JMML

Question 1

What is the definition of JMML ?

Answer 1

• clonal hematopoietic disorder of childhood
• granulocytic and monocytic proliferation
• blasts and promonocytes <20%
• erythroid and megakaryocytic abnormalities are often seen
• BCR-ABL is absent
• RAS pathway mutations are common

Question 2

What are the clinical and hematological

criteria ?

Answer 2

• ALL 4 criteria are required:
  
  • peripheral blood monocyte count > 1 x 10^9/ L
  • blast percentage in peripheral blood and bone marrow of <20%
  • splenomegaly
  • no Ph chromosome or BCR-ABL1 fusion

Question 3

What are the genetic criteria for JMML ?

Answer 3

• Any 1 criterion is sufficient
  
  • somatic mutation in PTPN11, KRAS, or NRAS
  • Clinical diagnosis of Neurofibromatosis 1 or NF1 mutation
  • Germline CBL mutation with loss of heterozygosity of CBL

Question 4

What are the other criteria for the diagnosis of JMML ?

Answer 4

• If the cases do not meet genetic or clinical/hematological criteria must meet the following in addition to anything else present:
  
  • monosomy 7 or any other chromosomal abnormality
  • or >2 of the following:
    
    • increased hemoglobin F for age
    • myeloid or erythroid precursors in PB
    • hypersensity to granulocyte-macrophage stimulating factor
    • hyperphosphorylation of STAT5

Question 5

What is the epidemiology of JMML ?

Answer 5

• accounts for < 2-3% of all luekemias in kids
  
  • but 20-30% of MDS/MPN cases in kids <14 y.o.
• 75% of cases occur in kids < 3 years of age
• twice as common in boys vs. girls
• 15% of cases: Noonan syndrome (CBL mutation)
• 10% of cases: NF1

Question 6

What is the etiology of JMML ?

Answer 6

• unknown
• NF1 kids have a 200-500x increased risk of this malignancy
• Noonan kids develop a JMML-like disorder which in some goes away without treatment and in others is aggressive
• mutations in PTPN11 or KRAS in these patients

Question 7

What is the localization of JMML ?

Answer 7

• PB and BM always show evidence of myelomonocytic proliferation
• liver and spleen IMP
  
  • show leukemic infiltration almost always
• any organ can be infiltrated, other common ones:
  
  • LN, skin, respiratory system and GI tract

Question 8

What are the clinical features of JMML ?

Answer 8

• usually present with constitutional symptoms and evidence of infection
• marked hepatosplenomegaly
• enlarged lymph nodes and leukemic infiltrate of the tonsils
• signs of bleeding are common
• ~1/4 of patients have skin rashes (eczematous eruptions or indurations with central clearing)
• IMP: rarely involves the CNS unless a myeloid sarcoma develops

Question 9

What can be seen in clinically in JMML

patients with a normal karyotype ?

Answer 9

• markedly increased hemoglobin F
• polyclonal hypergammaglobulinemia
• autoantibodies

Question 10

What mutations can be seen in

most JMML cases ?

Answer 10

• 5 canonical mutations
  
  • PTPN11
  • KRAS
  • NRAS
  • NF1
  • CBL
• diagnosed by molecular in >85% of cases

Question 11

What disease must be exluded in JMML,

particularly if genets come back negative ?

Answer 11

• Disorders that have clinical and hematological findings similar to JMML
  
  • infection
  • Wiskott-Aldrich syndrome
  • malignant infantile osteoporosis

Question 12

What are the peripheral blood findings

in JMML ?

Answer 12

• most important specimen for diagnosis
  
  • leukocytosis, thrombocytopenia and anemia
  • due to granulocytes (neutrophils, some left shift) and monocytes
    
    • < 5% blasts
• nRBCs are often seen
  
  • macrocytosis is seen in patients with monosomy 7
  • normocytic RBCs are more common
• thrombocytopenia is common and may be severe

Question 13

What are the typical bone marrow findings

in JMML ?

Answer 13

• non-specific findings
• hypercellular with granulocytic proliferation but in some cases erythroid precursors predominate
• monocytes are less prominent in the bone marrow
• blasts <20% (including promonocytes)
  
  • Auer rods are NEVER present
• dysplasia is usually minimal but can be seen in the granulocytic lineage
• megakaryocytic dysplasia is unusual

Question 14

What is the genetic profile of JMML ?

Answer 14

• monosomy 7 in ~25% of patients
• normal karyotype in 65% of patients
• 85% of patients have driving mutations in ~5 key genes
  
  • PTPN11
    
    • heterozygous somatic gain of function mutations are the most frequent
  • NRAS
  • KRAS
  • CBL
  • NF1

Question 15

How is NF-1 associated with RAS ?

Answer 15

• NF-1 gene product (Neurofibromin)
  
  • negative modulator of RAS function
  • loss of heterozygosity with a loss of the normal NF-1 allele in leukemic cells leads to RAS hyperactivity

Note: ~15% of cases remain RAS mutation negative

Question 16

What are secondary abnormalities observed

in JMML ?

Answer 16

• secondary abnormalities are rare (<50% of cases)
  
  • can have a second hit to RAS pathway
  • or mutations in:
    
    • SETBP1
    • JAK3
    • SH2B3
    • ASXL1
  • usually mean progression rather than at diagnosis

Question 17

Read section on genetic susceptibility to JMML

p. 91

Question 18

What are the prognosis and predictive

factors for JMML ?

Answer 18

• JMML with somatic PTPN11 mutation
  
  • rapidly fatal if not treated (< 1 year)
  • poor predictors: low platelet count, patient age >2 at diagnosis and high Hgb F
• JMML with NRAS or KRAS mutation
  
  • aggressive with early stem cell transplantation needed
• overlapping features between JMML and RALD
  
  • RALD has leukopenia though
  • RALD has an indolent clinical course
• CBL mutations
  
  • spontaneous remission of JMML most of the time