Juvenile Myelomonocytic Leukemia (JMML)

JUVENILE
MYELOMONOCYTIC
LEUKEMIA
DR. REENAZ SHAIK
MD PATHOLOGY

CONTENTS
• Hematopoiesis
• Definition
• Epidemiology
• Etiology
• Localization
• Clinical features
• Diagnostic criteria
• Microscopy
• Cytochemistry and Immunophenotype
• Genetic Profile
• Prognostic factors
• Differential Diagnosis

Overview
Juvenile myelomonocytic leukemia (JMML) is a rare
cancer of the blood that affects young children.
JMML happens when types of white blood cells called
monocytes and myelocytes do not mature normally.
JMML can happen spontaneously or can be associated
with other genetic disorders in some children

Definition
• Juvenile myelomonocytic leukaemia (JMML) is a clonal haematopoietic
disorder of childhood characterized by a proliferation principally of the
granulocytic and monocytic lineages.
• Rare paediatric myelodysplastic/myeloproliferative neoplasm overlap
disease.
• JMML is associated with mutations in the RAS pathway genes resulting in
the myeloid progenitors being sensitive to granulocyte monocyte colony-
stimulating factor (GM-CSF).

Definition
• There is a sustained, abnormal, and excessive production of myeloid
progenitors and monocytes, aggressive clinical course, and poor outcomes.
• Unlike acute leukemia, there is no maturation arrest in myeloid
differentiation; hence the number of blasts in the peripheral blood (PB) or
bone marrow (BM) may be low even in the presence of a high total
leukocyte count (TLC).

Interesting facts
The differentiation pathway is shunted towards the monocytic
differentiation and the progenitor colonies of JMML cells show a
spectrum of differentiation, including blasts, pro-monocytes,
monocytes, and macrophages.
The overproduction of the myeloid lineage cells leads to a
suppression of other cell lines; consequently, these patients can
present with anemia and thrombocytopenia.
It is also called as:
•Juvenile chronic myeloid leukemia
•CMML of childhood
•Chronic and subacute myelomonocytic leukemia
•Infantile monosomy 7 syndrome

EPIDEMIOLOGY
The annual incidence of JMML is estimated to be
approximately 0.13 cases per 1,00,000 children
aged 0―14 years.
It accounts for < 2―3% of all leukaemia's in
children, but for 20―30% of all cases of
myelodysplastic and myeloproliferative diseases
in patients aged < 14 years
Patient age at diagnosis ranges from 1 month to
early adolescence, but 75% of cases occur in
children aged < 3 years.

ETIOLOGY
Neurofibromatosis type-1 (NF-1) and Noonan
syndrome (NS) are known to be predisposing clinical
conditions for JMML.
NF-1:
Autosomal dominant inheritance.
Patients of NF-1 have symptoms such as cafe-au-lait
macules, neurofibromas, axillary or inguinal freckling,
lisch nodules, optic glioma, and osseous lesions.
The cafe-au-lait macules in NF-1 appear by the age
of one year, hence establishing the diagnosis of NF-1
in infants with JMML may be difficult.
Rarely JMML can be the first presentation of NF-1.

ETIOLOGY
Noonan syndrome (NS) is a genetic disease
characterized by facial dysmorphism, growth delay,
and heart disease.
Children with NS develop JMML-like myeloproliferative
disorders (NS/JMML) occasionally, which usually occurs
at young ages and has a tendency to regress
spontaneously.
Recently studies have demonstrated germline
mutations in the RAS pathway genes i.e.
Protein tyrosine phosphatase non-receptor type 11
(PTPN11) in 50%,
Son of Sevenless (SOS)-1 in 10%,
Kirsten rat sarcoma (KRAS) in <5%, and
Rapidly accelerated fibrosarcoma (RAF) in <5% in
NS

LOCALISATION
The peripheral blood and bone marrow always show evidence of
myelomonocytic proliferation.
Leukemic infiltration of the liver and spleen is found in virtually all cases.
The lymph nodes, skin, respiratory system, and gut are other common sites of
involvement, although any tissue can be infiltrated.

