同: juvenile myelomonocytic leukemia

同: juvenile myelomonocytic leukemia

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/04/18 21:24:00」(JST)

wiki en

w

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]

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).^[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]

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

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]

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:^[1]

All 3 of the following:

No Philadelphia chromosome or BCR/ABL fusion gene.^[2]
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 >10 x 10⁹/L.
Clonal chromosomal abnormality (e.g., monosomy 7).
Granulocyte macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.^[10]

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:

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.

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.^[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.

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.

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:^{[citation needed]}

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?]^{[clarification needed]} of children with JMML is approximately 5%.^{[citation needed]} 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]}

References

^ ^a ^b "Myelodysplastic/Myeloproliferative Diseases Treatment - National Cancer Institute".
^ ^a ^b 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.
^ ^a ^b ^c ^d 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.
^ ^a ^b ^c 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.
^ 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.
^ 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. PMID 24426365.
^ Niemeyer C. M. (2014). "RAS diseases in children". Haematologica 99 (11): 1653–1662. doi:10.3324/haematol.2014.114595. PMID 25420281.
^ "Juvenile myelomonocytic leukemia.". Semin Diagn Pathol 28 (4): 298–303. Nov 2011. PMID 22195407.
^ ^a ^b ^c 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.
^ ^a ^b 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

The JMML Foundation
European Working Group of MDS and JMML in Childhood

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 慢性骨髄性白血病の臨床症状および診断 clinical manifestations and diagnosis of chronic myeloid leukemia
2. 骨髄異形成症候群の臨床症状および診断 clinical manifestations and diagnosis of the myelodysplastic syndromes
3. 骨髄増殖性腫瘍の概要 overview of the myeloproliferative neoplasms
4. 若年性黄色肉芽腫（JXG） juvenile xanthogranuloma jxg
5. 造血腫瘍の分類 classification of the hematopoietic neoplasms

English Journal

Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML.

Hirabayashi S, Flotho C, Moetter J, Heuser M, Hasle H, Gruhn B, Klingebiel T, Thol F, Schlegelberger B, Baumann I, Strahm B, Stary J, Locatelli F, Zecca M, Bergstraesser E, Dworzak M, van den Heuvel-Eibrink MM, De Moerloose B, Ogawa S, Niemeyer CM, Wlodarski MW.SourcePediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany;
Blood.Blood.2012 Jan 11. [Epub ahead of print]
Somatic mutations of the spliceosomal machinery occur frequently in adult patients with myelodysplastic syndrome (MDS). We re-sequenced SF3B1, U2AF35 and SRSF2 in 371 children with MDS or juvenile myelomonocytic leukemia (JMML). We found missense mutations in two JMML cases and in one child with sys
PMID 22238327

Molecular targets for the treatment of juvenile myelomonocytic leukemia.

Liu X, Sabnis H, Bunting KD, Qu CK.SourceDivision of Hematology and Oncology, Department of Medicine, Center for Stem Cell and Regenerative Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Advances in hematology.Adv Hematol.2012;2012:308252. Epub 2011 Nov 13.
Significant advances in our understanding of the genetic defects and the pathogenesis of juvenile myelomonocytic leukemia (JMML) have been achieved in the last several years. The information gathered tremendously helps us in designing molecular targeted therapies for this otherwise fatal disease. Va
PMID 22162691

Japanese Journal

若年性骨髄単球性白血病 (今月の特集 MDS/MPNを知ろう)

臨床検査 59(10), 990-997, 2015-10
NAID 40020599109

JMMLその分子病態と治療

血液内科 = Hematology 70(5), 632-637, 2015-05
NAID 40020491370

若年性骨髄単球性白血病(JMML)の急性転化

血液内科 70(3), 397-402, 2015-03
NAID 40020447112

Related Pictures

Leukemia Skin Symptoms Definition of « JMML » Jmml is one of the many conditions that 查看《jmml》原图，原图尺寸 Marrow findings in JMML - 1. Jmml Symptoms JMML Juvenile Myelomonocytic Leukemia (JMML)