Juvenile myelomonocytic leukemia
Encyclopedia
Juvenile myelomonocytic leukemia (JMML) is a serious chronic leukemia
(cancer of the blood) that affects children mostly aged 4 and younger. The average age of patients at diagnosis is 2 years old. The World Health Organization
has included JMML in the category of Myelodysplastic and Myeloproliferative disorders. The name JMML now encompasses all diagnoses formerly referred to as Juvenile Chronic Myeloid Leukemia (JCML), Chronic Myelomonocytic Leukemia of Infancy, and Infantile Monosomy 7 Syndrome.
in their leukemia cells that can be identified with laboratory testing. This includes:
(discolored but not raised, or small and raised but not containing pus), lymphadenopathy
(enlarged lymph nodes), moderate hepatomegaly (enlarged liver), marked splenomegaly (enlarged spleen), leukocytosis (high white blood cell count in blood), absolute monocytosis (high monocyte count in blood), anemia
(low red blood cell count in blood), and thrombocytopenia
(low platelet count in blood). Most of these conditions are common, nonspecific signs and symptoms.
Children with JMML and Neurofibromatosis 1 (NF1) (about 14% of children with JMML are also clinically diagnosed with NF1, though up to 30% carry the NF1 gene mutation) may also exhibit any of the following symptoms associated with NF1 (in general, only young children with NF1 are at an increased risk of developing JMML):
Children with JMML and Noonan's Syndrome may also exhibit any of the following most-common symptoms associated with Noonan's Syndrome:
All 3 of the following:
Two or more of the following criteria:
These criteria are identified through blood tests and bone marrow tests.
Blood tests: A complete blood count
(CBC) will be performed on a child suspected of having JMML and throughout the treatment and recovery of a child diagnosed with JMML.
The differential diagnosis
list includes infectious diseases like Epstein-Barr virus
, cytomegalovirus
, human herpesvirus 6, histoplasma
, mycobacteria
, and toxoplasma
, which can produce similar symptoms.
The following procedures are used in one or both of the current clinical trials listed above:
is that in JMML, the spleen acts as a trap for leukemic cells, which leads to their enlarged size. The fear is that since radiation therapy
and chemotherapy
attack active leukemia cells rather than dormant ones, if the spleen is not removed it may harbor JMML cells that can later lead to relapse. The impact of splenectomy for post-transplant relapse, though, is unknown. The COG JMML Study includes splenectomy as a standard treatment for all clinically stable patients. The EWOG-MDS JMML Study allows each child’s physician to determine whether or not a splenectomy should be done, and large spleens are commonly removed prior to bone marrow transplant. When a splenectomy is scheduled, JMML patients are advised to receive vaccines against Streptococcus pneumoneae and Haemophilus influenza at least 2 weeks prior to the procedure. Following splenectomy, penicillin may be administered daily in order to protect the patient against bacterial infections that the spleen would otherwise have protected against; this daily preventative regimen will usually continue until the patient is an adult.
against JMML before bone marrow transplant has not been studied and is still unknown. Chemotherapy by itself has proven unable to bring about long-term survival in JMML.
, with about a 50% survival rate. The risk of relapsing after transplant is high, and has been recorded as high as 50%. Generally, JMML clinical researchers recommend that a patient have a bone marrow transplant scheduled as soon as possible after diagnosis. A younger age at bone marrow transplant appears to predict a better outcome.
Relapse: After bone marrow transplant, the relapse rate for children with JMML may be as high as 50%. Relapse often occurs within a few months after transplant and the risk of relapse drops considerably at the one-year point after transplant. A significant number of JMML patients do achieve complete remission and long-term cure after a second bone marrow transplant, so this additional therapy should always be considered for children who relapse.
Without treatment, the survival [5 years?] of children with JMML is approximately 5%. Only Hematopoietic Stem Cell Transplantation (HSCT), commonly referred to as a bone marrow or (umbilical) cord blood transplant, has been shown to be successful in curing a child of JMML. With HSCT, recent research studies have found the survival rate to be approximately 50%. Relapse is a significant risk after HSCT for children with JMML. It is the greatest cause of death in JMML children who have had stem cell transplants. Relapse rate has been recorded as high as 50%. Many children have been brought into remission after a second stem cell transplant.
