Juvenile myelomonocytic leukemia

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Juvenile myelomonocytic leukemia
Specialty Oncology, hematology   OOjs UI icon edit-ltr-progressive.svg
Usual onsetUnder 4 years old [1]
Treatment Stem cell transplant
FrequencyOne to two children out of one million diagnosed each year [1]

Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia (cancer of the blood) that affects children, commonly those aged four and younger. [2] 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 two (2) years old. [2] The World Health Organization has included JMML as a subcategory of myelodysplastic and myeloproliferative disorders.

Contents

Signs and symptoms

The following symptoms are typical ones that lead to testing for JMML, though children with JMML may exhibit any combination of them:

Most of these conditions show 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):

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

Genetics

About 90% of JMML patients have some form of a genetic abnormality in their leukemia cells that is identifiable with laboratory testing. [3] This includes: [4]

Diagnosis

The following criteria are required in order to diagnose JMML: [8]

All 4 of the following:

At least one of: [10]

Or two or more of the following criteria:

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 widely used JMML treatment protocols: stem cell transplantation and drug therapy. [12] There are four common subtypes of internationally accepted treatment protocols, which are based and clinically tested in the geographical location of the patient: [13] [14] [15]

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 a splenectomy on post-transplant regression is unknown. [16] 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 two weeks prior to the procedure. Following splenectomy, penicillin may have to be administered daily to protect the patient against bacterial infections that the spleen would otherwise have protected against; this daily preventative regimen will often continue indefinitely. [17]

Chemotherapy

The role of chemotherapy or other pharmacologic treatments against JMML before bone marrow transplant has not undergone final clinical testing, and its importance is still unknown. Chemotherapy by itself has proven unable to bring about long-term survival in JMML.

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. [3] [11] 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. It is predicted that the younger the patient is at the time of a bone marrow transplant, the better outcome of the procedure will be. [19]

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: [22]

CharacteristicValues indicating a more favorable prognosis
SexMale
Age at diagnosis< 2 years old
Other existing conditionsDiagnosis of Noonan syndrome

Without treatment, the survival rate of children under the age of five (5) of children with JMML is approximately 5%. [23] Only Hematopoietic Stem Cell Transplantation (HSCT), commonly referred to as bone marrow or (umbilical) cord blood transplant, is 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 most leading cause of death in JMML children who have had stem cell transplants. Relapse rate has been recorded as high as 50%. If the first treatment was not entirely successful, many children have been brought into remission after a doctor recommended second stem cell transplant. [24]

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.[ citation needed ]

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 three months of age, it is thought that JMML is a congenital condition in these infants. [12] [13] [25]

History

Juvenile myelomonocytic leukemia (JMML) is a myelodysplastic and myeloproliferative disorder. [9] [26] [3] The diagnostic criteria were originally laid down by Neimeyer et al. in 1997 [27] and 1998 and were incorporated in the WHO classification in 2008. [28]

See also

Related Research Articles

<span class="mw-page-title-main">Leukemia</span> Blood cancers forming in the bone marrow

Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, AR, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce additional normal blood cells. It may be autologous, allogeneic or syngeneic.

<span class="mw-page-title-main">Tumors of the hematopoietic and lymphoid tissues</span> Tumors that affect the blood, bone marrow, lymph, and lymphatic system

Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making aplasia, myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.

<span class="mw-page-title-main">Myeloid sarcoma</span> Medical condition

A myeloid sarcoma is a solid tumor composed of immature white blood cells called myeloblasts. A chloroma is an extramedullary manifestation of acute myeloid leukemia; in other words, it is a solid collection of leukemic cells occurring outside of the bone marrow.

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<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Medical condition

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

Acute myelomonocytic leukemia (AMML) is a form of acute myeloid leukemia that involves a proliferation of CFU-GM myeloblasts and monoblasts. AMML occurs with a rapid increase amount in white blood cell count and is defined by more than 20% of myeloblast in the bone marrow. It is classified under "M4" in the French-American-British classification (FAB). It is classified under "AML, not otherwise classified" in the WHO classification.

<span class="mw-page-title-main">Childhood leukemia</span> Medical condition

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Bone marrow failure occurs in individuals who produce an insufficient amount of red blood cells, white blood cells or platelets. Red blood cells transport oxygen to be distributed throughout the body's tissue. White blood cells fight off infections that enter the body. Bone marrow also contains platelets, which trigger clotting, and thus help stop the blood flow when a wound occurs.

Guo Mei is a hematologist and associate director of 307th Hospital of Chinese People’s Liberation Army and deputy director of Radiation Research Institute.

Refractory cytopenia of childhood is a subgroup of myelodysplastic syndrome (MDS), having been added to the World Health Organization classification in 2008. Before then, RCC cases were classified as childhood aplastic anemia. RCC is the most common form of MDS in children and adolescents, accounting for approximately half of all MDS cases.