CLINICAL FEATURES
• Most patients present with constitutional symptoms or evidence of infection.
• Marked hepatosplenomegaly, lymphadenopathy, and leukemic infiltrates
may give rise to markedly enlarged tonsils.
• Dry cough, tachypnoea and interstitial infiltrates on chest X-ray are signs of
pulmonary infiltration.
• Gut infiltration may predispose patients to diarrhoea and gastrointestinal
infections.
• Signs of bleeding are common, and about a quarter of all patients have skin
rashes (eczematous eruptions or indurations with central clearing).

CLINICAL FEATURES
• Cafe―au―lait spots might be indicative of an underlying germline
condition such as NF1 or Noonan syndrome―like disorder.
• JMML rarely involves the central nervous system (CNS), although a small
number of patients with CNS myeloid sarcoma and ocular infiltrates.
Notable features of JMML cases are:
• Markedly increased synthesis of haemoglobin F, particularly in cases with a
normal karyotype.
• Polyclonal hypergammaglobulinaemia and the presence of autoantibodies.
• In vitro hypersensitivity of JMML myeloid progenitors to granulocyte
macrophage colony stimulating factor (also called CSF2) is a hallmark of the
disease.

CLINICAL FEATURES
In RAS pathway mutation negative cases,
EXCLUDE:
• Infection
• Wiskott―Aldrich syndrome (eczemathrombocytopenia immunodeficiency syndrome)
• Malignant infantile osteopetrosis

DIAGNOSTIC CRITERIA
Clinical and haematological criteria (all 4 criteria are required):
• Peripheral blood monocyte count ≥ 1 x 109 /L
• Blast percentage in peripheral blood and bone marrow of < 20%
• Splenomegaly
• No Philadelphia (Ph) chromosome or BCR-ABL1 fusion

DIAGNOSTIC CRITERIA
Genetic criteria (any 1 criterion is sufficient) :
• Somatic mutation in PTPN11, KRAS or NRAS
• Clinical diagnosis of neurofibromatosis type 1 or NF1 mutation
• Germline CBL ( Casitas B Lineage lymphoma) mutation and loss of
heterozygosity of CBLb

DIAGNOSTIC CRITERIA
Other criteria Cases that do not meet any of the genetic criteria above must meet the following
criteria in addition to the clinical and haematological criteria above:
Monosomy 7 or any other chromosomal abnormality
or
≥ 2 of the following:
• Increased haemoglobin F for age
• Myeloid or erythroid precursors on peripheral blood smear
• Granulocyte-macrophage colony-stimulating factor (also called CSF2) hypersensitivity in
colony assay
• Hyperphosphorylation of STAT5

MICROSCOPY
RBC: Macrocytosis (particularly in patients with monosomy 7), but normocytic red blood
cells are more common; microcytosis due to iron deficiency or acquired thalassaemia
phenotype. Nucleated red blood cells are often seen.
WBC: The median reported white blood cell counts are 25―30 x 109/L.
Leucocytosis consists mainly of neutrophils, with some immature cells (e.g. promyelocytes
and myelocytes) and monocytes.
Blasts (including promonocytes) usually account for < 5% of the white blood cells, and
always < 20%.
Eosinophilia and basophilia are observed in a minority of cases.
Platelets: Platelet counts vary, but thrombocytopenia is typical and may be severe

MICROSCOPY
Bone marrow findings alone are not diagnostic.
• The bone marrow aspirate and biopsy are hypercellular with granulocytic
proliferation, although in some patients erythroid precursors may predominate.
• Monocytes in the bone marrow are often less prominent than in the peripheral
blood, generally accounting for 5―10% of the bone marrow cells.
• Blasts (including promonocytes) account for < 20% of the bone marrow cells, and
Auer rods are never present.
• Dysplasia is usually minimal; however, dysgranulopoiesis (including pseudo Pelger-
Huët neutrophils and hypo granularity) may be noted in some cases, and erythroid
precursors may be enlarged.
• Megakaryocytes are often reduced in number, but marked megakaryocytic
dysplasia is unusual.

