Juvenile bleeding, Tendency to bleed from the nose

Juvenile myelomonocytic leukemia (JMML)

Juvenile
myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder
(MPD) of early childhood. The median age at diagnosis is 2 years. There is a
male 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 nervous
system 1.

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The
World Health Organization has included JMML in the category of myelodysplastic
and myelomproliferative disorders .Since about 10% of patients are diagnosed
before 3 months of age, it is thought that JMML is a congenital condition in
these infants. Genetics studies showed about 80% of JMML patients have some
sort of genetic abnormality 2.

 

In JMML, too many myelocytes and
monocytes (two types of white blood cells) are produced from immature blood
stem cells called blasts. These myelocytes (the cells in the granulocytic
series that give rise to mature granulocytes or neutrophils, eosinophils and
basophils), monocytes and blasts overwhelm the normal cells in the bone marrow
and other organs, causing the symptoms of JMML.

 

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Causes of Juvenile Myelomonocytic
Leukemia (JMML)

 

The
cause of JMML is unknown, but doctors do know that certain medical conditions —
such as neurofibromatosis type 1 and Noonan syndrome — can make a child more
likely to develop it.

 

Signs
and Symptoms of Juvenile Myelomonocytic Leukemia (JMML)

Fever, Persistently feeling very
tired and fatigued, General weakness, Shortness of breath, Weight loss, Easy
bruising and/or bleeding, Tendency to bleed from the nose and gums, Recurring
infections such as bronchitis or tonsillitis, Sore mouth due to mouth ulcers,
Skin rash, Painless swelling of lymph nodes in the neck, underarm, abdomen or
groin

                     

Diagnosis
of Juvenile Myelomonocytic Leukemia (JMML)

Major
criteria (all three required)

·        
No
Philadelphia chromosome or BCR/ABL fusion gene

·        
Peripheral
blood monocytosis is greater than 1 × 109/L

·        
Fewer
than 20% blasts (including promonocytes) in the blood and bone marrow

Minor
criteria (two or more required)

·        
Foetal
haemoglobin (Hb F) increased for age

·        
Immature
granulocytes in the peripheral blood

·        
White
blood cell count is greater than 1 × 109/L

·        
Clonal
chromosomal abnormality (e.g., monosomy 7)

·        
Granulocyte-macrophage
colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in
vitro 3.

                                          

Treatment of Juvenile
Myelomonocytic Leukemia (JMML) 4

Treatment
options for JMML may include (alone or in combination):

1.    Surgery:
Patients with JMML generally have large spleens, and hypersplenism may give
rise 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 a
clinical and hematologicresponse to repeat cycles of oral 6-mercaptopurine and
subcutaneouscytarabine in three JMML cases. However, there was no influence on length
of survival reported partial remission with regression oforganomegaly, and
improvement of WBC and platelet counts in seven of 21children treated with
6-mercaptopurine as a single agent or in combinationwith cytarabine or
etoposide. Responses to 6-mercaptopurine in children younger than 2 years
presenting with a normal platelet count have also been reported Many other
single agents and combination-type therapies have been applied but were
generally followed by poor response.

·        
Intensive chemotherapy: Most
approaches of intensive chemotherapy arise from treatment protocols for acute
myeloid leukemia (AML). Therefore, the ongoing JMML
protocol of the Children’s Oncology Group applies cytoreductive therapy
consisting of fludarabine 30 mg/m2 and cytarabine 2 g/m2 daily for 5
consecutive days concomitantly with 13-cis retinoic acid.

·        
Interferon: The
apparently increased sensitivity of JMML to interferon-prompted some
investigators to apply the cytokine in JMML. Besides some nonresponses, several
transient responses in vivo have been reported. A prospective study of the
Pediatric Oncology Group with interferon-_ 30,000 units/m2 subcutaneously daily
for 14 days followed by the same dose three times weekly was stopped for excessive
toxicity.

·        
13-Cis retinoic acid: Spontaneous
growth of JMML myeloid progenitors in vitro can be inhibited by 10-6 to 10-8 m
13-cis retinoic acid. Based on these laboratory observations,10 children with
JMML were treated daily with 100 mg/m2 isotretinoin orally. Response was
evaluated by reduction of WBC and decrease oforganomegaly.

3.    Radiation
therapy: Radiation therapy to the spleen does not generally
result in a decrease in spleen size or reduction of platelet transfusion
requirement.

4.    Stem
cell transplantation: Allogeneic SCT is the
only curative approach for JMML, resulting in long-term survival in
approximately one third of the patients. The malignant JMML clone is difficult
to eradicate even with SCT, and post-transplant relapse rate is high.
Generally, SCT shortly after diagnosis is recommended, and younger age at SCT
may predict for improved survival. Ra

Clinical Trials for
JMML5

·        
Patient participation in clinical trials
is important in order to develop new and better treatments.

·        
Parents should talk to their child’s
physician about whether taking part in a clinical trial would be a good
treatment option for their child.

·        
Examples of therapies currently under
study to achieve longer-lasting remissions for JMML patients are listed here.

·        
Etanercept (Enbrel) blocks the hormone
called the “tumor necrosis factor” (TNF), which has been shown to play a role
in helping the growth of JMML cells. This drug has been approved for the
treatment of rheumatoid arthritis and juvenile rheumatoid arthritis. Studies
are trying to determine its effectiveness in the treatment of relapsed JMML
patients.

·        
Tipifarnib (Zarnestra) is a type of drug
called a “farnesyl transferase inhibitor” that may stop the growth of JMML
cells by blocking the enzymes necessary in the mechanisms of cancer cell
growth. This drug has demonstrated significant clinical effectiveness according
to a clinical trial conducted by the Children’s Oncology Group.