Juvenile myelomonocytic leukemia (JMML)Juvenilemyelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder(MPD) of early childhood. The median age at diagnosis is 2 years. There is amale predominance with a male: female ratio of 2:1. Pallor, fever, infection,skin bleeding and cough are the most common presenting symptoms.
Typically,there is marked hepatosplenomegaly. JMML rarely involves the central nervoussystem 1. TheWorld Health Organization has included JMML in the category of myelodysplasticand myelomproliferative disorders .Since about 10% of patients are diagnosedbefore 3 months of age, it is thought that JMML is a congenital condition inthese infants. Genetics studies showed about 80% of JMML patients have somesort of genetic abnormality 2. In JMML, too many myelocytes andmonocytes (two types of white blood cells) are produced from immature bloodstem cells called blasts. These myelocytes (the cells in the granulocyticseries that give rise to mature granulocytes or neutrophils, eosinophils andbasophils), monocytes and blasts overwhelm the normal cells in the bone marrowand other organs, causing the symptoms of JMML. Available from:https://www.
google.co.za/search?q=myelocytes+monocytes+in+blood&source=lnms&tbm=isch&sa=X&ei=cpxgU- Causes of Juvenile MyelomonocyticLeukemia (JMML) Thecause of JMML is unknown, but doctors do know that certain medical conditions —such as neurofibromatosis type 1 and Noonan syndrome — can make a child morelikely to develop it. Signsand Symptoms of Juvenile Myelomonocytic Leukemia (JMML) Fever, Persistently feeling verytired and fatigued, General weakness, Shortness of breath, Weight loss, Easybruising and/or bleeding, Tendency to bleed from the nose and gums, Recurringinfections such as bronchitis or tonsillitis, Sore mouth due to mouth ulcers,Skin rash, Painless swelling of lymph nodes in the neck, underarm, abdomen orgroin Diagnosisof Juvenile Myelomonocytic Leukemia (JMML) Majorcriteria (all three required) · NoPhiladelphia chromosome or BCR/ABL fusion gene · Peripheralblood monocytosis is greater than 1 × 109/L · Fewerthan 20% blasts (including promonocytes) in the blood and bone marrow Minorcriteria (two or more required) · Foetalhaemoglobin (Hb F) increased for age · Immaturegranulocytes in the peripheral blood · Whiteblood cell count is greater than 1 × 109/L · Clonalchromosomal abnormality (e.
g., monosomy 7) · Granulocyte-macrophagecolony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors invitro 3. Treatment of JuvenileMyelomonocytic Leukemia (JMML) 4Treatmentoptions for JMML may include (alone or in combination): 1. Surgery:Patients with JMML generally have large spleens, and hypersplenism may giverise to increased morbidity with excessive transfusion requirements. Therefore,early splenectomy for amelioration of disease has been recommended.
2. Pharmacologic treatment:· Low-dose conventional chemotherapy:6-Mercaptopurine,often used as single-drug therapy, was first described in 1977. They recorded aclinical and hematologicresponse to repeat cycles of oral 6-mercaptopurine andsubcutaneouscytarabine in three JMML cases. However, there was no influence on lengthof survival reported partial remission with regression oforganomegaly, andimprovement of WBC and platelet counts in seven of 21children treated with6-mercaptopurine as a single agent or in combinationwith cytarabine oretoposide. Responses to 6-mercaptopurine in children younger than 2 yearspresenting with a normal platelet count have also been reported Many othersingle agents and combination-type therapies have been applied but weregenerally followed by poor response.
· Intensive chemotherapy: Mostapproaches of intensive chemotherapy arise from treatment protocols for acutemyeloid leukemia (AML). Therefore, the ongoing JMMLprotocol of the Children’s Oncology Group applies cytoreductive therapyconsisting of fludarabine 30 mg/m2 and cytarabine 2 g/m2 daily for 5consecutive days concomitantly with 13-cis retinoic acid.· Interferon: Theapparently increased sensitivity of JMML to interferon-prompted someinvestigators to apply the cytokine in JMML. Besides some nonresponses, severaltransient responses in vivo have been reported. A prospective study of thePediatric Oncology Group with interferon-_ 30,000 units/m2 subcutaneously dailyfor 14 days followed by the same dose three times weekly was stopped for excessivetoxicity. · 13-Cis retinoic acid: Spontaneousgrowth of JMML myeloid progenitors in vitro can be inhibited by 10-6 to 10-8 m13-cis retinoic acid.
Based on these laboratory observations,10 children withJMML were treated daily with 100 mg/m2 isotretinoin orally. Response wasevaluated by reduction of WBC and decrease oforganomegaly.3.
Radiationtherapy: Radiation therapy to the spleen does not generallyresult in a decrease in spleen size or reduction of platelet transfusionrequirement.4. Stemcell transplantation: Allogeneic SCT is theonly curative approach for JMML, resulting in long-term survival inapproximately one third of the patients. The malignant JMML clone is difficultto eradicate even with SCT, and post-transplant relapse rate is high.Generally, SCT shortly after diagnosis is recommended, and younger age at SCTmay predict for improved survival.
RaClinical Trials forJMML5· Patient participation in clinical trialsis important in order to develop new and better treatments.· Parents should talk to their child’sphysician about whether taking part in a clinical trial would be a goodtreatment option for their child.· Examples of therapies currently understudy to achieve longer-lasting remissions for JMML patients are listed here.· Etanercept (Enbrel) blocks the hormonecalled the “tumor necrosis factor” (TNF), which has been shown to play a rolein helping the growth of JMML cells. This drug has been approved for thetreatment of rheumatoid arthritis and juvenile rheumatoid arthritis. Studiesare trying to determine its effectiveness in the treatment of relapsed JMMLpatients.· Tipifarnib (Zarnestra) is a type of drugcalled a “farnesyl transferase inhibitor” that may stop the growth of JMMLcells by blocking the enzymes necessary in the mechanisms of cancer cellgrowth.
This drug has demonstrated significant clinical effectiveness accordingto a clinical trial conducted by the Children’s Oncology Group.