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
(cancer of the blood) that affects children mostly aged 4 and younger. The average age of patients at diagnosis is 2 years old. The World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
has included JMML in the category of Myelodysplastic and Myeloproliferative disorders. The name JMML now encompasses all diagnoses formerly referred to as Juvenile Chronic Myeloid Leukemia (JCML), Chronic Myelomonocytic Leukemia of Infancy, and Infantile Monosomy 7 Syndrome.
Frequency
JMML accounts for 1-2% of childhood leukemias each year; in the United States, an estimated 25-50 new cases are diagnosed each year, which also equates to about 3 cases per million children. There is no known environmental cause for JMML. Since about 10% of patients are diagnosed before 3 months of age, it is thought that JMML is a congenital condition in these infants.Genetics
About 80% of JMML patients have some sort of genetic abnormalityGenetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
in their leukemia cells that can be identified with laboratory testing. This includes:
- 15-20% of patients with neurofibromatosis 1 (NF1)
- 25% of patients with mutationMutationIn molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in one of the RAS family of oncogeneOncogeneAn oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
s (only in their leukemia cells) - Another 35% of patients with a mutation in a gene called PTPN11PTPN11Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
(again, only in their leukemia cells).
Symptoms
The following symptoms are typical ones which lead to testing for JMML, though children with JMML may exhibit any combination of them: pallor, fever, infection, bleeding, cough, poor weight gain, a maculopapular rashMaculopapular rash
A maculopapular rash is a type of rash characterized by a flat, red area on the skin that is covered with small confluent bumps. The term "maculopapular" is a compound: macules are small, flat discolored spots on the surface of the skin; and papules are small, raised bumps...
(discolored but not raised, or small and raised but not containing pus), lymphadenopathy
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
(enlarged lymph nodes), moderate hepatomegaly (enlarged liver), marked splenomegaly (enlarged spleen), leukocytosis (high white blood cell count in blood), absolute monocytosis (high monocyte count in blood), anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
(low red blood cell count in blood), and thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(low platelet count in blood). Most of these conditions are common, nonspecific signs and symptoms.
Children with JMML and Neurofibromatosis 1 (NF1) (about 14% of children with JMML are also clinically diagnosed with NF1, though up to 30% carry the NF1 gene mutation) may also exhibit any of the following symptoms associated with NF1 (in general, only young children with NF1 are at an increased risk of developing JMML):
- 6 or more café-au-lait (flat, coffee-colored) spots on the skin
- 2 or more neurofibromas (pea-size bumps that are noncancerous tumors) on or under the skin
- Plexiform neurofibromas (larger areas on skin that appear swollen)
- Optic gliomaGliomaA glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
(a tumor on the optic nerve that affects vision) - Freckles under the arms or in the groin
- 2 or more Lisch nodules (tiny tan or brown-colored spots on the iris of the eye)
- Various bone deformations including bowing of the legs below the knee, scoliosisScoliosisScoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
, or thinning of the shin bone
Children with JMML and Noonan's Syndrome may also exhibit any of the following most-common symptoms associated with Noonan's Syndrome:
- Congenital heart defects, in particular, pulmonic stenosisPulmonary valve stenosisPulmonary valve stenosis is a heart valve disorder in which outflow of blood from the right ventricle of the heart is obstructed at the level of the pulmonic valve. This results in the reduction of flow of blood to the lungs. Valvular pulmonic stenosis accounts for 80% of right ventricular outflow...
(a narrowing of the valve from the heart to the lungs) - Undescended testicles in males
- Excess skin and low hair line on back of neck
- Widely set eyes
- Diamond-shaped eyebrows
- Ears that are low-set, backward-rotated, thick outer rim
- Deeply-grooved philtrum (upper lip line)
- Learning delays
Diagnosis
The following criteria are required in order to diagnose JMML:All 3 of the following:
- No Philadelphia chromosomePhiladelphia chromosomePhiladelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia . It is the result of a reciprocal translocation between chromosome 9 and 22, and is specifically designated t...
or BCR/ABL fusion geneFusion geneA fusion gene is a hybrid gene formed from two previously separate genes. It can occur as the result of a translocation, interstitial deletion, or chromosomal inversion...
. - Peripheral blood monocytosisMonocytosisMonocytosis is an increase in the number of monocytes circulating in the blood. Monocytes are white blood cells that give rise to macrophages and dendritic cells in the immune system....
