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Juvenile myelomonocytic leukaemia

Leukaemia is the most common cancer among children. It affects more than 350 children a year in our country, a third of which are under 4 years of age.  Leukaemia accounts for 30% of all paediatric cancers, with B-acute lymphoblastic leukaemia being the most common form among children (80% of cases). Acute myeloid leukaemia affects approximately 20% of paediatric leukaemia patients, especially below the age of 2 years. Juvenile myelomonocytic leukaemia is a rare and severe form of leukaemia that affects fewer than 10 children a year in our country.

The information provided on www.fcarreras.org is intended to support, not replace, the relationship that exists between patients/visitors to this website and their physician.

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Information endorsed by… Information endorsed by the Spanish Society of Hematology and Hemotherapy.

Information provided by Dr. Laura Belver, researcher in juvenile myelomonocytic leukaemia at the Josep Carreras Leukaemia Research Institute

Leukaemia is a type of blood cell and bone marrow cancer. See section Leukaemia, bone marrow and blood cells.

Juvenile myelomonocytic leukaemia (JMML) is a very rare type of leukaemia, with an incidence of only 1.2 cases per million children under the age of 14, and is more common in boys than in girls (2 out of every 3 patients). Each year, between 5 and 10 cases of JMML are diagnosed in Spain, the vast majority in children under the age of 2, although it can also occur at older ages, especially in patients with neurofibromatosis type 1. Approximately 10% of JMML cases occur in babies under 3 months of age.

JMML occurs when stem cells or progenitor cells in the bone marrow, which are responsible for generating all blood cells, behave abnormally, proliferating uncontrollably and producing large numbers of monocytes in the blood, which infiltrate different organs in the patient.

 

In most cases of JMML, a single genetic mutation is enough to trigger the disease, which is unusual in cancer, where several accumulated mutations are normally required. This mutation usually appears spontaneously, without any known specific cause or way to prevent it. However, some developmental disorders, such as neurofibromatosis type 1 or CBL syndrome, may make a child more prone to developing juvenile myelomonocytic leukaemia (JMML). In 90% of patients, the causative mutation is found in one of these five genes: PTPN11, KRAS, NRAS, CBL or NF1.

In the remaining 10%, the genetic mutation that acts as the trigger for the disease is still unknown.

Leukaemia, like other types of cancer, is not contagious. See section Leukaemia, bone marrow and blood cells.

JMML is highly heterogeneous and has always been difficult to classify. Over time, it has been referred to by different names, including juvenile chronic myeloid leukaemia, childhood chronic myelomonocytic leukaemia and childhood monosomy 7 syndrome. See JMML classification.

Today, classification is mainly based on which gene is mutated, as this influences the behaviour of the disease. Cases associated with mutations in the PTPN11, NRAS or KRAS genes usually follow a more aggressive course, as do those related to NF1, whereas some cases associated with CBL mutations may even resolve spontaneously without the need for treatment.

In addition to the mutated gene, the accumulation in the cell’s DNA of a chemical modification called methylation is also assessed. Patients with higher levels of methylation usually have a more aggressive disease and a poorer prognosis, which is why this information is increasingly used as a classification tool and to guide treatment decisions.

The clinical presentation of  LMMJ is variable and, in general, symptoms at diagnosis are due to leukaemic cells having infiltrated the bone marrow and other organs, hindering their correct functioning.

This can lead to:

  • Tiredness, weakness, dizziness and paleness, as a result of low levels of red blood cells in the blood (anaemia).
  • Appearance of bruises and small pink spots on the skin (petechiae), as well as other types of bleeding such as nosebleeds or gum bleeding, due to low numbers of platelets in the blood.
  • Fever and infections that do not evolve well (bronchitis, tonsillitis…), due to deficient generation of immune system cells.
  • Sometimes painful swelling of the lymph nodes, the liver or spleen occur, due to the accumulation of leukaemic cells. 
  • Pain or a feeling of fullness in the ribs
  • Dry cough
  • Loss of appetite and insufficient growth

At the onset of the disease, all these symptoms can be mistaken for those of a viral infection, therefore obtaining a final diagnosis of the patient can take several weeks. However, in general, this does not affect the child’s curative options.

In addition to the basic blood and bone marrow tests common to all types of leukaemia (morphology and cell count, immunophenotyping) cytogenetic analyses, to detect chromosomal abnormalities, and molecular analyses, to detect mutations, are essential for typing and classifying the disease.

As in other types of leukaemia, JMML is characterised by an abnormal accumulation of blasts in the bone marrow. These immature cells, which under normal conditions account for less than 5% of bone marrow cellularity, progressively invade the marrow as the disease advances. In JMML, this percentage must be between 5% and 20%. In addition, diagnosis requires a very marked increase in the number of blood cells called monocytes. Alongside these morphological features, confirmation comes with the identification of mutations in one of the five reference genes —PTPN11, KRAS, NRAS, CBL or NF1— and the absence of genetic alterations associated with other leukaemias, such as the BCR::ABL translocation or rearrangements of the KMT2A gene.

