line (port or Hickman) for chemotherapy, transfusions, and blood draws. Non-drug care includes regular sterile dressing changes, line flushing, and watching for redness, pain, or fever. Good line care reduces catheter infections and clots, which can be serious in immunocompromised children.Physiotherapy and gentle exercise
Long hospital stays and steroids or chemotherapy can weaken muscles and bones. Tailored physiotherapy and light daily activity help maintain strength, joint movement, and balance, and can reduce fatigue and improve mood. Exercise plans are adjusted to blood counts and infection risk so they are safe.Nutritional support and feeding programs
Children with JMML and NF1 may have poor appetite, weight loss, or feeding difficulties. Dietitians design high-calorie, high-protein, easy-to-digest meals and snacks; when needed, tube feeding or special formulas are used. Good nutrition supports immune function, healing after HSCT, and overall growth and development.Oral and dental care
Chemotherapy and low blood counts increase the risk of mouth sores, gum bleeding, and infections. Regular gentle tooth-brushing with a soft brush, mouth rinses, and early dental assessments help prevent severe mucositis and dental problems, making eating easier and lowering infection risk.Psychological and emotional support
NF1-associated JMML is frightening for children and families, and NF1 alone can already cause learning and emotional challenges. Psychologists and counselors provide age-appropriate explanations, coping strategies, and support for anxiety and depression, while helping parents manage stress and decision-making.Educational support and school coordination
Because treatment is long, children may miss school and fall behind. Hospital teachers and school liaison staff help adapt teaching plans, provide homework support, and plan gradual reintegration to class. This maintains normal development and gives the child a sense of routine and future.Genetic counseling for the family
NF1 is usually an autosomal dominant condition with a 50% chance of being passed to children. Genetic counselors explain inheritance, recurrence risk, and testing options, and help relatives understand why NF1 increases JMML risk and what surveillance is recommended for family members.Skin and eye surveillance for NF1 complications
Even while treating JMML, NF1-related tumors (plexiform neurofibromas, optic pathway gliomas) and skin changes need monitoring. Regular dermatology and ophthalmology checks help detect new problems early and guide decisions about surgery or targeted therapies for NF1 complications.Avoidance of unnecessary radiation exposure
Children with NF1 already have an increased cancer risk, so teams try to minimize radiation from imaging (for example using ultrasound or MRI when possible instead of CT) and avoid radiotherapy unless absolutely required. This reduces long-term secondary cancer risk.Fertility preservation discussions
Conditioning regimens for HSCT (such as busulfan and cyclophosphamide) can damage fertility. When age and timing allow, specialists talk with families about options such as sperm banking in adolescents or ovarian tissue preservation in selected cases, helping families make informed decisions before treatment.Pain, symptom, and palliative care services
Palliative care is not only for end-of-life; it focuses on comfort and quality of life during the whole illness. This team helps with pain, nausea, sleep problems, and difficult emotions, and supports family communication and decision-making alongside active leukemia treatment.Activity and injury prevention with enlarged spleen
Many children with JMML have a very big spleen, which can rupture if hit. Families are advised to avoid rough sports, contact activities, and falls. Seat belts and protective measures are emphasized, and any sudden left-upper-abdominal pain or shoulder tip pain is treated as an emergency.Structured home monitoring plans
Parents are taught how to check temperature, look for bleeding, bruises, breathing problems, and behavior changes, and how to respond. Clear “action plans” for when to go to hospital (for example any fever above the threshold given by the team) improve safety and reduce delay in treatment.Social work and financial counseling
Long cancer treatment affects income, travel costs, and housing. Social workers help families access financial aid, housing near transplant centers, and practical support. This reduces stress so caregivers can focus more on the child’s health.Participation in clinical trials
Because NF1-associated JMML is rare and standard options are limited, families may be offered clinical trials for new drugs or transplant strategies, such as MEK inhibitors or modified conditioning regimens. Trials provide access to promising therapies and help improve future care, but risks and benefits must be carefully discussed.
Drug treatments
Important: Doses for these hospital-only medicines come from official prescribing information and leukemia/transplant guidelines. They are always adjusted by pediatric specialists for age, weight, organ function, and combination regimens. Never change or start any medicine without your oncology team.
