Case 96 – summary

Thank you for participating in our case this week.

This week we have been looking at a case of JMML (Juvenile myelomonocytic leukaemia), which is a rare clonal haematopoietic disorder of childhood, characterised by the proliferation of granulocytic and monocytic lineages. Blasts and promonocytes account for < 20% of the WBC in the peripheral blood and bone marrow. Erythroid and megakaryocytic abnormalities are often present. BCL-ABL fusion is absent. Mutations involving genes of the RAS pathway are characteristic.

Incidence is estimated as 1 in 1 million children. But with increased frequency in children with Noonan syndrome and neurofibromatosis (NF1). It accounts for < 2 – 3 % of all leukaemia in children, but for 20- 30 % of all cases of MDS/MPNs in those aged < 14 years. Age of diagnosis ranges from 1 month to early adolescence. 75% of cases are in children aged < 3 years. Boys are affected twice as frequently as girls.

WHO diagnostic criteria for JMML (revised 4th edition, 2017):

1. Clinical and haematological criteria (all 4 criteria are required)

  • Peripheral blood monocytes > 1 x 10^9/L
  • Blast in peripheral blood and bone marrow < 20%
  • Splenomegaly
  • No Philadelphia chromosome or BCR-ABL fusion

2. Genetic criteria (any 1 is sufficient)

  • Somatic mutation in PTPN11, KRAS or NRAS (if a mutation is found, must consider whether it might be a germ line mutation and the diagnosis of TAM of Noonan syndrome considered)
  • Clinical diagnosis of neurofibromatosis type 1 or NF1 mutation
  • Germline CBL mutation and loss of heterozygosity of CBL

3. 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:

  • > 2 of the following :
    • Increased HbF for age
    • Myeloid or erythroid precursors on peripheral blood smear
    • Granulocyte-macrophage colony-stimulating factor (CSF2) hypersensitivity in colony assay
    • Hyperphosphorylation of STAT5

Clinical Features:

  • Most present with constitutional symptoms or infection
  • Generally marked hepato-splenomegaly
  • Spleen size may occasionally be normal at diagnosis but rapidly increases thereafter
  • 50% may have lymphadenopathy
  • Leukaemic infiltrations
    • Enlarged tonsils
    • Dry cough, tachypnoea, interstitial infiltrates on CXR (pulmonary infiltration)
    • Diarrhoea, GI infections (gut infiltration)
  • 25% may have rashes, cafe-au-lait spots may indicate NF1 or Noonan syndrome
  • Raised HbF
  • Polyclonal hypergammaglobulinaemia and presence of autoantibodies
  • In vitro hypersensitivity of JMML myeloid progenitors to granulocyte-macrophage colony-stimulating factor (CSF2) – though this is infrequently performed nowadays
  • Peripheral blood typically shows leukocytosis, thrombocytopenia and often anaemia.
    • Leukocytosis consists mainly of neutrophils, monocytes and some immature cells e.g. promyelocytes and myelocytes.
    • Blasts usually <5% and always < 20%
    • Eosinophilia and basophils can sometimes be present
    • Normocytic red cell indices is the most common, but macrocytosis can be seen particularly in monosomy 7
    • Thrombocytopenia can be severe

Molecular abnormalities:

  • RAS pathway mutation now allow molecular diagnosis in approx 85-90% of all JMML (PTPN11, NRAS, KRAS, NF1 and CBL)
  • Most common gene is PTPN11 – found in 35% of JMML
    • PTPN11 encodes a protein tyrosine phosphatase, SH2.
    • Germ-line missense mutations in PTPN11 are found in about 50% of Noonan syndrome patients, this is a more indolent JMML that may resolve spontaneously
    • The acquired PTPN11 mutations in JMML are not the same, and are more aggressive
  • Mutations in NRAS or KRAS are seen in about 30% of JMML
  • About 10-15% have homozygous mutations in CBL. These are also thought to be heterozygous germ-line events and somatic loss of heterozygosity
  • Germ-line mutations of NF1 found in about 10% of JMML
    • Children with NF1 are at 200-350 times increased risk of developing JMML

Genetics:

Monosomy 7 is present in about 25% patients. Other abnormalities in 10% and normal karyotype in 65%.

Immunophenotype

There is no specific immunopheotypic abnormalities reported in JMML.

Differentials:

In RAS pathway mutation-negative cases, other clinical and haematological conditions must be excluded, for example:

  • Infection
  • Wiscott-Aldrich syndrome (eczema-thrombocytopenia-immunodeficiency syndrome)
  • Malignant infantile osteopetrosis
  • HLH

Prognosis:

JMML with somatic PTPN11 mutation or in those with NF1 are rapidly fatal if left untreated. Median survival without allogeneic haematopoietic stem cell transplantation is about 1 year.

Poor prognostic factors include low platelet count ( < 33 x 10^9/L), aged > 2years and high Haemoglobin F levels at diagnosis.

KRAS and NRAS mutation generally has an aggressive course. Most children with JMML and germ-line CBL mutations experience spontaneous regression of JMML.

Management of JMML

JMML has a diverse molecular etiology. Clinical genetics assessment should be considered. Some JMML can be indolent particularly in the context of Noonan syndrome. But these are the exceptions.

Patients with CBL mutation can be managed with a watch and wait approach initially, and to consider HSCT if there is disease progression.

However, most cases of JMML require HSCT for cure. Even so, the relapse rate post HSCT is reported to be 40 – 50%.

If a matched sibling donor is unavailable, then a matched unrelated donor should be sought, or to consider unrelated umbilical cord blood unit transplant.

HSCT from an HLA-haploidentical relative is still experimental in JMML, but can be considered if an urgent allograft is needed but lack any other suitable donors.

Conditioning is usually a myeloablative busulfan-based regime (e.g. busulfan, cyclophosphamide and melphalan) without total body irradiation (TBI), in order to minimise the late effects from TBI in very young children.

ATG is often used in the conditioning regime if a MUD or UCBT is used in children with JMML, as it reduces the complications from GvHD.

GvHD prophylaxis should also be tailored according to patients’ genetic lesions and other risk factors influencing the relapse rate. Those with high risk relapse rate should be given low-intensity GvHD prophylaxis in order to maximise GvL effect.

Indiscriminate splenectomy prior to HSCT in children with spleen enlargement is not recommended. However, in the presence of massive splenomegaly with hypersplenism and/or platelet refractoriness, it could be considered in selected cases.

The use of conventional chemotherapy is an area of controversy and there are no established recommendations. Some have used 6-mercaptopurine and/or low dose cytarabine to reduce leukocytosis and spleen size. In children with blastic transformation or life threatening pulmonary infiltration, fludarabine and high dose cytarabine may be temporary holding measures.

Clinical trials are ongoing looking at azacitidine and MEK inhibitors.

In relapse disease following allograft, DLI is not recommended. A second HSCT should be used as salvage therapy, either from the same or a different donor.

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