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<span class="mw-page-title-main">Transfusion-dependent anemia</span>

Transfusion-dependent anemia is a form of anemia characterized by the need for continuous blood transfusion. It is a condition that results from various diseases, and is associated with decreased survival rates. Regular transfusion is required to reduce the symptoms of anemia by increasing functional red blood cells and hemoglobin count. Symptoms may vary based on the severity of the condition and the most common symptom is fatigue. Various diseases can lead to transfusion-dependent anemia, most notably myelodysplastic syndromes (MDS) and thalassemia. Due to the number of diseases that can cause transfusion-dependent anemia, diagnosing it is more complicated. Transfusion dependence occurs when an average of more than 2 units of blood transfused every 28 days is required over a period of at least 3 months. Myelodysplastic syndromes is often only diagnosed when patients become anemic, and transfusion-dependent thalassemia is diagnosed based on gene mutations. Screening for heterozygosity in the thalassemia gene is an option for early detection.

References

  1. 1 2 "Juvenile Myelomonocytic Leukemia". St. Jude Children's Research Hospital . Retrieved 2003-09-24.
  2. 1 2 Leukemia & Lymphoma Society. "Treatment". www.lls.org. Retrieved 2023-03-23.
  3. 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.
  4. ↑ Niemeyer C. M. (2014). "RAS diseases in children". Haematologica. 99 (11): 1653–1662. doi:10.3324/haematol.2014.114595. PMC   4222471 . PMID   25420281.
  5. ↑ "Neurofibromatosis | Types, Symptoms, Diagnosis & Treatment". www.cincinnatichildrens.org. Retrieved 2023-04-25.
  6. ↑ Prior, Ian A.; Hood, Fiona E.; Hartley, James L. (2020-07-15). "The Frequency of Ras Mutations in Cancer". Cancer Research. 80 (14): 2969–2974. doi:10.1158/0008-5472.CAN-19-3682. ISSN   0008-5472. PMC   7367715 . PMID   32209560.
  7. ↑ Kratz, Christian P.; Niemeyer, Charlotte M.; Castleberry, Robert P.; Cetin, Mualla; Bergsträsser, Eva; Emanuel, Peter D.; Hasle, Henrik; Kardos, Gabriela; Klein, Cornelia; Kojima, Seiji; Stary, Jan; Trebo, Monika; Zecca, Marco; Gelb, Bruce D.; Tartaglia, Marco (2005-09-15). "The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease". Blood. 106 (6): 2183–2185. doi:10.1182/blood-2005-02-0531. ISSN   0006-4971. PMC   1895140 . PMID   15928039.
  8. ↑ "Myelodysplastic/Myeloproliferative Diseases Treatment - National Cancer Institute". 2003-09-24.
  9. 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. S2CID   28142057.
  10. ↑ Lee, Ming-Luen; Yen, Hsiu-Ju; Chen, Shu-Jen; Hung, Giun-Yi; Tsao, Pei-Chen; Soong, Wen-Jue (1 April 2016). "Juvenile Myelomonocytic Leukemia in a Premature Neonate Mimicking Neonatal Sepsis". Pediatrics & Neonatology. 57 (2): 149–152. doi: 10.1016/j.pedneo.2013.06.009 . ISSN   1875-9572. PMID   24269860.
  11. 1 2 Yoshida N, Doisaki S, Kojima S (2012). "Current management of juvenile myelomonocytic leukemia and the impact of RAS mutations". Paediatric Drugs. 14 (3): 157–63. doi:10.2165/11631360-000000000-00000. PMID   22480363. S2CID   30523534.
  12. 1 2 Leukemia & Lymphoma Society. "Treatment". www.lls.org. Retrieved 2023-03-23.
  13. 1 2 Seeger, Nancy C. (2018-10-02). "Childhood Leukemia: A Guide for Families, Friends, & Caregivers, 5th ed.". Journal of Consumer Health on the Internet. 22 (4): 398–400. doi:10.1080/15398285.2018.1544824. ISSN   1539-8285. S2CID   86528106.
  14. ↑ Karagün, Barbaros Şahin; Şaşmaz, İlgen; Antmen, Bülent; Kılınç, Yurdanur (2014-09-05). "Juvenile Myelomonocytic Leukemia (JMML)". The Journal of Pediatric Research. 1 (3): 118–126. doi: 10.4274/jpr.09797 . ISSN   2147-9445.