Azacitidine (Vidaza / azacitidine for injection)
Azacitidine is a hypomethylating agent and is currently the only drug specifically approved in the United States for children with newly diagnosed JMML, including those with NF1, given as IV infusion once daily on days 1–7 of 28-day cycles (often 3–6 cycles and sometimes as a bridge to HSCT). It works by changing DNA methylation, turning back on genes that control growth and death in leukemia cells. Common side effects include low blood counts, nausea, vomiting, and injection-site reactions.Trametinib (Mekinist)
Trametinib is an oral MEK1/2 inhibitor originally approved for BRAF-mutated solid tumors, but phase II trials in children with relapsed or refractory JMML showed about half of patients responding and many using it as a bridge to HSCT. It blocks MEK in the RAS–MAPK pathway, slowing abnormal cell signaling downstream of NF1 loss. Typical study dosing is a daily oral dose adjusted for body weight; side effects include rash, diarrhea, heart function changes, and eye problems, so close monitoring is required.Cytarabine (Ara-C)
Cytarabine is a nucleoside analog chemotherapy used in some JMML protocols as a cytoreductive agent before transplant or in relapse. It gets built into DNA of dividing cells and stops DNA synthesis, leading to cell death. It is usually given by IV infusion in cycles; main toxicities include low blood counts, infections, mouth sores, and at high doses, neurologic or eye side effects, so dosing must follow pediatric leukemia protocols.Fludarabine phosphate (Fludara / fludarabine phosphate injection)
Fludarabine is a purine analog often used in reduced-intensity and some standard conditioning regimens for HSCT in JMML. It damages DNA and interferes with repair and synthesis in lymphoid and myeloid cells, helping create space in the marrow and suppressing immunity so donor cells can engraft. Typical conditioning doses are IV over several days; side effects include profound immune suppression, infections, neurotoxicity, and kidney-related dose adjustments.Busulfan (Busulfex / busulfan injection)
Busulfan is an alkylating agent widely used in myeloablative conditioning for pediatric HSCT. It cross-links DNA in dividing marrow cells, causing deep but controlled marrow suppression so donor stem cells can take over. It is given as an IV infusion with doses carefully adjusted using blood level monitoring (therapeutic drug monitoring). Main toxicities are severe low blood counts, liver injury (veno-occlusive disease), seizures (prophylaxis is used), and long-term fertility effects.Melphalan (Evomela / melphalan injection)
Melphalan is another alkylating agent used in some conditioning regimens for HSCT, alone or with busulfan or fludarabine. It cross-links DNA to kill dividing cells and help achieve marrow ablation. Doses are given IV over one or two days before transplant. Typical side effects include severe bone marrow suppression, nausea, hair loss, and mucositis; high-dose use requires careful kidney and liver monitoring.Cyclophosphamide
Cyclophosphamide is an alkylating agent and immunosuppressant used in some JMML transplant conditioning regimens together with busulfan, and later as part of graft-versus-host disease prophylaxis in some protocols. It is activated in the liver and cross-links DNA. Side effects include low blood counts, bladder irritation (hemorrhagic cystitis, so hydration and mesna are used), nausea, hair loss, and long-term fertility issues.Treosulfan (treosulfan for injection)
Treosulfan is an alkylating agent increasingly used as a less-toxic conditioning drug in children who need HSCT, including those with JMML, often in combination with fludarabine and/or thiotepa. It causes DNA cross-linking but may have a more favorable toxicity profile in some pediatric studies. Side effects include profound marrow suppression, infections, mucositis, and organ toxicity, so dosing is strictly protocol-based.Thiotepa
Thiotepa is an alkylating agent sometimes added to busulfan or treosulfan-based conditioning to intensify anti-leukemic effect. It can cross the blood–brain barrier and helps clear residual JMML cells. It is given IV, often 1–2 days before transplant; common toxicities are bone marrow suppression, skin redness/peeling, mucositis, and risk of infections.Mycophenolate mofetil
This immunosuppressant is often used after HSCT together with calcineurin inhibitors to prevent or treat graft-versus-host disease (GVHD). It blocks purine synthesis in lymphocytes, reducing donor immune attack against the child’s tissues while allowing some graft-versus-leukemia effect. Side effects include gastrointestinal upset, infections, low blood counts, and teratogenicity; doses are weight-based and adjusted by transplant teams.Cyclosporine
