Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein. This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER. Juvenile myelomonocytic leukemia (JMML) is a rare leukemia that occurs approximately ten times less frequently than acute myeloid leukemia in children. The annual incidence is about 1 to 2 cases per 1 million people.[1] JMML is the most common myeloproliferative neoplasm observed in young children, presenting at a median age of approximately 1.8 years. It occurs more commonly in boys (male-to-female ratio, approximately 2.5:1). References: Common clinical features at diagnosis include the following:[1] Patients may also present with an elevated white blood cell count and increased circulating monocytes.[1] References: The World Health Organization (WHO) classifies juvenile myelomonocytic leukemia (JMML) as a RAS pathway activation–driven myeloproliferative neoplasm (MPN) of early childhood.[1] For information about the classification system for acute myeloid leukemia (AML), see the World Health Organization (WHO) Classification System for Childhood AML section in Childhood Acute Myeloid Leukemia Treatment. References: In children presenting with clinical features suggestive of juvenile myelomonocytic leukemia (JMML), current criteria for a definitive diagnosis are described in Table 1.[1] References: The pathogenesis of juvenile myelomonocytic leukemia (JMML) has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (see Figure 1).[1,2] In addition, distinctive RNA expression and DNA methylation patterns have been reported. These patterns are correlated with clinical factors such as age and appear to be associated with prognosis.[3,4] Syndromes and genetic features associated with an increased risk of developing JMML include the following:[5,6] Importantly, some children with Noonan syndrome have hematologic features indistinguishable from JMML that self-resolve during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.[2,10] In a large prospective cohort of 641 patients with Noonan syndrome and a germline PTPN11 variant, 36 patients (approximately 6%) showed myeloproliferative features, with 20 patients (approximately 3%) meeting the consensus diagnostic criteria for JMML.[10] CBL germline variants result in an autosomal dominant developmental disorder that is often characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML.[13,15] Some individuals with CBL germline variants experience spontaneous regression of their JMML but develop vasculitis later in life,[13] whereas patients with only somatic CBL variants require therapy.[15] JMML arising from germline variants is clinically indistinguishable from JMML arising from somatic variants, which necessitates studies of both normal and leukemic tissue.[15]CBL variants are nearly always mutually exclusive of RAS and PTPN11 variants.[11] References: Molecular Features of JMML The genomic landscape of JMML is characterized by variants in one of five genes of the RAS pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[1,2,3] In a series of 118 consecutively diagnosed JMML cases with RAS pathway–activating variants, PTPN11 was the most commonly altered gene, accounting for 51% of cases (19% germline and 32% somatic) (see Figure 2).[1] Patients with NRAS variants accounted for 19% of cases, and patients with KRAS variants accounted for 15% of cases. NF1 variants accounted for 8% of cases, and CBL variants accounted for 11% of cases. Although variants among these five genes are generally mutually exclusive, 4% to 17% of cases have variants in two of these RAS pathway genes,[1,2,3] a finding that is associated with poorer prognosis.[1,3] The variant rate in JMML leukemia cells is very low, but additional variants beyond those of the five RAS pathway genes described above are observed.[1,2,3] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was altered in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also altered at low rates in JMML (e.g., SETBP1 was altered in 6%–9% of cases).[1,2,3,4]JAK3 variants are also observed in a small percentage (4%–12%) of JMML cases.[1,2,3,4] Cases with germline PTPN11 and germline CBL variants showed low rates of additional variants (see Figure 2).[1] The presence of variants beyond disease-defining RAS pathway variants is associated with an inferior prognosis.[1,2] A report describing the genomic landscape of JMML found that 16 of 150 patients (11%) lacked canonical RAS pathway variants. Among these 16 patients, 3 were observed to have in-frame fusions involving receptor tyrosine kinases (DCTN1::ALK, RANBP2::ALK, and TBL1XR1::ROS1 gene fusions). These patients all had monosomy 7 and were aged 56 months or older. One patient with an ALK gene fusion was treated with crizotinib plus conventional chemotherapy and achieved a complete molecular remission and proceeded to allogeneic bone marrow transplant.[3] Genomic and Molecular Prognostic factors Several genomic factors affect the prognosis of patients with JMML, including the following: References: Historically, more than 90% of patients with juvenile myelomonocytic leukemia (JMML) died despite the use of chemotherapy.[1] However, with the application of hematopoietic stem cell transplant, survival rates of approximately 50% are now observed.[2] Patients appeared to follow three distinct clinical courses: Favorable prognostic factors for survival after any therapy include the following:[3,4] In contrast, being older than 2 years and having high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[3,4] References: Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence.[2] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life: For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care. The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[3] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website. References: Treatment options for juvenile myelomonocytic leukemia (JMML) include the following: HSCT HSCT currently offers the best chance of cure for JMML.[1,2,3,4,5] Evidence (HSCT): Disease recurrence is the primary cause of treatment failure for children with JMML after HSCT and occurs in 30% to 40% of cases.[1,2,3] While the role of donor lymphocyte infusions is uncertain,[10] reports indicate that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.