DEFINITION
Clonal hematopoetic disorder caused by an acquired genetic defect in PLURIPOTENT STEM CELLS. It starts in MYELOID CELLS of the bone marrow, invades the blood and then other organs.
JMML mostly occurs in infancy and early childhood. It is similar in some ways to adult chronic myelomonocytic leukemia (CMML) in that, with both JMML and CMML, the change takes place in monocytes.
JMML cells accumulate in the bone marrow and other organs, crowding out normal healthy cells and interfering with the production of sufficient numbers of healthy blood cells such as white blood cells, red blood cells and platelets.
JMML has been known by other names, such as juvenile chronic myelogenous leukemia, chronic granulocytic leukemia, CMML of childhood, chronic and subacute myelomonocytic leukemia and infantile monosomy 7 syndrome.
EPIDEMIOLOGY
JMML accounts for approximately 1.5 percent of childhood leukemia cases. The median age at diagnosis is 2 years. The disease occurs most commonly in infants and children younger than 6 years.
JMML is rarely diagnosed in newborns but many patients are diagnosed at between 3 and 12 months. JMML is more prevalent in males than in females by a ratio of 2.5 to 1.
SYMPTOMS
The International JMML Working Group includes the following signs and symptoms in their diagnostic criteria for JMML:
Enlarged liver, enlarged spleen and/or enlarged lymph nodes.
• Pallor.
• Fever.
• Rash.
Other symptoms and signs that have been described are developmental delay, decrease in appetite, irritability and dry cough.
Characteristic findings in children with JMML: (A) Hepatosplenomegaly in a 2-year old boy at the time of diagnosis. (B) Pulmonary interstitial infiltration by leukemic cells. © Skin infiltration by leukemic cells. (D) Peripheral blood smear with a dysplastic monocyte with nuclear bridging and a blast cell.
DIAGNOSIS
The tests used to diagnose JMML include blood tests and bone marrow aspiration and biopsy to check for additional signs and symptoms, including cytogenetic abnormalities, such as:
• A persistent elevated monocyte count in the blood (greater than 1,000/microliter [1,000/μl] of blood);
• The absence of the Philadelphia chromosome (Ph chromosome) and the BCR-ABL gene rearrangement. The Ph chromosome is an abnormality of chromosome 22 found in the marrow and blood cells of patients with CML (Chronic myeloid leukemia);
• Less than 20 percent blasts in the blood or bone marrow.
Some patients may also have:
• Moderate to severe anemia (low red cell counts) and thrombocytopenia (low platelet counts);
• Increased white cell counts (not more than 100,000/μl).
About 50 percent of JMML patients have certain red blood cell changes including:
• Higher levels of hemoglobin F than is normal for the age of the patient;
• Low levels of carbonic anhydrase (an enzyme);
• Expression of the i antigen on the surface of the red cells.
About 85 percent of JMML patients may have a cytogenetic abnormality. Some of the cytogenetic abnormalities that have been noted in JMML patients include:
• Monosomy 7 and other chromosome 7 abnormalities, which occur in approximately 25 to 30 percent of patients;
• Abnormalities involving chromosomes 3 and 8, which occur in 5 to 10 percent of cases;
• Mutations of the RAS family of genes, which occur in about 25 percent of patients;
• Mutation of the NF1 gene. About 30 percent of JMML patients have the NF1 gene mutation and about 14 percent of JMML patients are also diagnosed with neurofibromatosis 1. In other words, although neurofibromatosis 1 is associated with the NF1 gene mutation, not all children with the NF1 gene mutation develop neurofibromatosis 1. A child with neurofibromatosis 1 has about a 500-fold increased risk of developing JMML or another myeloid disorder;
• Mutation of the PTPN11 gene, which occurs in about 35 percent of patients. The genetic cause for Noonan syndrome is a mutation of the PTPN11 gene. Children with JMML who have the PTPN11 gene mutation may have features associated with Noonan syndrome. These typically include heart malformation, short stature, learning disabilities, indentation of the chest, impaired blood clotting and facial changes.
