Juvenile Myelomonocytic Leukemia

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Epidemiology

Incidence: 1.2 per million children per year

Median age at diagnosis: 1.8 years; 35% below 1 year of age, and only 4% above 5

years of age Male:female ratio of 2:1

Association with neurofibromatosis type 1 (NF-1): Children with NF-1 have more than a 200-fold increased risk of JMML. Fifteen percent of children with JMML have NF-1.

Children with Noonan syndrome or trisomy 8 mosaicism are at increased risk of developing JMML. Most cases of neonates with Noonan syndrome with JMML-like presentation resolve spontaneously.

Clinical Features

JMML usually occurs before 2 years of age. Physical findings include:

Skin: eczema, xanthoma, cafe-au-lait spots, macular-papular rash

Lymphadenopathy

Hepatosplenomegaly

Bleeding

Respiratory symptoms: chronic tachypnea, cough, wheezing Fever, infection.

Laboratory Features

Blood:

WBC count: The majority of patients have >25,000/mm3 WBC counts. Monocytosis may be present for months before overt symptoms of JMML appear. Thrombocytopenia

Immature myeloid cells with orderly maturation in peripheral blood Nucleated red blood cells Bone marrow: increased cellularity, increased myeloid series, increased monocytes, less than 20% blasts Cytogenetics:

Monosomy 7: 25-30%, patients with monosomy 7 show lower WBC counts, higher percent monocytes in the blood, decreased myeloid:erythroid ratio in the bone marrow, high mean corpuscular volume, and normal to moderately high fetal hemoglobin levels. Monosomy 7 occurs with the same frequency in JMML, whether it is associated with NF-1 or not 7q-: 5%

Normal karyotype: 60%

Other cytogenetic abnormalities: 5%.

Table 13-18 lists diagnostic guidelines for JMML. Differential Diagnosis

It is important to distinguish JMML from chronic active viral infections such as EBV, cytomegalovirus, and human herpes virus 6 (HHV-6) infections. All of these infections

Table 13-18. Diagnostic Guidelines for Juvenile Myelomonocytic Leukemia (JMML)a

Suggestive clinical features

Laboratory criteria:

Minimum criteria for tentative diagnosis (all three must be fulfilled)

Criteria for definite diagnosis (at least two must be fulfilled)

Hepatosplenomegaly

Lymphadenopathy

Pallor

Skin rash

Fever

No Philadelphia chromosome and no

BCR/ABL rearrangement Peripheral blood monocyte count greater than 1 x 109/L

Blasts less than 20% of bone marrow cells Hemoglobin F increased for age Myeloid precursors in peripheral blood smear White blood cell count greater than 10 x 109/L Clonal abnormality

Granulocyte monocyte colony-stimulating factor hypersensitivity of myeloid progenitors in vitro aJMML includes patients with monosomy 7. There are no major clinical differences in children with JMML, with or without monosomy 7. The main difference is that JMML without monosomy 7 is associated with high fetal hemoglobin as compared to JMML with monosomy 7.

From Niermeyer CM, et al. Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood 1998;91:365-7, with permission.

can present with hepatosplenomegaly, lymphadenopathy, leukocytosis, thrombocytopenia, and elevated hemoglobin F levels. The following tests are useful:

1. Bone marrow examination to see if hemophagocytosis is present. If present, then it favors viral illness.

2. Viral antibody titers.

3. Polymerase chain reaction (PCR) for viruses.

4. Bone marrow colony-forming units granulocyte macrophage (CFU-GM) studies for granulocyte macrophage colony-stimulating factor (GM-CSF) sensitivity.

Biology

JMML is a clonal disorder that arises from a pluripotent hematopoietic stem cell. The leukemic progenitor cell of JMML is capable of producing erythroid, myeloid, monocytic, megakaryocytic, and possibly lymphoid lineages. It is probably a heterogeneous disease in the context of clonal involvement of different lineages.

The distinct characteristic of JMML mononuclear cells, of both blood and bone marrow, is that they yield excessive numbers of granulocyte-macrophage colonies when cultured in a semisolid system, even without the addition of exogenous growth factors. The endogenous production of interleukin 1 (IL-1), GM-CSF, and tumor necrosis factor a (TNF-a) by monocytes accounts for the exuberant spontaneous growth of CFU-GM growth. TNF-a exerts bidirectional actions:

1. It inhibits normal hematopoiesis.

2. It induces proliferation of the JMML clone-derived monocyte-macrophage elements.

The inhibitory effect of TNF-a on normal hematopoiesis causes bone marrow suppression and results in anemia and thrombocytopenia. Splenomegaly also contributes to the development of anemia and thrombocytopenia. IL-1 stimulates accessory cells to produce more GM-CSF.

