• 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

Genetics

About 90% of JMML patients have some sort of genetic abnormality in their leukemia cells that can be identified with laboratory testing.^[9] This includes:^[10]

• 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).

Diagnosis

The following criteria are required in order to diagnose JMML:^[1]

All 4 of the following:

• No Philadelphia chromosome or BCR/ABL fusion gene.^[12]
• 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)
• Splenomegaly

At least one of:^[1]

• Mutation in RAS or PTPN11
• Diagnosis of neurofibromatosis 1
• Chromosome 7 monosomy

Or 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 >10 x 10⁹/L.
• Clonal chromosomal abnormality (e.g., monosomy 7).
• Granulocyte macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.^[14]

These criteria are identified through blood tests and bone marrow tests.

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 are two internationally accepted treatment protocols, which are geographically based:{{citation needed|date=March 2017}}

• 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 approaches listed above:

Splenectomy

The theory behind splenectomy in JMML is that the spleen may trap leukemic cells, leading to the spleen's enlargement, by harboring dormant JMML cells that are not eradicated by radiation therapy or chemotherapy for the active leukemia cells, thus leading to later relapse if the spleen is not removed. However, the impact of splenectomy on post-transplant relapse, though, is unknown. The COG JMML study includes splenectomy as a standard component of 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 pneumoniae 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 often continue indefinitely.{{citation needed|date=March 2017}}

Chemotherapy

The role of chemotherapy or other pharmacologic treatments against JMML before bone marrow transplant has not been studied completely and its importance 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 with ongoing durability 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 (Isotretinoin): In the lab, 13-cis-retinoic acid has inhibited 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

Radiation to the spleen does not generally result in a decrease in spleen size or reduction of platelet transfusion requirement.

Stem cell transplantation

The only treatment that has resulted in cures for JMML is stem cell transplantation, also known as a bone marrow transplant, with about a 50% survival rate.^[9][14] 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{{Clarify|date=July 2010}} 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{{Clarify|date=July 2010}} 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.

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:{{Citation needed|date=July 2010}}

Without treatment, the survival [5 years?]{{Clarify|date=July 2010}} of children with JMML is approximately 5%.{{Citation needed|date=July 2010}} 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. {{Citation needed|date=July 2010}}

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.

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{{citation needed|date=March 2017}}

History

Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic and myeloproliferative disorder.^[12][2][9] The diagnostic criteria were originally laid down by Neimeyer et al. in 1997^[20] and 1998 and were incorporated in the WHO classification in 2008.^[21]

See also

• List of cutaneous conditions
• Hematologic diseases
• List of cancer types

References