Around 90% of children with JMML have particular genetic mutations, including:
- K-RAS (Kirsten Rat Sarcoma) and N-RAS (Neuroblastoma Rat Sarcoma)
- CBL (Casitas B-lineage Lymphoma)
- NF1 (Neurofibromatosis type 1)
- PTPN 11 (Protein Tyrosine Phosphatase, Non-receptor type 11)
- Chromosome7 deletion
- Additional mutations: Research has shown that patients who have additional mutations (also called secondary mutations) such as in the SETBP1 (SET binding protein 1) gene and the JAK3 (Janus Kinase 3) gene are less likely to achieve a cure compared with those with only one mutation.
For children with JMML, the only possibility of a cure is an Autologous stem cell transplant autologous stem cell transplant (ASCT). Relapse will occur in up to 50% of patients following the ASCT.
For patients with JMML, factors which have been linked to a poor prognosis (i.e. high likelihood of relapse) include:
- Age >2 years old at diagnosis
- SETBP1 and JAK3 mutations, particularly SETBP1
- Low platelet count <33 x 109/L, (normal range: 150-400 x 109/L)
- High haemoglobin foetal (F) levels ≥10%, (normal range: 0.3 to 4.4 %)
What are the symptoms of JMML?
JMML generally progresses slowly, so there may be few symptoms at the onset. The most common symptoms of JMML are listed below; however, children with JMML can show any combination of these symptoms:
- Pale appearance
- General fatigue or weakness
- Decrease in appetite and/or weight loss
- Recurrent infections
- Bruising easily or bleeding
- Developmental delays
- Enlarged liver, spleen or lymph nodes
- Abdominal pain, bone and joint pain (due to overcrowding with monocytes)
In 2013, the discovery of the T618I mutation of CSF3Rgene (colony-stimulating factor 3 receptor) in over 80% of CNL patients has greatly clarified the field of research in CNL. This CSF3RT618I mutation represents a biomarker for diagnosis. The new edition of the 2016 World Health Organization (WHO) classification system for tumours of the hematopoietic and lymphoid tissues, now includes the CSF3RT618I mutation in its diagnostic criteria for CNL.
While CSF3RT618I mutations occur in more than 80% of patients with CNL, they do not occur in some 20% of CNL patients, and these mutations are also known to occur in patients with atypical CML. Consequently, the WHO diagnosis 2016 also requires the exclusion other causes of neutrophilia, including infections and inflammatory processes, metastatic cancer, and plasma cell cancers with secondary neutrophilia. Demonstration of the absence of the BCR-ABL1 mutation, PDGFRA, PDGFRB, or FGFR1, or PCM1-JAK2 rearrangements helps exclude atypical Chronic myeloid leukaemia (CML) and chronic eosinophilic leukaemia (Table 1).
Several recent studies have found other mutations in CNL patients, including JAK2 (Janus Kinase 2), CALR(Calreticulin), ASXL1 (Additional sex combs-like 1) and SETBP1 (SET binding protein 1) mutations. Further research is needed to determine whether these mutations can serve as prognostic markers that will help guide doctors making treatment decisions.
The diagnosis of CNL requires a number of investigations to be able to apply the 2016 WHO diagnostic criteria for CNL.
- Blood samples to measure the complete blood cell counts (number and quality of white blood cells, red blood cells and platelets)
- Bone marrow biopsies: samples of bone marrow cells are obtained by bone marrow aspiration.
The cells from the blood and marrow samples are examined under a microscope by a haematologist (doctor who specialises in diseases of the blood). To achieve a definite diagnosis, the bone marrow will be examined for the following:
- Cell genetic abnormalities
- Karyotyping: This evaluates the number and structure of the chromosomes to identify any abnormalities.
- Polymerase chain reaction test: This test is occasionally performed to determine certain changes in the structure or function of genes.
How is JMML diagnosed?