[11] In a prospective study, four children with relapsed JMML after stem cell transplant were treated with azacitidine. Three patients responded to azacitidine and were able to proceed to a second transplant.[12] The role of conventional antileukemia therapy in the treatment of JMML is not defined. Determining the role of specific agents in the treatment of JMML is complicated because of the absence of consensus response criteria.[13] Some agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and mercaptopurine), isotretinoin, and farnesyl inhibitors, but none of these have been shown to improve outcome.[13,14,15,16,17]; [18][Level of evidence B4] References: Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website. The following is an example of a national and/or institutional clinical trial that is currently being conducted: The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above. Treatment of Juvenile Myelomonocytic Leukemia (JMML) Added text to state that in a prospective study, four children with relapsed JMML after stem cell transplant were treated with azacitidine. Three patients responded to azacitidine and were able to proceed to a second transplant (cited Rubio-San-Simón et al. as reference 12). Treatment Options Under Clinical Evaluation Added NCT05849662 as an open clinical trial available for patents with newly diagnosed JMML. This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages. Purpose of This Summary This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of juvenile myelomonocytic leukemia. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions. Reviewers and Updates This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH). Board members review recently published articles each month to determine whether an article should: Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary. The lead reviewers for Juvenile Myelomonocytic Leukemia Treatment are: Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries. Levels of Evidence Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Permission to Use This Summary PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]." The preferred citation for this PDQ summary is: PDQ® Pediatric Treatment Editorial Board. PDQ Juvenile Myelomonocytic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq/childhood-jmml-treatment-pdq. Accessed <MM/DD/YYYY>. 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Questions can also be submitted to Cancer.gov through the website's Email Us. Last Revised: 2024-06-14 This information does not replace the advice of a doctor. Ignite Healthwise, LLC disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use and Privacy Policy. Learn how we develop our content. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Ignite Healthwise, LLC.Topic Contents
Juvenile Myelomonocytic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]
Incidence
Clinical Presentation
World Health Organization Classification
Diagnostic Criteria
GM-CSF = granulocyte-macrophage colony-stimulating factor; JMML = juvenile myelomonocytic leukemia; WHO = World Health Organization. a Germline variants inPTPN11,KRAS, orNRAS(which cause Noonan syndrome) may lead to JMML-like transient myeloproliferative disorder. b Occasional cases have heterozygous splice-site variants. c Such asRRASorRRAS2. d For cases that do not meet the genetic criteria or if genetic testing is not available. These individuals must meet the following criteria in addition to the clinical, hematologic, and laboratory criteria. Clinical, Hematologic, and Laboratory Criteria (All Criteria Are Required for Diagnosis) 1. Peripheral blood monocyte count is ≥1 × 109 /L 2. Blasts and promonocytes constitute <20% of peripheral blood and bone marrow 3. Clinical evidence of organ infiltration, most commonly splenomegaly 4. Absence of theBCR::ABL1fusion gene 5. Absence of aKMT2Arearrangement Genetic Criteria (1 Criterion is Sufficient for Diagnosis) 1. A variant in a component or a regulator of the canonical RAS pathway: a) A clonal somatic variant inPTPN11,KRAS, orNRASa b) A clonal somatic or germline variant inNF1and a loss of heterozygosity or compound heterozygosity inNF1 c) A clonal somatic or germline variant inCBLand a loss of heterozygosity inCBLb 2. A noncanonical clonal RAS pathway pathogenic variantc or fusions that activate genes located upstream of the RAS pathway, such asALK,PDGFRB, andROS1 Other Criteria (2 or More Are Required for Diagnosis)d 1. Circulating myeloid (promyelocytes, myelocytes, metamyelocytes) and erythroid precursors 2. Increased hemoglobin F for age 3. Thrombocytopenia with hypercellular bone marrow, often with megakaryocytic hypoplasia. Dysplastic features may or may not be evident 4. Myeloid progenitors are hypersensitive to GM-CSF (detected by clonogenic assays or by measuring STAT5 phosphorylation in the absence or with low dose of exogenous GM-CSF) Pathogenesis and Risk Factors
Figure 1. Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and the gene mutations found to date contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML. NL/MGCL: Noonan-like/multiple giant cell lesion; CFC: cardia-facio-cutaneous; JMML: juvenile myelomonocytic leukemia. Reprinted from Leukemia Research, 33 (3), Rebecca J. Chan, Todd Cooper, Christian P. Kratz, Brian Weiss, Mignon L. Loh, Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium, Pages 355-62, Copyright 2009, with permission from Elsevier.Genomics of Juvenile Myelomonocytic Leukemia (JMML)
Figure 2. Alteration profiles in individual JMML cases. Germline and somatically acquired alterations with recurring hits in the RAS pathway and PRC2 network are shown for 118 patients with JMML who underwent detailed genetic analysis. Blast excess was defined as a blast count ≥10% but <20% of nucleated cells in the bone marrow at diagnosis. Blast crisis was defined as a blast count ≥20% of nucleated cells in the bone marrow. NS, Noonan syndrome. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 [11]: 1334-40, 2015), copyright (2015).Clinical Prognostic Factors
Special Considerations for the Treatment of Children With Cancer
Treatment of JMML
Treatment Options Under Clinical Evaluation
Latest Updates to This Summary (06 / 14 / 2024)
About This PDQ Summary
Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein.Juvenile Myelomonocytic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]