>1 x 109/L. - Less than 20% blasts (including promonocytePromonocyteA promonocyte is a cell arising from a monoblast and developing into a monocyte.-External links:* * - "Bone marrow smear"*...
s) in the blood and bone marrowBone marrowBone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
(blast count is less than 2% on average)
Two or more of the following criteria:
- Hemoglobin FFetal hemoglobinFetal hemoglobin, or foetal haemoglobin, is the main oxygen transport protein in the fetus during the last seven months of development in the uterus and in the newborn until roughly 6 months old...
increased for age. - Immature granulocyteGranulocyteGranulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
s and nucleated red cells in the peripheral blood. - White blood cellWhite blood cellWhite blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
count>1 x 109/L. - Clonal chromosomal abnormality (e.g., monosomy 7).
- Granulocyte macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.
These criteria are identified through blood tests and bone marrow tests.
Blood tests: A complete blood count
Complete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
(CBC) will be performed on a child suspected of having JMML and throughout the treatment and recovery of a child diagnosed with JMML.
The differential diagnosis
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
list includes infectious diseases like Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
, cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
, human herpesvirus 6, histoplasma
Histoplasma
Histoplasma is a genus of dimorphic fungi commonly found in bird and bat fecal material. Histoplasma contains a few species, including—H. capsulatum—the causative agent of histoplasmosis; and Histoplasma capsulatum var. farciminosum , causing epizootic lymphangitis in horses...
, mycobacteria
Mycobacterium
Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
, and toxoplasma
Toxoplasma gondii
Toxoplasma gondii is a species of parasitic protozoa in the genus Toxoplasma. The definitive host of T. gondii is the cat, but the parasite can be carried by many warm-blooded animals . Toxoplasmosis, the disease of which T...
, which can produce similar symptoms.
Treatment
There is an internationally accepted treatment protocol for JMML. Currently, 2 clinical treatment protocols most widely used to study JMML and improve treatment for these children are geographically-based:- North America: The Children’s Oncology Group (COG) JMML Study
- Europe: The European Working Group for Myelodysplastic Syndromes (EWOG-MDS) JMML Study
The following procedures are used in one or both of the current clinical trials listed above:
Splenectomy
The theory behind splenectomySplenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
is that in JMML, the spleen acts as a trap for leukemic cells, which leads to their enlarged size. The fear is that since radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
and chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
attack active leukemia cells rather than dormant ones, if the spleen is not removed it may harbor JMML cells that can later lead to relapse. The impact of splenectomy for post-transplant relapse, though, is unknown. The COG JMML Study includes splenectomy as a standard treatment for all clinically stable patients. The EWOG-MDS JMML Study allows each child’s physician to determine whether or not a splenectomy should be done, and large spleens are commonly removed prior to bone marrow transplant. When a splenectomy is scheduled, JMML patients are advised to receive vaccines against Streptococcus pneumoneae and Haemophilus influenza at least 2 weeks prior to the procedure. Following splenectomy, penicillin may be administered daily in order to protect the patient against bacterial infections that the spleen would otherwise have protected against; this daily preventative regimen will usually continue until the patient is an adult.
Chemotherapy/Pharmacologic Treatment
The role of chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
against JMML before bone marrow transplant has not been studied and is still unknown. Chemotherapy by itself has proven unable to bring about long-term survival in JMML.
- Low-dose conventional chemotherapy: Studies have shown no influence from low-dose conventional chemotherapy on JMML patients’ length of survival. Some combinations of 6-mercaptopurine with other chemotherapy drugs have produced results such as decrease in organ size and increase or normalization of platelet and leukocyte count.
- Intensive chemotherapy: Complete remission from JMML has not been possible through use of intensive chemotherapy, but it is still used at times because it has improved the condition of a small but significant number of JMML patients who do not display an aggressive disease. The COG JMML Study administers 2 cycles of fludarabine and cytarabine for 5 consecutive days along with 13-cis retinoic acid during and afterwards. The EWOG-MDS JMML Study, however, does not recommend intensive chemotherapy before bone marrow transplant.
- 13-cis Retinoic acid (a.k.a. Accutane): In the lab, 13-cis-retinoic acid has been proven to inhibit the growth of JMML cells. The COG JMML Study therefore includes 13-cis-retinoic acid in its treatment protocol, though its therapeutic value for JMML remains controversial.
