Updated on 23.03.2024

Introduction:

• It is a RAS pathway activation driven myeloproliferative disorder of childhood, characterized by proliferation of granulocytic & monocytic lineages

Epidemiology:

• Account for less than 2-3% of all leukemias in children.
• 1.2 cases per million children 0-14 years of age per year
• M:F= 2:1
• Seen from 1 month of age to early adolescence(Median age 2 years)
• May be associated with Neurofibromatosis type 1 & Noonan’s syndrome
• Some are associated with germline CBL syndrome (associated with autoimmune vasculitis)

Pathogenesis:

• Mutations in RAS genes (90% cases):  NRAS, KRAS  and rarely RRAS, RRAS2, RIT1 etc
• Mutations in regulators of the RAS pathway: PTPN11, NF1, CBL etc
• Hypersensitivity to G-CSF
• Myeloid progenitor cells in JMML have ability to form spontaneous granulocyte macrophage colonies in vitro & have marked hyper sensitivity to GM-CSF

Clinical Features:

• Failure to thrive
• Malaise, pallor
• Fever due to infection
• Evidence of bleeding
• Maculopapular skin rash
• Café au lait spots – In patients with NF-1
• Hepatosplenomegaly
• Lymphadenopathy
• Enlarged tonsils due to leukemic infiltration
• Skin infiltration by tumour cells is often seen
• May cause myeloid sarcoma of CNS, facial palsy and diabetes insipidus.

Investigations:

• Hemogram
  • Leucocytosis – 25 -35 x 10⁹ / L
  • Monocytosis- >1000/cmm. They have atypical morphology.
  • Normocytic/ macrocytic anaemia, nRBCs are seen
  • Thrombocytopenia
  • Neutrophilia with abnormal nuclear segmentation and pseudo- Pelger- Huet anomaly. 
  • Increased promyelocytes & myelocytes
  • Basophilia and eosinophilia may be present.
  • Blasts - < 5%
• Bone marrow
  • Hypercellular with granulocytic proliferation with no/minimal dysplastic changes
  • Erythroid hyperplasia may be present with megaloblastic change
  • Limited monocytic infiltration (5-10% of cells).
  • Blasts < 20%
  • Megakaryocytes – Reduced number
• S. Protein electrophoresis- Polyclonal hypergammaglobulinemia
• Serum lysozyme levels – Increased.
• HbF levels- Increased
• Immunophenotyping-Aberrant blast population expressing CD7 and decreased levels of CD13 and CD33. HLA-DR expression in decreased in monocytes.
• IHC for lysozyme and CD38 – Positive in tissues (detects monocytic components)
• Cytochemistry
  • Bone marrow – Nonspecific esterase - positive (monocytes)
• Cytogenetics- Monosomy 7
• Molecular studies
  • No BCR / ABL fusion gene
  • Mutation in genes of RAS pathway: KRAS, NRAS, PTPN11, NF1, CBL
• Hypersensitivity to GM-CSF

Criteria for Diagnosis:

• Clinical, haematological, and laboratory criteria (all 5 criteria are required)
  • Peripheral blood monocyte count ≥ 1,000/cmm
  • Blast and promonocyte percentage in peripheral blood and bone marrow of < 20%
  • Clinical evidence of organ infiltration, most commonly splenomegaly
  • No Philadelphia (Ph) chromosome or BCR-ABL1 fusion
  • No KMT2A (MLL1) gene rearrangement
• Genetic criteria (any 1 criterion is sufficient)
  • Mutation in a component or a regulator of the canonical RAS pathway:
    • Clonal somatic mutation in PTPN11, KRAS, or NRAS
    • Clonal somatic or germline NF1 mutation and loss of heterozygosity or compound heterozygosity of NF1
    • Clonal somatic or germline CBL mutation and loss of heterozygosity of CBL
  • Non-canonical clonal RAS pathway pathogenic variant or fusions causing activation of genes upstream of the RAS pathway, such as ALK, PDGFR-B, ROS1, among others.

If genetic criteria are not met or where genetic testing is not available, must meet ≥ 2 of the following:

• Increased haemoglobin F for age
• Myeloid (promyelocytes, myelocytes, metamyelocytes) and erythroid precursors on peripheral blood smear
• Thrombocytopenia with hypercellular marrow often showing decreased number of megakaryocytes. Dysplastic features may or may not be evident.
• Hypersensitivity of myeloid progenitors to GM-CSF as tested in clonogenic assays in methylcellulose or by measuring STAT5 phosphorylation in the absence or with low dose of exogenous GM-CSF.

Prognosis:

• Untreated- 30% die within 1 year
• Median survival – 5 months to 4 years
• Poor Prognostic Factors
  • Age > 2 years at the time of presentation
  • Platelet count < 33 x 10⁹ / L
  • Hb F levels > 15%
• Common cause of death – Respiratory failure due to leukemic infiltration

Pretreatment Work-up:

• History
• Examination:            Spleen:
• Neurofibromatosis
• BSA
• Flow cytometry
• BMA and Bx
• Haemoglobin
• TLC, DLC
• Abs Monocyte Count
• Platelet count
• Peripheral smear
• HbF level
• LFT: Bili- T/D    SGPT:     SGOT:Albumin:      Globulin:
• Creatinine
• Electrolytes: Na:         K:         Ca:Mg:           PO4:
• Uric acid
• LDH
• HIV
• HBsAg
• HCV
• Cytogenetics
• BCR-ABL- 1
• ECHO- LVEF-              %
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment:

• Spontaneous resolution may be seen in JMML in Noonan syndrome
• Watchful waiting must be done in all asymptomatic JMML patients. Meanwhile donor search must be initiated.In patients aged <2 years with favorable cytogenetics, resolution may occur without treatment
• Start Tab. 6MP- 50mg/m2/day +/- Cis Retinoic acid- 100mg/m2/day, if
  • Counts are very high
  • Pulmonary symptoms like cough/ tachypnea
  • Prominent organomegaly
• If child becomes progressively ill- Inj. Cytarabine- 40mg/m2/day for 5 days.
• Allogeneic stem cell transplant
  • Done after remission induction which can be done by 
    • AML like induction chemotherapy
    • Low dose chemotherapy
    • Azacytidine
    • Interferon alfa
    • Cis Retinoic acid
  • Cure is seen in 50% patients
  • Poor outcome if age >4 years and in female patient.
  • Conditioning with- Busulfan, cyclophosphamide and melphalan
  • Pretransplant splenectomy does not affect the outcome.
  • MUD is as good as MSD

Other Treatment Options:

• Newer approaches that are being studied:
  • GM-CSF antagonist- E21R
  • Inhibitors of RAF-1 gene expression
  • Blockers of RAS protein farnesylation
  • Angiogenesis inhibitors