  15. ↑ Flotho, C.; Kratz, C. P.; Niemeyer, C. M. (2007-11-01). "How a rare pediatric neoplasia can give important insights into biological concepts: a perspective on juvenile myelomonocytic leukemia". Haematologica. 92 (11): 1441–1446. doi: 10.3324/haematol.11280 . ISSN   0390-6078. PMID   18024390. S2CID   17912138.
  16. ↑ Zaorsky, Nicholas G.; Williams, Graeme R.; Barta, Stefan K.; Esnaola, Nestor F.; Kropf, Patricia L.; Hayes, Shelly B.; Meyer, Joshua E. (February 2017). "Splenic irradiation for splenomegaly: A systematic review". Cancer Treatment Reviews. 53: 47–52. doi:10.1016/j.ctrv.2016.11.016. ISSN   1532-1967. PMC   7537354 . PMID   28063304.
  17. ↑ Meyerson, Howard; Awadallah, Amad; Blidaru, Georgetta; Osei, Ebenezer; Schlegelmilch, June; Egler, Rachel; Abu-Arja, Rolla; Ding, Hilda (October 2017). "Juvenile myelomonocytic leukemia with prominent CD141+ myeloid dendritic cell differentiation". Human Pathology. 68: 147–153. doi:10.1016/j.humpath.2017.03.025. PMID   28414089.
  18. ↑ Wintering, Astrid; Dvorak, Christopher C.; Stieglitz, Elliot; Loh, Mignon L. (23 November 2021). "Juvenile myelomonocytic leukemia in the molecular era: a clinician's guide to diagnosis, risk stratification, and treatment". Blood Advances. 5 (22): 4783–4793. doi:10.1182/bloodadvances.2021005117. PMC   8759142 .
  19. 1 2 3 Koyama, M.; Nakano, T.; Takeshita, Y.; Sakata, A.; Sawada, A.; Yasui, M.; Okamura, T.; Inoue, M.; Kawa, K. (September 2005). "Successful treatment of JMML with related bone marrow transplantation after reduced-intensity conditioning". Bone Marrow Transplantation. 36 (5): 453–454. doi:10.1038/sj.bmt.1705047. ISSN   1476-5365. PMID   15968292. S2CID   8427672.
  20. ↑ Yoshimi, Ayami; Niemeyer, Charlotte M.; Bohmer, Viktoria; Duffner, Ulrich; Strahm, Brigitte; Kreyenberg, Hermann; Dilloo, Dagmar; Zintl, Felix; Claviez, Alexander; Wössmann, Willi; Kremens, Bernhard (2005). "Chimaerism analyses and subsequent immunological intervention after stem cell transplantation in patients with juvenile myelomonocytic leukaemia". British Journal of Haematology. 129 (4): 542–549. doi: 10.1111/j.1365-2141.2005.05489.x . ISSN   1365-2141. PMID   15877738.
  21. 1 2 Pulsipher, M A; Adams, R H; Asch, J; Petersen, F B (2004-01-01). "Successful treatment of JMML relapsed after unrelated allogeneic transplant with cytoreduction followed by DLI and interferon-alpha: evidence for a graft-versus-leukemia effect in non-monosomy-7 JMML". Bone Marrow Transplantation. 33 (1): 113–115. doi: 10.1038/sj.bmt.1704287 . ISSN   0268-3369. PMID   14704663. S2CID   22909903.
  22. ↑ Satwani, Prakash; Kahn, Justine; Dvorak, Christopher C. (2015-02-01). "Juvenile Myelomonocytic Leukemia". Pediatric Clinics of North America. Childhood Leukemia and Cancer. 62 (1): 95–106. doi:10.1016/j.pcl.2014.09.003. ISSN   0031-3955. PMID   25435114.
  23. ↑ Castleberry, Robert P.; Loh, Mignon L.; Jayaprakash, Nalini; Peterson, April; Casey, Vicky; Chang, Myron; Widemann, Brigitte; Emanuel, Peter D. (2005-11-16). "Phase II Window Study of the Farnesyltransferase Inhibitor R115777 (Zarnestra®) in Untreated Juvenile Myelomonocytic Leukemia (JMML): A Children's Oncology Group Study". Blood. 106 (11): 2587. doi:10.1182/blood.V106.11.2587.2587. ISSN   0006-4971.
  24. ↑ Feng, Xiaoqin; Peng, Zhiyong; He, Yuelin; Li, Chunfu; Ruan, Yongsheng; Liu, Xuan; Ding, Rongfang; Tan, Wanxia (2019-11-13). "Improvement of Survival in JMML By Induction Regimen of Decitabine + Cytarabine + Fludarabine before Hematopoietic Stem Cell Transplantation: Study of 33 Cases in Single Center". Blood. 134 (Supplement_1): 4267. doi: 10.1182/blood-2019-130488 . ISSN   0006-4971. S2CID   209233950.
  25. ↑ Karagün, Barbaros Şahin; Şaşmaz, İlgen; Antmen, Bülent; Kılınç, Yurdanur (2014-09-05). "Juvenile Myelomonocytic Leukemia (JMML)" (PDF). The Journal of Pediatric Research. 1 (3): 118–126. doi:10.4274/jpr.09797.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
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