MICROSCOPY
Leukemic infiltrates are common in the skin, where myelomonocytic cells
infiltrate the papillary and reticular dermis.
In the lung, leukemic cells spread from the capillaries of the alveolar septa into
alveoli.
In the spleen, they infiltrate the red pulp and have a predilection for trabecular
and central arteries.
In the liver, the sinusoids and portal tracts are infiltrated.

Leucocytosis with neutrophilia with
immature forms and monocytosis,
WBC count is 20 - 30 x 109/L with
granulocytes and monocytes and
occasional dysplasia (which may not
be prominent)
Anemia: most commonly
normochromic and nucleated red
blood cells are often identified
Macrocytosis seen in cases with
monosomy 7
Thrombocytopenia
Blasts and blast equivalents are usually
less than 5% (no more than 20%)

CYTOCHEMISTRY
No specific cytochemical abnormalities have been reported.
In bone marrow aspirate smears, cytochemical staining for ,
Alpha-naphthyl acetate esterase or alpha-naphthyl butyrate esterase,
alone or in combination with staining for naphthol AS-D chloroacetate
esterase (CAE), may be helpful in identifying the monocytic component.
Neutrophil alkaline phosphatase scores are reported to be elevated in about
50% of cases, but this test is not helpful in establishing the diagnosis

IMMUNOPHENOTYPE
No specific immunophenotypic abnormalities have been reported in JMML.
In extramedullary tissues, the monocytic component is best identified using
immunohistochemical techniques that detect lysozyme and CD68R.
Flow cytometry, which enables simultaneous analysis of cell phenotype and cell
signalling, shows that JMML cells exhibit an aberrant response of phospho-
STAT5A to sub saturating doses of granulocyte macrophage colony
stimulating factor.

GENETIC PROFILE
Karyotyping studies:
• Monosomy 7 in about 25% of patients.
• The Philadelphia (Ph) chromosome and the BCR―ABL1 fusion gene are absent.
• JMML occurs, at least in part, due to aberrant signal transduction of the RAS signalling
pathway.
• As many as 85% of patients harbour driving molecular alteration in one of five particular
genes cPTPN11, NRAS, KRAS, CBL and NF1, which encode proteins that when mutated
are predicted to activate RAS effector pathways.
• Heterozygous somatic gain-of-function mutations in PTPN11 are the most frequent
alterations, occurring in approximately 35% of patients.
• Typical oncogenic heterozygous somatic NRAS and KRAS mutations in codons 12, 13,
and 61 account for 20― 25% of JMML cases.

CLINICAL TESTING AND WORKUP
Complete blood count (CBC) can be taken to evaluate the size, number, and
maturity of blood cells.
Bone marrow aspiration and biopsy is a procedure in which a small amount
of fluid and cells (aspiration) are taken from the bone marrow along with a
piece of bone. The biopsied material is then examined under a microscope for
changes indicative of JMML.
Molecular genetic testing can reveal characteristic RAS, PTPN1, NF1,
or CBL gene and this is now used routinely at paediatric centres to evaluate
children suspected of having JMML.

CLINICAL TESTING AND WORKUP
GM-CSF hypersensitivity assay
• It is a useful test for diagnosing. This exam requires bone marrow or peripheral blood
samples to be sent to a specialized lab.
• GM-CSF is a growth factor, a substance that is required to stimulate the growth of living
cells. Increasing amounts of GM-CSF are added to the samples.
• Healthy cells do not grow when low levels of GM-CSF are present, but JMML cells grow. So,
if a patient’s sample responds to GM-CSF, it is indicative of JMML.
• There are disadvantages to this test, specifically that it requires a long turnaround time
(weeks) and is not widely available (it can only be done in a specialized lab).
• Researchers are working to develop a quicker test based upon the same principle of GM-
CSF hypersensitivity assay.