Cyclosporine is a calcineurin inhibitor given orally or IV after HSCT to prevent GVHD by blocking T-cell activation. In NF1-associated JMML, it is part of standard transplant care rather than direct leukemia treatment. Side effects include high blood pressure, kidney dysfunction, tremor, and gum overgrowth, so drug levels and kidney function are closely monitored.Tacrolimus
Tacrolimus is another calcineurin inhibitor used similarly to cyclosporine, sometimes preferred based on center experience. It blocks calcineurin-dependent activation of T-cells, reducing GVHD risk. It is given IV or orally with level monitoring; side effects include kidney problems, tremors, high blood pressure, high blood sugar, and infection risk.Methotrexate (low-dose post-transplant)
Low-dose methotrexate is commonly given on specific days after HSCT, together with calcineurin inhibitors, to prevent GVHD. It interferes with folate metabolism and DNA synthesis in rapidly dividing T-cells. Side effects at these doses include mucositis, liver enzyme elevation, and delayed blood count recovery, so careful timing and supportive care are essential.Granulocyte-colony stimulating factor (G-CSF)
G-CSF is a growth factor sometimes used after HSCT or intensive therapy to help white blood cells recover faster. It binds to receptors on bone marrow precursors and speeds up neutrophil production. Benefits include shorter neutropenia and fewer infections in some settings, but use is balanced carefully in leukemia because of concerns about stimulating malignant cells, so decisions are individualized.Broad-spectrum intravenous antibiotics
When a child with JMML has fever and low neutrophils, immediate IV antibiotics such as a broad-spectrum beta-lactam (for example piperacillin–tazobactam or cefepime, chosen by local guidelines) are life-saving. These drugs kill or stop growth of many bacteria while cultures are pending. Side effects include allergic reactions, diarrhea, and selection of resistant organisms.Antifungal agents (for example, fluconazole, echinocandins)
Children with prolonged neutropenia or HSCT often receive antifungals to prevent or treat invasive fungal infections. These medicines block fungal cell membrane or cell wall synthesis. They are given orally or IV depending on the drug and situation; side effects include liver enzyme changes, drug interactions, and, for some agents, kidney or heart effects.Antiviral agents (for example, acyclovir, ganciclovir)
After HSCT, latent viruses such as herpes simplex or cytomegalovirus can reactivate. Antiviral drugs block viral DNA replication and are used as prophylaxis or treatment, guided by viral blood tests. Side effects may include kidney injury, low blood counts, and neurologic symptoms at high doses, so monitoring is frequent.Trimethoprim–sulfamethoxazole (PJP prophylaxis)
This combination antibiotic is commonly used to prevent Pneumocystis jirovecii pneumonia in immunocompromised children, including those with JMML or post-HSCT. It interferes with folate metabolism in the organism. It is usually given a few days per week; side effects include allergic rash, low blood counts, and, rarely, serious skin reactions, so doctors watch closely.Intravenous immunoglobulin (IVIG)
IVIG may be used in selected children with low immunoglobulin levels and recurrent infections, especially after transplant. It provides pooled antibodies from donors, offering short-term passive immunity against many infections. Side effects include headache, flushing, infusion reactions, and, rarely, kidney problems or clotting; premedication and slow infusion reduce risks.Corticosteroids (for example, prednisone, methylprednisolone)
Steroids are not primary antileukemic drugs in JMML, but they are often used to treat GVHD, allergic reactions, or severe inflammation. They suppress immune responses by many mechanisms, including reduced cytokine production and T-cell activity. Short-term side effects include mood changes, high blood sugar, and infection risk; long-term use can cause growth delay, bone weakening, and weight gain, so they are tapered as soon as safely possible.
Dietary molecular supplements
Note: None of these supplements can treat or cure NF1-associated JMML. They may be considered only with the oncology team, to support nutrition during intensive therapy.
High-protein oral supplements (medical nutrition drinks) – provide concentrated calories and protein to support growth, immune function, and healing when appetite is poor.