Molecular Events

The constitutive activation of the RAS signaling pathway plays a central role in the proliferative responses to growth factors in JMML. RAS signaling proteins regulate cellular proliferation by switching between an active guanosine triphosphate state (RAS-GTP) and an inactive guanosine diphosphate state (RAS-GDP). In JMML, there may be mutations of RAS gene or there may be defective regulation of RAS gene, which results in the aberrant transmission of proliferative signals from GM-CSF to the nucleus. The conversion of RAS-GTP to the RAS-GDP is induced by GTP-ase-activating proteins (GAPS); thus, GAPS acts as a negative regulator of Ras. There are two GAPS; RAS-GAP and neurofibromin, the protein made by nf-1 gene. An understanding of the crucial role of RAS in the pathogenesis of JMML has led to the trials with molecularly targeted therapies.

Figure 13-2 shows the biology of JMML and its correlation with hematologic findings.

Natural History

Spontaneous remission occurs in a few cases. The majority of patients progress, if untreated.

Blastic transformation occurs in 15% of patients and is associated with additional cytogenetic abnormalities in some patients.

Blastic Bone Metastases
Fig. 13-2. Biology of JMML and its correlation with hematologic findings.

Most often patients die of respiratory failure, due to leukemic infiltrates and/or infections.

Erythroleukemia-like phase with anemia, erythroid hyperplasia, and megaloblastoid cells may develop in some patients.

Occasionally, pre-B ALL develops.

Prognosis

Adverse factors include:

Age at diagnosis: 2 years or more

High fetal hemoglobin level at diagnosis

Platelet count below 33,000/mm3 at diagnosis (considered to be the strongest indicator of prognosis).

Treatment

JMML responds poorly to chemotherapy.

13-Cis Retinoic Acid

13-Cis retinoic acid (CRA; Isotretinoin, Accutane) is used to induce durable responses. CRA reduces spontaneous growth of JMML cells in vitro. Additionally, it induces maturation of normal and JMML hematopoietic cells.

Dose: 100 mg/m2/day or 3 mg/kg/day for children less than 1 year of age.

Note: Each dose of CRA must be drawn from the caplet into a tuberculin syringe and given immediately to the patient.

Hematopoietic Stem Cell Transplantation

HSCT is the only curative treatment available for children with JMML. If a suitable family member donor is available, the patient is treated with HSCT. Splenectomy is usually recommended before HSCT. Allogeneic HSCT cures 30% of the patients with JMML. If a suitable family member donor is not available, an unrelated donor should be employed, if available. Treatment with CRA should be given in the interim.

Chemotherapy

If there is progression of the disease treatment with intensive chemotherapy may be required. However, the responses are usually short lived. The following chemotherapy is suggested:

Ara-C 100 mg/m2/day by continuous infusion (days 0-4) Etoposide 100 mg/m2/day intravenously (days 0-4) Low-dose Ara-C 15 mg/m2/day subcutaneously (days 6-15)

Note that there are no standard chemotherapy regimens available for treatment of JMML. Ara-C-based regimens appear to be used most often.

Farnesyl Protein Transferase Inhibitor

RAS protein is synthesized as a cytosolic precursor that undergoes post-translational enzymatic processing in what is known as the prenylation process. Prenylation of RAS protein allows it ultimately to localize to the inner leaflet of plasma membrane. The first obligatory step in prenylation of RAS protein is the addition of farnesyl moiety catalyzed by farnesyl transferase. Farnesylation of RAS protein is essential for the function of RAS. For this reason, a clinical trial of farnesyl protein transferase (FPTase) inhibitor is being conducted in a phase II setting by the Children's Oncology Group (COG) in the United States for treatment of JMML, in sequential combination with fludarabine and Ara-C chemotherapy, splenectomy, and ultimately HSCT.

Other Investigational Therapies

Other investigational therapies include the use of analogues of GM-CSF and the use of GM-CSF/diphtheria fusion molecule.

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