There is currently no specific treatment to treat (JMML). The only treatment that has demonstrated curative potential is haematopoietic progenitor cell transplantation (bone marrow transplant) from an HLA-compatible donor. Despite this, it is a therapy that is not without risks and complications and, approximately 30% of children relapse after transplantation.

The decision on when to transplant depends largely on the causative mutation and the behaviour of the disease: in most cases, transplantation is recommended as soon as possible once the diagnosis has been confirmed, while in cases associated with CBL syndrome, given its tendency towards spontaneous resolution, watchful waiting may be chosen, closely observing the patient before deciding whether intervention is necessary. It is highly recommended that the child be treated in a reference centre with haematologists experienced in treating this disease.

Before carrying out the transplant, it is necessary to control the disease and keep the child in the best possible condition while a compatible donor is located. Traditionally, this was achieved with intensive chemotherapy regimens, but in recent years azacitidine, a drug that acts by reversing DNA methylation, has been incorporated as a more effective and much better tolerated alternative. Patients who achieve temporary remission of the leukaemia during this phase generally have a better long-term prognosis.

Immediately before the transplant, the child receives a new course of high-dose chemotherapy, usually with busulfan, cyclophosphamide and melphalan, known as conditioning, the aim of which is to prepare the body to receive and accept the donor’s new bone marrow.

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When chemotherapy is administered intravenously, to avoid repeatedly puncturing a vein, a special device called a catheter is used. The catheter is inserted into a large vein and allows both the administration of medicines, and the drawing of blood for tests, thereby avoiding repeated punctures in the child.

There is a type of catheter, called a port-a-cath, which is connected to a round plastic or metal reservoir that remains under the skin of the chest. The port-a-cath is very practical in children because, as it remains under the skin, it prevents the child from pulling it out, is less likely to become infected than other types of catheter and allows the child to bathe.

The chances of cure are determined by the characteristics of the patient, of the disease (genetic/molecular alterations), and by the response to treatment.

Around 50% of patients achieve long-term complete remission after bone marrow transplantation, although the risk of relapse is significant: between 30 and 40% of children will relapse within the first year. In some cases, a second bone marrow transplant is considered for these children.

JMML has historically represented a clinical challenge mainly due to the limited number of therapeutic options for its treatment, the high risk of mortality in children with the most aggressive forms of the disease and the small number of patients, which makes it very difficult to recruit enough participants to conduct clinical trials with reliable results.

Although bone marrow transplantation is currently the only curative treatment, advances in research into this disease have made it possible to identify new therapeutic strategies that are currently under study. The most relevant is the use of MEK inhibitors, such as trametinib (Mekinist®). The typical mutations in JMML (PTPN11, KRAS, NRAS, CBL or NF1) affect a mechanism that controls cell division known as the RAS pathway, causing it to become hyperactivated and the cells to proliferate uncontrollably. MEK inhibitors block this pathway, preventing the mutations from sustaining the growth of the leukaemia. These treatments are showing promising results in some cases, but it is common for the tumour to find a way to escape this attack. For this reason, efforts are increasingly focusing on their use as a bridge to bone marrow transplantation, in combination with azacitidine. Currently, these trials are not active in Spain, although in exceptional cases in which approved treatments have not worked, access to trametinib through compassionate use may be considered.

After completing treatment, the child will continue to have regular check-ups with their haematologist and with other specialists if necessary. This follow-up includes blood and bone marrow tests, as well as monitoring the child’s general development in the long term. These check-ups are necessary in order to detect early and act quickly in the event of a possible relapse or the appearance of treatment-related after-effects, and they are progressively spaced out until they take place once a year.

CHILDHOOD LEUKAEMIA MATERIAL

The Josep Carreras Foundation has a story “The tough baby” aimed at children or siblings suffering from leukaemia. It is especially aimed at children up to the age of 6. If you want to order it, please send us an e-mail to imparables@fcarreras.es.

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We also invite you to follow us through our main social media (Facebook, Twitter and Instagram) where we often share testimonies of overcoming this disease.

If you live in Spain, you can also contact us by sending an e-mail to imparables@fcarreras.es so that we can help you get in touch with other people who have overcome this disease.

* In accordance with Law 34/2002 on Information Society Services and Electronic Commerce (LSSICE), the Josep Carreras Leukemia Foundation informs that all medical information available on www.fcarreras.org has been reviewed and accredited by Dr. Enric Carreras Pons, Member No. 9438, Barcelona, ​​Doctor in Medicine and Surgery, Specialist in Internal Medicine, Specialist in Hematology and Hemotherapy and Senior Consultant of the Foundation; and by Dr. Rocío Parody Porras, Member No. 35205, Barcelona, ​​Doctor in Medicine and Surgery, Specialist in Hematology and Hemotherapy and attached to the Medical Directorate of the Registry of Bone Marrow Donors (REDMO) of the Foundation).

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