Omega-3 fatty acids (from fish oil or algae) – may help support heart and brain health and reduce inflammation, but they can slightly thin the blood, so they must be used cautiously in children with low platelets or upcoming procedures.
Vitamin D – helps maintain bone health and immune function; many children on steroids or with limited sun exposure are deficient, so supplementation after measuring levels can support bones and possibly reduce fracture risk.
Calcium – often paired with vitamin D in children on steroids or limited mobility to support bone mineralization and reduce osteoporosis risk after HSCT or long treatment.
Multivitamin without iron (when diet is restricted) – provides a balanced mix of vitamins when intake is low; iron is usually avoided unless there is clear deficiency because many children already collect excess iron from transfusions.
Probiotics (case-by-case) – may help gut microbiome balance and diarrhea in some patients, but they can cause bloodstream infection in severely immunocompromised children, so they are usually avoided during profound neutropenia and only considered under specialist advice.
Glutamine (nutritional amino acid) – sometimes used in research settings to support gut mucosa and reduce mucositis, but evidence is mixed; any use should be within protocols.
Zinc – important for immune and skin health; if laboratory tests show deficiency, replacing zinc can support wound healing and taste, but excessive zinc can disturb copper balance.
Folate and B-vitamins from food or supplements – essential for red blood cell production; deficiency can worsen anemia and neuropathy, but high-dose supplements should not be taken without medical advice during chemotherapy.
Electrolyte solutions (oral rehydration) – balanced fluids with salts and glucose help prevent dehydration from vomiting or diarrhea during treatment and support kidney function when taking nephrotoxic drugs.
Immune-booster, regenerative and stem-cell-related drugs
Granulocyte-colony stimulating factor (G-CSF) – stimulates the bone marrow to produce neutrophils after intensive therapy or transplant, shortening periods of severe neutropenia; this reduces serious infections but is used cautiously in leukemia and always under protocol.
Erythropoiesis-stimulating agents (ESAs) in selected cases – in some settings, ESAs stimulate red blood cell production in the marrow and may reduce transfusions, but they are used rarely in childhood leukemia and only after careful risk–benefit assessment.
Thrombopoietin receptor agonists (for example, eltrombopag in special situations) – can stimulate platelet production in some marrow failure conditions; in JMML their use is very individualized and generally experimental, because stimulating abnormal clones is a concern.
Mesenchymal stromal cell infusions (experimental) – donor-derived mesenchymal stromal cells have been used in research to treat steroid-refractory GVHD and support tissue repair; they modulate immune responses rather than directly fighting leukemia.
Donor lymphocyte infusions (DLI) – after HSCT, infusions of extra donor immune cells can boost the graft-versus-leukemia effect if JMML persists or relapses, but they also raise GVHD risk; doses are small and carefully escalated.
Investigational cellular or gene-targeted therapies – future approaches may include engineered T-cells or gene-editing strategies targeting the RAS pathway or NF1, but these are still in research. Families may be offered enrollment in early-phase clinical trials at specialized centers.
Surgeries and procedures
Allogeneic hematopoietic stem cell transplantation (HSCT)
HSCT is the central procedure for curing most children with NF1-associated JMML. After conditioning chemotherapy, donor stem cells are infused through a vein like a blood transfusion. Over weeks, these cells repopulate the bone marrow and replace the abnormal JMML clone with a healthy donor immune and blood system.Central venous catheter insertion
A surgical or interventional procedure places a tunneled catheter or port into a large central vein, usually under general anesthesia. This device allows safe, repeated access for chemotherapy, transfusions, blood tests, and stem cell infusion, reducing painful repeated needle sticks.Bone marrow aspiration and biopsy
Under anesthesia or sedation, a needle is inserted into the pelvic bone to collect marrow samples. This is essential for diagnosing JMML, measuring response to azacitidine or trametinib, checking for minimal residual disease, and evaluating engraftment after transplant.Splenectomy (rare, selected cases)
If the spleen stays massively enlarged and causes pain, low blood counts, or risk of rupture despite other treatments, surgeons may remove it before or after transplant. This can improve symptoms and blood counts but increases lifelong infection risk, so vaccinations and antibiotic prophylaxis are critical.Surgery for NF1-related tumors
Some children with NF1 have plexiform neurofibromas or other tumors that interfere with organ function or cause pain. When safe, these tumors may be partially removed or reduced before or after leukemia treatment. Surgical planning must consider the child’s blood counts, infection risk, and long-term NF1 management.