To make a definite diagnosis of JMML, the criteria set out in the 2016 WHO classification of JMML of myeloid neoplasms and acute leukaemia must be met. They are as follows:
JMML diagnostic criteria – 2016 WHO classification
- Clinical and haematologic features (All four features are mandatory)
- Peripheral blood monocyte count ≥1 x 109/L
- Percentage of blast cells in peripheral blood and bone marrow <20%
- Splenomegaly (enlarged spleen)
- No Philadelphia chromosome, also called re-arrangement of BCR-ABL1 (Breakpoint Cluster Region-Abelson Murine Leukaemia Viral proto-oncogene 1)
- Genetic studies (One finding is sufficient)
- Somatic mutation in PTPN11, K-RAS or N-RAS (Noonan syndrome must be excluded)
- Clinical diagnosis of NF1 or NF1 mutation
- CBL mutation and loss of heterozygosity (genetic variability) of CBL
- For patients without genetic features, besides the clinical and haematologic features listed under 1, the following criteria must be fulfilled:
- Monosomy 7 or any other chromosomal abnormality, or at least two of the following criteria:
- Haemoglobin F (foetal haemoglobin) increased for patient’s age
- Precursors of bone marrow cells or red blood cells seen on peripheral blood smear. Precursor cells are a type of partially differentiated cell which has the capacity to differentiate into only one cell type.
- Granulocyte-macrophage-colony-stimulating factor hypersensitivity in colony assay present
- Hyperphosphorylation of STAT5 (Signal Transducer and Activator of Transcription 5)
JMML is diagnosed by the use of blood tests, bone marrow aspiration and biopsy, including analysis of chromosomes and their abnormalities:
- Full blood count:Also called a complete blood count, this measures the numbers of red blood cells, white blood cells, platelets as well as the level of haemoglobin and the haematocrit, which is the proportion of red blood cells to plasma (fluid component in the blood).
- Bone marrow examination:A bone marrow biopsy is the collection of a sample of bone marrow from the hip bone, generally under local anaesthesia, and its examination under the microscope to determine the number and type of cells present and the level of haematopoiesis (process by which blood cells are formed). A percentage of blast cells <20% is required as part of the diagnosis of JMML.
Other tests may be conducted to assess the patient’s general health and performance of the vital organs. These include:
- Further blood tests
- Genetic testing, with particular reference to the characteristic RAS, PTPN1, NF1, CBL or BCR/ABL1
- Spinal tap/lumbar puncture
- Human leukocyte antigen (HLA) typing
- GM-CSF (Granulocyte-macrophage colony-stimulating factor) hypersensitivity assay
How is JMML treated?
At present, the only successful treatment option for the cure of JMML is an allogeneic stem cell transplant (ASCT). Chemotherapy may alleviate symptoms but cannot offer a cure. Splenectomy before transplantation has not been shown to be of benefit.
Stem cell transplantation
The only effective treatment for JMML currently is an ASCT, which achieves a cure in approximately 50% of patients. Without an ASCT, median survival time for patients with JMML is around one year.
An ASCT is indicated for the majority of children with JMML, particularly for those with NF1 and somatic PTPN11 mutations, and most of those with somatic K-RAS mutations and somatic N-RAS mutation. A certain proportion of patients with somatic N-RAS mutation or CBL mutation have spontaneous regression; therefore, a ‘watch and wait’ strategy is more appropriate for these patients.
A better outcome with an ASCT is often seen for patients of a younger age.
However, an ASCT for these children carries the risk of severe toxicity, during the procedure and later in life.
Prior to children patients receiving the infusion of donor blood cells as part of their ASCT, they normally receive a conditioning regimen. This usually consists of high-dose chemotherapy to eliminate the cancer cells and prevent the immune system rejecting the new stem cells. A period of two to four weeks is generally needed for the stem cells to multiply and make new blood cells, a process which is called engraftment.
Patients are generally conditioned for the ASCT with a regimen of busulfan, cyclophosphamide and melphalan. Total body irradiation is sometimes used as part of the conditioning regimen; however, this is controversial given the possible side effects later in life, such as short stature, learning difficulties, secondary cancers, and sterility.
Graft-versus-host disease is a serious problem that occurs with ASCTs. It happens when the graft (donated marrow or stem cells) reacts against the host (patient receiving the stem cells). The T-cells in the donated stem cells attack and destroy the host’s cells as they see them as foreign bodies. Symptoms of graft-versus-host disease include skin rashes, diarrhoea and liver damage. Graft-versus-host disease can be very mild and short-lived (acute form) or it can be severe and even life threatening, lasting for years (chronic form).