PATHOGENESIS
The pathogenesis of juvenile myelomonocytic leukemia (JMML) has been speculated to arise from dysregulation of the Ras signal transduction pathway.
Schematic diagram of the RAS signal transduction pathway: Upon binding of cytokines to receptor tyrosine kinases, several adapter molecules (such as Src homology 2 domain-containing proteins [SHC], Src homology 2 domain-containing protein tyro-sine phosphatase 2 [SHP2], growth factor receptor-bound protein 2 [GRB2] and GRB2-associated binding protein 2 [GAB2]) are activated and stimulate guanosine nucleotide exchange factors (GNEF) such as son-of-sevenless homolog 1 (SOS1). GNEF transform RAS into its active GTP-bound state. RAS signaling is terminated by intrinsic RAS-GTP hydrolysis (accelerated by GTPase activating proteins [GAP] such as neurofibromin). Active RAS interacts with several effector pathways. v-raf murine sarcoma viral oncogene homolog (RAF), mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) are serially activated by phosphorylation reactions; active ERK is transferred to the nucleus and regulates cell cycle progression. PI3K is a lipid kinase catalyzing the formation of phosphatidylinositol-triphosphate, a second messenger molecule with activating effect on v-akt murine thymoma viral oncogene homolog (AKT). This protein kinase interacts with target of rapamycin (TOR), a regulator of apoptosis and cell cycle. Other abbreviations: GTP, guanosine triphosphate; GDP, guanosine diphosphate.
It is a hallmark for JMML that leukemic cells demonstrate selective hypersensitivity in vitro to granulocyte macrophage colony-stimulating factor (GM-CSF). Until now, genetic abnormalities in three genes (protein-tyrosine phosphatase, non-receptor type 11 [PTPN11]), RAS, and neurofibromatosis type 1 [NF1]), all of which are positioned in the GM-CSF/Ras signal transduction pathway, account for up to 75% of patients with JMML. Approximately 20 to 30% of patients with JMML have activating RAS mutations, and 12 to 15% of patients with JMML have inactivating NF1 mutations. Mutations in PTPN11 were demonstrated to account for approximately 50% of patients with Noonan syndrome. Interestingly, approximately 30 to 40% of patients with JMML without clinical manifestations of Noonan syndrome have PTPN11 mutations. These mutations are mutually exclusive and functionally equivalent in their involvement in JMML pathogenesis.
THERAPY
There are two widely used JMML treatment protocols.
They are
• The Children’s Oncology Group (COG) JMML Study in North America
• The European Working Group of MDS and JMML in Childhood (EWOG-MDS) Study.
The following procedures are used in one or both of the current clinical trials listed above:
Splenectomy
The theory behind splenectomy 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.
Chemotherapy/Pharmacologic Treatment
The role of chemotherapy 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 transplant, 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 cyclophosphamide 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 busulfan 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 melphalan in its conditioning regimen.
• Graft versus leukemia: Graft versus leukemia[clarification needed] 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 immunosuppressant 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[clarification needed] and to prevent a relapse. Donor lymphocyte infusion (DLI), on the other hand, does not frequently work to bring children with JMML back into remission.
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.
BIBLIOGRAPHY
Chronic Myelomonocytic Leukemia (CMML) and Juvenile Myelomonocytic Leukemia
KUDO K, KOJIMA S. Recent Advances in the Pathogenesis of Juvenile Myelomonocytic Leukemia. Japanese Journal of Pediatric Hematology; 19(1) 1-9 (2005)
Flotho C, Kratz C, Niemeyer C. How a rare pediatric neoplasia can give important insights into biological concepts: a perspective on juvenile myelomonocytic leukemia. haematologica/the hematology journal; 92(11) 1441-1446