Preventions and risk-reduction tips
Because NF1-associated JMML results from inherited and somatic gene changes, there is no known way to fully prevent it. Prevention focuses on lowering risks from infections, treatment complications, and late effects.
Keeping all scheduled follow-up visits at NF1 and oncology clinics so blood tests and early warning signs are detected quickly.
Using strict infection-control habits at home and hospital, including hand-washing, masks during neutropenia if advised, and avoiding sick contacts.
Staying up-to-date with recommended vaccines (including extra vaccines after splenectomy or HSCT), following the transplant team’s schedule.
Avoiding unnecessary radiation (scans and radiotherapy) whenever safer alternatives exist, due to higher cancer risk in NF1.
Protecting the enlarged spleen from trauma by avoiding rough sports, trampolines, and high-risk activities until the team says it is safe.
Following medication and prophylaxis plans exactly (for example antibiotics, antifungals, antivirals), which lowers infection-related deaths.
Encouraging a balanced diet, good sleep, and age-appropriate movement to support immunity, muscle strength, and recovery from therapy.
Managing sun exposure and skin checks to detect NF1-related skin and soft-tissue changes early and to reduce other skin cancer risks.
Avoiding tobacco smoke and other avoidable environmental toxins in the home, which can worsen lung and heart stress during treatment.
Seeking psychological and social support early to prevent burnout in caregivers and older children, improving adherence to complex care plans.
When to see doctors (urgent and routine)
Families should keep regular planned visits with the NF1 and oncology team even when the child seems well, because JMML and NF1 complications can progress quietly. Any new or worsening tiredness, pale skin, bruising, or enlarged belly should be discussed promptly.
Emergency medical attention is needed right away (often to the nearest emergency department) if the child has fever at or above the temperature threshold given by the team, breathing difficulty, fast or labored breathing, severe cough, chest pain, sudden severe abdominal or left-side pain (possible spleen problems), seizures, confusion, uncontrolled bleeding, or exposure to someone with a serious infection like chickenpox or measles.
After HSCT, any new rash, yellowing of the eyes, dark urine, severe diarrhea, or sudden weight gain and swelling may be signs of graft-versus-host disease or liver complications and should be reported immediately. The team usually gives families written instructions and emergency contact numbers, and following these closely is very important for safety.
Diet – what to eat and what to avoid
Focus on energy-dense, protein-rich foods such as eggs, yogurt, cheese, nut butters (if not allergic), lentils, fish, and lean meats to support growth, immunity, and healing during treatment.
Offer frequent small meals and snacks rather than three large meals, especially on days with nausea or low appetite; cold or room-temperature foods may be better tolerated.
Include fruits and vegetables that can be washed and peeled (for example bananas, oranges, cooked carrots, potatoes), which provide vitamins and fiber while staying safer for neutropenic patients.
Encourage plenty of safe fluids like clean water, oral rehydration drinks, and certain juices to prevent dehydration, especially when diarrhea or vomiting occurs.
Use medical nutrition drinks if needed when the child cannot meet calorie needs with regular food; these should be chosen with the dietitian.
Avoid raw or undercooked animal products (like raw eggs, sushi, rare meat) and unpasteurized milk or juices during periods of low neutrophils, to lower bacterial infection risk.
Avoid salad bar foods and unwashed raw vegetables when neutrophil counts are low, because they may carry bacteria or fungi difficult to remove.
Limit very salty, sugary, or heavily processed foods that can worsen blood pressure, weight, and metabolic stress, especially when on steroids or calcineurin inhibitors.
Avoid herbal or “immune booster” products without oncology approval, because some interact with chemotherapy or transplant drugs, or may contain unsafe contaminants.
Keep all food-safety rules strictly – separate raw and cooked foods, cook meats thoroughly, refrigerate leftovers quickly, and discard food that looks or smells spoiled.
