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| {{Juvenile myelomonocytic leukemia}} | | {{Juvenile myelomonocytic leukemia}} |
| | '''For patient information page, please click [[ Juvenile myelomonocytic leukemia (patient information)|here]]''' |
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| {{CMG}} | | {{CMG}} |
| ==Overview== | | ''' |
| | ==[[Juvenile myelomonocytic leukemia overview|Overview]]== |
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| == Frequency == | | ==[[Juvenile myelomonocytic leukemia pathophysiology|Pathophysiology]]== |
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| == Genetics == | | ==[[Juvenile myelomonocytic leukemia epidemiology and demographics|Epidemiology and Demographics]]== |
| About 80% of JMML patients have some sort of genetic abnormality in their leukemia cells that can be identified with laboratory testing. This includes:
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| *15-20% of patients with [[neurofibromatosis 1]] (NF1)
| | ==[[Juvenile myelomonocytic leukemia risk factors|Risk Factors]]== |
| *25% of patients with mutations in one of the [[Ras (protein)|RAS]] family of [[oncogene]]s (only in their leukemia cells)
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| *Another 35% of patients with a mutation in a gene called [[PTPN11]] (again, only in their leukemia cells).
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| == Symptoms == | | ==[[Juvenile myelomonocytic leukemia screening|Screening]]== |
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| == Diagnosis == | | ==[[Juvenile myelomonocytic leukemia natural history|Natural History, Complications and Prognosis]]== |
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| The following criteria are required in order to diagnose JMML:
| | ==[[Juvenile myelomonocytic leukemia classification|Classification]]== |
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| All 3 of the following:
| | ==[[Juvenile myelomonocytic leukemia causes|Causes]]== |
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| *No Philadelphia chromosome or BCR/ABL fusion gene.
| | ==[[Juvenile myelomonocytic leukemia differential diagnosis|Differentiating Juvenile myelomonocytic leukemia from other Disorders]]== |
| *Peripheral blood monocytosis >1 x 109/L.
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| *Less than 20% blasts (including promonocytes) in the blood and bone marrow (blast count is less than 2% on average)
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| Two or more of the following criteria:
| | == Diagnosis == |
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| *Hemoglobin F increased for age.
| | :[[Juvenile myelomonocytic leukemia history and symptoms| History and Symptoms]] | [[Juvenile myelomonocytic leukemia physical examination | Physical Examination]] | [[Juvenile myelomonocytic leukemia staging | Staging]] | [[Juvenile myelomonocytic leukemia laboratory tests | Lab Studies]] | [[Juvenile myelomonocytic leukemia electrocardiogram|Electrocardiogram]] | [[Juvenile myelomonocytic leukemia chest x ray|Chest X Ray]] | [[Juvenile myelomonocytic leukemia MRI|MRI]] | [[Juvenile myelomonocytic leukemia CT|CT]] | [[Juvenile myelomonocytic leukemia echocardiography|Echocardiography]] | [[Juvenile myelomonocytic leukemia other diagnostic studies|Other Diagnostic Studies]] |
| *Immature granulocytes and nucleated red cells in the peripheral blood.
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| *White blood cell count>1 x 109/L.
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| *Clonal chromosomal abnormality (e.g., monosomy 7).
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| *Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.
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| These criteria are identified through blood tests and bone marrow tests.
| | ==Treatment== |
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| '''Blood tests''': A Combined 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. | | :'''Medical:''' [[Juvenile myelomonocytic leukemia medical therapy|Medical Therapy]] |
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| '''NOTE''': | | :'''Surgical:''' [[Juvenile myelomonocytic leukemia surgery|Surgical Therapy]] |
| JMML can show many of the same signs as infectious diseases like Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, histoplasma, mycobacteria, and toxoplasma. Therefore, it is important that your doctor rule out these other potential causes of your child’s symptoms during the diagnosis process.
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| == Treatment ==
| | :'''Radiation:''' [[ Juvenile myelomonocytic leukemia radiation therapy |Radiation Therapy]] |
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| There is no 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:
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| - North America: The Children’s Oncology Group (COG) JMML Study
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| - Europe: The European Working Group for Myelodysplastic Syndromes (EWOG-MDS) JMML Study
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| - Other clinical trials open to patients with JMML may be searched for at the NIH Clinical Trials website.
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| The following procedures are used in one or both of the current clinical trials listed above:
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| ===Splenectomy===
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| 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 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 spleenectomy 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.
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| ===Chemotherapy/Pharmacologic Treatment===
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| 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.
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| ====Low-dose conventional chemotherapy====
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| 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.
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| ====Intensive chemotherapy====
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| 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.
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| ====13-cis Retinoic acid (a.k.a. [[Accutane]])====
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| 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.
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| ===Radiation/Radiotherapy===
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| Radiation to the spleen does not generally result in a decrease in spleen size or reduction of platelet transfusion requirement.
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| ===Stem cell transplantation (a.k.a. bone marrow transplant)===
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| 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.
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| ====Donor====
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| 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.
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| ====Conditioning regimen====
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| 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.
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| ====Graft versus leukemia====
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| 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.
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| ====Relapse====
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| 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.
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| ==== Prognosis ====
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| 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:
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| {| class="wikitable"
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| ! Characteristic
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| ! Values indicating a more favorable prognosis
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| | Sex
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| | Male
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| | Age at diagnosis
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| | < 2 years old
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| | Other existing conditions
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| | Diagnosis of [[Noonan syndrome]]
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| |}
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| Without treatment, the survival 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.
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| | ==Case Studies== |
| | ''' |
| ==References== | | ==References== |
| {{reflist}} | | {{reflist|2}} |
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| ==External links== | | ==External links== |
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| {{Hematological malignancy histology}} | | {{Hematological malignancy histology}} |
| {{SIB}}
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| [[Category:Hematology]] | | [[Category:Hematology]] |