Juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia
Classification and external resources
Specialty oncology
ICD-10 C93.1
ICD-O 9946
OMIM 607785
MeSH D054429

Juvenile myelomonocytic leukemia (JMML) is a serious chronic leukemia (cancer of the blood) that affects children mostly aged 4 and younger. 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. 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.[1]

Background

Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic and myeloproliferative disorder.[2][3][4] The diagnostic criteria were originally laid down by Neimeyer et al. in 1997[5] and 1998 and were incorporated in the WHO classification in 2008.[6]

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 90% of JMML patients have some sort of genetic abnormality in their leukemia cells that can be identified with laboratory testing.[4] This includes:[7]

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).[3][8] 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):[3]

Noonan syndrome (NS) may predispose to the development of JMML[9] or a myeloproliferative disorder (MPD) associated with NS (MPD/NS) which resembles JMML in the first weeks of life.[9] However, MPD/NS may resolve without treatment.[9] Children with JMML and Noonan's syndrome may also exhibit any of the following most-common symptoms associated with Noonan's syndrome:[3]

Diagnosis

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

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.

Treatment

There are two internationally accepted treatment protocols, which are geographically based:

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.

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.

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.[4][10] 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.

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

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

References

  1. 1 2 "Myelodysplastic/Myeloproliferative Diseases Treatment - National Cancer Institute".
  2. 1 2 Tiu R. V., Sekeres M. A. (2014). "Making sense of the myelodysplastic/myeloproliferative neoplasms overlap syndromes". Current Opinion in Hematology 21 (2): 131–40. doi:10.1097/MOH.0000000000000021. PMID 24378705.
  3. 1 2 3 4 Loh M. L. (2010). "Childhood myelodysplastic syndrome: Focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia". Hematology 2010 (1): 357–62. doi:10.1182/asheducation-2010.1.357. PMID 21239819.
  4. 1 2 3 Chang T. Y., Dvorak C. C., Loh M. L. (2014). "Bedside to bench in juvenile myelomonocytic leukemia: Insights into leukemogenesis from a rare pediatric leukemia". Blood 124 (16): 2487–2497. doi:10.1182/blood-2014-03-300319. PMID 25163700.
  5. ↑ Niemeyer C. M., Arico M, Basso G, Biondi A, Cantu Rajnoldi A, Creutzig U, Haas O, Harbott J, Hasle H, Kerndrup G, Locatelli F, Mann G, Stollmann-Gibbels B, Van't Veer-Korthof E. T., Van Wering E, Zimmermann M (1997). "Chronic myelomonocytic leukemia in childhood: A retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS)". Blood 89 (10): 3534–43. PMID 9160658.
  6. ↑ Sethi N, Kushwaha S, Dhingra B, Pujani M, Chandra J, Shukla S (2013). "Juvenile myelomonocytic leukemia". Indian Journal of Hematology and Blood Transfusion 29 (3): 164–6. doi:10.1007/s12288-012-0164-9. PMC 3710560. PMID 24426365.
  7. ↑ Niemeyer C. M. (2014). "RAS diseases in children". Haematologica 99 (11): 1653–1662. doi:10.3324/haematol.2014.114595. PMC 4222471. PMID 25420281.
  8. ↑ "Juvenile myelomonocytic leukemia.". Semin Diagn Pathol 28 (4): 298–303. Nov 2011. PMID 22195407.
  9. 1 2 3 Bastida P, García-Miñaúr S, Ezquieta B, Dapena J. L., De Toledo Sanchez (2011). "Myeloproliferative disorder in Noonan syndrome". Journal of Pediatric Hematology/Oncology 33 (1): e43–5. doi:10.1097/MPH.0b013e3181e7571e. PMID 20829714.
  10. 1 2 Yoshida N, Doisaki S, Kojima S (2012). "Current management of juvenile myelomonocytic leukemia and the impact of RAS mutations". Pediatric Drugs 14 (3): 157–63. doi:10.2165/11631360-000000000-00000. PMID 22480363.

External links

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