Radiation/Radiotherapy
Radiation to the spleen does not generally result in a decrease in spleen size or reduction of platelet transfusion requirement.Stem cell transplantation (a.k.a. bone marrow transplant)
The only treatment that has resulted in cures for JMML is a bone marrow transplantBone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
, with about a 50% survival rate. The risk of relapsing after transplant is high, and has been recorded as high as 50%. Generally, JMML clinical researchers recommend that a patient have a bone marrow transplant scheduled as soon as possible after diagnosis. A younger age at bone marrow transplant appears to predict a better outcome.
- Donor: Transplants from a matched family donor (MFD), matched unrelated donor (MUD), and matched unrelated umbilical cord blood donors have all shown similar relapse rates, though transplant-related deaths are higher with MUDs and mostly due to infectious causes. Extra medicinal protection, therefore, is usually given to recipients of MUD transplants to protect the child from Graft Versus Host Disease (GVHD). JMML patients are justified for MUD transplants if no MFD is available due to the low rate of survival without a bone marrow transplant.
- Conditioning regimen: The COG JMML Study involves 8 rounds of total-body irradiation (TBI) and doses of cyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
to prepare the JMML child’s body for bone marrow transplant. Use of TBI is controversial, though, because of the possibility of late side-effects such as slower growth, sterility, learning disabilities, and secondary cancers, and the fact that radiation can have devastating effects on very young children. It is used in this study, however, due to the concern that chemotherapy alone might not be enough to kill dormant JMML cells. The EWOG-MDS JMML Study includes busulfanBusulfanBusulfan is a cancer drug, in use since 1959.Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates...
in place of TBI due to its own research findings that appeared to show that busulfan was more effective against leukemia in JMML than TBI. The EWOG-MDS study also involves cyclophosphamide and melphalanMelphalanMelphalan hydrochloride is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.An alkylating agent adds an alkyl group to DNA...
in its conditioning regimen. - Graft versus leukemia: Graft versus leukemia has been shown many times to play an important role in curing JMML, and it is usually evidenced in a child after bone marrow transplant through some amount of acute or chronic Graft Versus Host Disease (GVHD). Evidence of either acute or chronic GVHD is linked to a lower relapse rate in JMML. Careful management of immunosuppressantImmunosuppressantAn immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...
drugs for control of GVHD is essential in JMML; importantly, children who receive less of this prophylaxis have a lower relapse rate. After bone marrow transplant, reducing ongoing immunosuppressive therapy has worked successfully to reverse the course of a bone marrow with a dropping donor percentage and to prevent a relapse. Donor lymphocyte infusionDonor lymphocyte infusionDonor lymphocyte infusion or buffy coat fusion is a form of adoptive immunotherapy used after hematopoietic stem cell transplantation.-History:...
(DLI), on the other hand, does not frequently work to bring children with JMML back into remission.
Relapse: After bone marrow transplant, the relapse rate for children with JMML may be as high as 50%. Relapse often occurs within a few months after transplant and the risk of relapse drops considerably at the one-year point after transplant. A significant number of JMML patients do achieve complete remission and long-term cure after a second bone marrow transplant, so this additional therapy should always be considered for children who relapse.
Prognosis
Prognosis refers to how well a patient is expected to respond to treatment based on their individual characteristics at time of diagnosis. In JMML, three characteristic areas have been identified as significant in the prognosis of patients:| Characteristic | Values indicating a more favorable prognosis |
|---|---|
| Sex | Male |
| Age at diagnosis | < 2 years old |
| Other existing conditions | Diagnosis of Noonan syndrome Noonan syndrome Noonan Syndrome is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome ; however, the genetic causes of Noonan syndrome and Turner syndrome... |
Without treatment, the survival [5 years?] of children with JMML is approximately 5%. Only Hematopoietic Stem Cell Transplantation (HSCT), commonly referred to as a bone marrow or (umbilical) cord blood transplant, has been shown to be successful in curing a child of JMML. With HSCT, recent research studies have found the survival rate to be approximately 50%. Relapse is a significant risk after HSCT for children with JMML. It is the greatest cause of death in JMML children who have had stem cell transplants. Relapse rate has been recorded as high as 50%. Many children have been brought into remission after a second stem cell transplant.
See also
- List of cutaneous conditions
- Hematologic diseases
- List of cancer types