PROGNOSIS
• Prognosis and predictive factors JMML with somatic PTPN11 mutation or occurring
in children with NF1 is invariably rapidly fatal if left untreated.
• The median survival time without allogeneic haematopoietic stem cell
transplantation is about 1 year.
• Low platelet count, patient age > 2 years at diagnosis and high haemoglobin F
levels at diagnosis are the main clinical predictors of short survival.
• JMML with KRAS or NRAS mutation generally has an aggressive course, with early
haematopoietic stem cell transplantation needed.

DIFFERENTIAL DIAGNOSIS
• Viral infections like Cytomegalovirus (CMV), Epstein-Barr virus (EBV), human
herpesvirus-6 (HHV-6), and parvovirus B19 may present with features
mimicking JMML.
• Infection with HHV-6 and CMV in JMML patients may show increased
spontaneous proliferation of granulocyte and monocyte precursors,
hypersensitivity to GM-CSF, and abnormal proliferation of B-lineage cells with
the NRAS mutation respectively, making the diagnosis difficult
• Immunodeficiencies, most commonly Wiskott-Aldrich syndrome (WAS) and
leukocyte adhesion defect (LAD) may present with similar features and
should be ruled out.

• Infantile malignant osteopetrosis can be a close mimicker of JMML
and can be ruled out in most cases by radiographic imaging which
shows increased bone density.
• Familial hemophagolymphohistiocytosis (HLH) may present with
similar symptomatology in infancy and should be ruled out with the
help of blood/bone marrow tests and genetic tests.

• MPN with receptor tyrosine kinase (RTK) translocations may mimic JMML.
• MPD with eosinophilia and constitutively activated platelet-derived growth factor
receptor alpha (PDGFR-α), PDGFR-ß, or fibroblast growth factor receptor 1 (FGFR1)
can present with leucocytosis and organomegaly in very young children, and thus
need to be differentiated from JMML. A clinical presentation akin to JMML is noted
in some patients with GATA2 deficiency.
• Infantile acute leukemia with KMT2A rearrangement can have a massive
enlargement of the liver and spleen and patients with low blast count may be
difficult to differentiate from JMML.

TREATMENT
• Currently, the only potentially curative option is allogeneic hematopoietic
stem cell transplantation.
• Approximately 50% of children with JMML who undergo hematopoietic
stem cell transplant will achieve long-term remissions.
• Some individuals with JMML have undergone the surgical removal of the
spleen (splenectomy) as part of their treatment plan.
• Additional treatment is symptomatic and supportive. For example,
antibiotics may be given to help prevent or fight infections.

INVESTIGATIONAL THERAPIES
• Most promising therapies being investigated for JMML is called a MEK
inhibitor, which will be tested in a Children’s Oncology Group sponsored
trial, ADVL1521 for children with relapsed or refractory JMML.
• DNA-hypomethylating agents, such as decitabine or azacitidine, have been
studied extensively in adults with myelodysplastic syndromes.
• Azacitidine is currently being testing in clinical trials in Europe

Resources
2016 WHO classification of tumors of Hematopoietic and
Lymphoid Tissues.
Gupta AK, Meena JP, Chopra A, Tanwar P, Seth R. Juvenile
myelomonocytic leukemia-A comprehensive review and
recent advances in management. Am J Blood Res. 2021 Feb
15;11(1):1-21
Franco Locatelli, Charlotte M. Niemeyer; How I treat
juvenile myelomonocytic leukemia. Blood 2015; 125 (7):
1083–1090

Juvenile Myelomonocytic Leukemia (JMML)

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