Graft-versus-host disease has been shown to have an important role in the treatment of JMML. Acute or chronic graft-versus-host disease is linked to a lower relapse rate in patients with JMML. Children who receive fewer immunosuppressant drugs in the conditioning regimen have lower relapse rates.
Small studies have reported that not using melphalan and/or substituting cyclophosphamide with fludarabine in the conditioning regimens may decrease acute graft-versus-host disease without affecting overall survival.
Relapse and second ASCT
A relapse represents the main failure of an ASCT for a child with JMML, with the rate being as high as 50%. ASCTs using HLA matched family donors, HLA-matched unrelated donors and HLA-matched unrelated umbilical cord blood donors have generated similar relapse rates, which means that the lack of an HLA matched donor does not prevent good ASCT outcomes. However, despite recent reductions in ASCTs-related deaths, the deaths are still higher with HLA matched unrelated donors, mostly due to infection.
Factors which predict an increased risk of relapse are an age of over four years and having a bone marrow blast percentage greater than 20%. A second ASCT may achieve a cure, particularly when combined with decreased immunosuppression, as this produces a stronger graft-versus-leukaemia effect. Second ASCTs were successfully carried out in 15 patients from the European Working Group/European Bone Marrow Transplant Group (EWOG/EBMT) trial, using the original donor as often as possible, and total body irradiation being the most common conditioning regimen. However, the intentional reduction in the cyclosporine conditioning regimen to prevent relapse did lead to an expected high rate of graft-versus-host disease.
These findings suggest that relapse does not inevitably mean a poor prognosis and that a second ASCT is a valid option for patients in good physical condition. However, whether or not the same donor would be used, if this was feasible, would be up to the discretion of your child’s medical team and what they feel would provide the best outcome for your child.
Without treatment, around one third of patients with JMML will progress rapidly leading to early death. However, there have been reports of some patients remaining in a stable condition despite not receiving treatment for up to 12 years. Nevertheless, without an ASCT, survival time of children with JMML is 10 to 12 months.
Two JMML treatment protocols are commonly used, although they are not internationally accepted as yet:
- The European Working Group of Myelodysplastic Syndromes in Childhood (EWOG-MDS) study protocol: An ASCT after a conditioning regimen of busulphan, cyclophosphamide and melphalan.
- The North American Children’s Oncology Group (COG) study protocol: An ASCT after conditioning with combination of busulfan and fludarabine.
Busulfan, cyclophosphamide, and melphalan are currently recommended as a conditioning regimen for all patients undergoing an ASCT until an appropriate reduced-toxicity regimen can be identified.
Long-term remission of JMML with chemotherapy treatment alone has not been achieved. Nevertheless, chemotherapy can improve the symptoms of JMML in patients who do not suffer from an aggressive form of the disease. Patients with JMML may be given 6 mercatopurine or low-dose intravenous cytarabine to control their symptoms; however, responses are usually temporary. In addition, chemotherapy treatment is given as part of the conditioning regimen prior to an ASCT.
Research into alternative treatments for JMML is focussed on targeted therapies (drugs that specifically interrupt the ability of the leukaemia to grow in the body) and immunotherapies (treatment that uses the body’s own immune system to fight the cancer). These include:
- Azacitidine: This anti-cancer drug works by ‘switching on’ genes that prevent the cancer cells growing and dividing.
- 13-cis retinoic acid: This retinoid drug (related to Vitamin A) is known to inhibit the growth of JMML cells in the laboratory.
- Tipifarnib: This is a farnesyl transferase inhibitor that works by blocking the enzymes necessary for cancer cell growth.
- Trametinib: This is a MEK (mitogen-activated protein kinase kinase enzyme) inhibitor which is being investigated in a COG-sponsored trial, for children with relapsed or refractory JMML.
Other agents that are being investigated for use in JMML include RAS mimetics, SHP-2 (Src homology phosphotyrosine phosphatase 2) inhibitors, anti-GM-CSF antibodies, and chimeric antigen receptor (CAR) T-cell therapy, which involves genetically engineering the patient’s T-cells to target and kill leukaemia cells.