Juvenile myelomonocytic leukemia

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.

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 abnormality 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 mutations in one of the RAS family of oncogenes (only in their leukemia cells)
 * Another 35% of patients with a mutation in a gene called PTPN11 (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 rash (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):


 * 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 glioma (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, scoliosis, 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 stenosis (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 chromosome or BCR/ABL fusion gene.
 * Peripheral blood monocytosis >1 x 109/L.
 * Less than 20% blasts (including promonocytes) in the blood and bone marrow (blast count is less than 2% on average)

Two or more of the following criteria:
 * Hemoglobin F increased for age.
 * Immature granulocytes and nucleated red cells in the peripheral blood.
 * White blood cell 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 (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.

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 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 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 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.

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:

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.