Frequently asked questions
Is NF1-associated JMML the same as regular JMML?
Both are forms of JMML driven by RAS–MAPK pathway activation, but NF1-associated JMML occurs in children who already have NF1. They share many clinical features, yet NF1 status affects genetic background, risk of other tumors, and often leads experts to recommend early HSCT.How common is JMML in children with NF1?
JMML is rare overall, but children with NF1 have a very high relative risk—about 200–350 times higher than children without NF1—although the absolute risk remains low (roughly 1 in 1000–2000 NF1 children).What causes NF1-associated JMML at the cell level?
NF1 normally produces neurofibromin, which turns off RAS signaling. When NF1 is mutated or lost in blood stem cells, RAS stays “on,” driving uncontrolled growth and survival of myelomonocytic cells. Additional mutations may accumulate, leading to full JMML.Is HSCT always required in NF1-associated JMML?
Most guidelines recommend early allogeneic HSCT for NF1-associated JMML because spontaneous remission is very uncommon and survival without transplant is poor. The exact timing depends on disease features, donor availability, and response to drugs like azacitidine.What is the role of azacitidine in treatment?
Azacitidine is now approved for newly diagnosed pediatric JMML and is used as first-line therapy in many children, including those with NF1. It can shrink spleen size, improve blood counts, and act as a bridge to HSCT, and in some non-NF1 cases, long remissions have been seen without transplant.Can targeted drugs like trametinib cure NF1-associated JMML?
MEK inhibitors such as trametinib can control advanced or relapsed JMML and help patients reach HSCT by blocking RAS–MAPK signaling, but current data suggest they are not usually curative alone. They are used mainly in clinical trials or specialized centers.What are the main risks of HSCT in these children?
Major risks include infections during low counts, graft-versus-host disease, liver and lung complications, infertility, growth and hormonal problems, and a small risk of transplant-related death. Careful donor selection, tailored conditioning (for example, busulfan or treosulfan plus fludarabine), and modern supportive care have improved survival.How is response to treatment measured?
Doctors monitor blood counts, spleen and liver size, bone marrow exams, and minimal residual disease or mutation levels using molecular tests. Clinical improvement and normalization or deep reduction of RAS-pathway mutations indicate good response, especially before HSCT.Can NF1 or JMML be passed to future children?
NF1 is usually inherited in an autosomal dominant way, so each child of a parent with NF1 has a 50% chance of inheriting NF1, though the exact JMML risk is still low. JMML itself is not directly “contagious” or inherited as a separate disease, but the NF1 gene change raises leukemia risk in affected offspring.What long-term follow-up is needed after HSCT?
Children need life-long follow-up to monitor for relapse, GVHD, infections, hormone and growth problems, learning difficulties, heart and lung function, secondary cancers, and NF1-related tumors. Regular visits with transplant, NF1, and primary care teams are essential.Does having NF1 change how other cancers are screened later?
Yes. NF1 increases the risk of several tumors (such as plexiform neurofibromas, malignant peripheral nerve sheath tumors, optic pathway gliomas, and some solid cancers), so NF1 clinics use age-specific screening and counseling even after JMML is cured.Are there lifestyle changes that really help?
While lifestyle cannot cure JMML, good nutrition, physical activity adapted to counts, adequate sleep, avoidance of tobacco smoke, and strong infection-control habits make treatment safer and recovery smoother. Emotional and social support also strongly affect quality of life.Can children with NF1-associated JMML attend school?
Many children continue school part-time or through home/hospital teaching during treatment and return more fully after HSCT recovery. Decisions depend on blood counts, infection risk, and how the child feels, and are planned together with the medical team and school.What is the outlook (prognosis) today?
Outcomes have improved with early HSCT, azacitidine, and better supportive care. Survival after HSCT now reaches a substantial proportion of children, though the exact numbers depend on disease features, donor type, and complications; relapses and late effects remain important challenges.Where can families find more information and support?
Families are usually referred to tertiary pediatric cancer centers, NF1 clinics, and national JMML or NF1 support organizations. International guidelines and patient-friendly resources from pediatric cancer groups help parents understand options and connect with other families facing NF1-associated JMML.
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.
The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: January 23, 2026.
