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Juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia
Literature review current through: Jan 2024.
This topic last updated: Aug 19, 2022.

INTRODUCTION — Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative/myelodysplastic disorder of infancy and childhood that is manifest as increased infiltration of the peripheral blood, bone marrow, and viscera by abnormal myelomonocytic cells. The vast majority of patients with JMML have somatic and/or germline mutations of genes within the RAS/MAPK signaling pathway. Allogeneic hematopoietic cell transplantation is the only curative therapy for JMML.

The clinical manifestations, diagnosis, prognosis, and treatment of JMML will be reviewed here. Chronic myelomonocytic leukemia (CMML) and chronic myeloid leukemia (CML) are discussed separately. Overviews of myelodysplastic syndromes and myeloproliferative neoplasms are discussed separately.

(See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

(See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

(See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

(See "Overview of the myeloproliferative neoplasms".)

PATHOGENESIS — Although much is known about the underlying molecular defects in JMML, the precise mechanisms by which these abnormalities cause this aggressive leukemia remain to be fully elucidated. The vast majority of children with JMML have somatic and/or germline mutations of genes involved in the RAS/MAPK signaling pathway. The resultant pathologic activation of signaling causes hypersensitivity of myeloid progenitor cells to the granulocyte-monocyte colony stimulating factor (GM-CSF) [1-4]. In vitro hypersensitivity of monocyte/macrophage colonies to GM-CSF long represented a diagnostic tool for JMML, and is still used as a minor diagnostic criterion for those patients without an identified underlying molecular defect. (See 'Diagnosis' below.)

Mutations in NF1, PTPN11, KRAS, NRAS, or CBL are found in more than 90 percent of patients with JMML. Alterations of JAK2, TET2, RUNX1, ASXL1, and FLT3, which are commonly associated with myeloproliferative neoplasms (MPNs) of adulthood, are rarely seen in JMML [1,5-9]. In most cases, the mutations associated with JMML are mutually exclusive within a given individual, suggesting that a mutation in any one of these genes is sufficient to activate the signaling pathway and drive the proliferation of JMML cells [2]. Secondary mutations of other signaling molecules are seen in a minority of patients, and these secondary mutations may be associated with tumor progression and worse clinical outcomes [10,11].

DNA methylation patterns correlate with outcomes in JMML. DNA hypermethylation and epigenetic silencing of genes involved with cell proliferation (eg, CDKN2B, RASA4) may contribute to treatment resistance [12,13]. However, it is uncertain if these effects contribute to the pathogenesis of JMML or are epiphenomena of a broader hypermethylation phenotype [14].

Ras pathway — Ras signaling proteins are ubiquitously expressed small guanosine triphosphatase (GTPase) molecules that play diverse roles in cell cycle control, proliferation, survival, and differentiation. Activation of Ras stimulates the mitogen-activated protein kinase (MAPK) cascade, which includes Raf, PI3K, and Ral-GDS. Key components of the pathway are illustrated in the figure (figure 1).

Mutations of RAS/MAPK pathway genes that have been reported in JMML include:

NF1 (neurofibromin)

PTPN11 (SHP2)

KRAS

NRAS

CBL (Casitas B-lineage lymphoma)

Mutations associated with JMML activate the RAS pathway by several mechanisms [1,15]. Some of these mutations block inactivation of the Ras proteins leaving them in an "on" state. As an example, neurofibromin (NF1), a GTPase activating protein (GAP), normally functions to accelerate GTP hydrolysis and thereby "turns off" Ras. Mutation of NF1 blunts this mechanism for deactivation of Ras and results in increased Ras activity.

Other mutations promote the activation of Ras. Mutations in PTPN11 lead to activation of SHP2 and ultimately Ras. RAS mutations can result in increased activation and/or resistance to GAP inactivation. Mutations of CBL, which encodes an E3 ubiquitin ligase that contributes to degradation of certain signaling molecules, is postulated to lead to cytokine-independent growth. Regardless of the upstream mechanism of activation, increased Ras activity stimulates the MAPK cascade, including Raf, P13K, and Ral-GDS [16].

While mutations in hematopoietic cells are the cause of JMML in nearly all cases, mutations in other cells in the bone marrow microenvironment may play a role in other cases. This was suggested in an animal model of JMML in which PTPN11 mutations in bone marrow stroma cells, but not in the hematopoietic cells themselves, caused an MPN that is indistinguishable from that mutation of PTPN11 in hematopoietic cells [17]. This suggests that abnormal Ras signaling in the bone marrow milieu alone may be sufficient to cause JMML, and might account for some of the patients who lack the characteristic mutations of JMML in hematopoietic cells.

Germline RAS/MAPK pathway mutations and associated disorders — A group of distinctive genetic syndromes arise from germline mutations in genes of the RAS/MAPK pathways. These mutations induce constitutive activation of the pathway, and are collectively known as "RASopathies," or neuro-cardio-facio cutaneous syndromes [18,19]. These disorders have a propensity to develop malignancies, including myeloproliferative neoplasms. The most frequent and best known of these syndromes are:

Neurofibromatosis type 1 – Associated with germline mutations in NF1. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Noonan syndrome – Associated with germline mutations in PTPN11 in one-half of affected children; others may have germline mutations of NRAS or KRAS [20]. (See "Causes of short stature", section on 'Noonan syndrome' and 'Noonan syndrome (NS)' below.)

Germline mutations may cause a transient myeloproliferative disorder (TMD) that can resolve spontaneously. As an example, a TMD is diagnosed during the neonatal/early infancy period in some children with Noonan syndrome (NS); this NS-associated TMD generally resolves spontaneously over several months, and close observation is an appropriate strategy for these children [21,22]. (See 'Noonan syndrome (NS)' below.)

Germline mutations of other genes associated with this pathway are found in a variety of congenital or developmental disorders and may cause disease affecting other organ systems. As an example, children with germline CBL mutations may develop vasculopathies (eg, optic atrophy, hypertension, cardiomyopathy, arteritis) in the second decade of life [23,24].

Acquired JMML mutations can arise in utero — Polymerase chain reaction sequencing of dried blood from Guthrie cards detected mutations of PTPN11, NRAS, or KRAS in each of seven children who were diagnosed with JMML between age 2 and 19 months [25]. These represented acquired rather than inherited mutations, but this finding suggests that the JMML clone arose before birth in these children. Others have also detected acquired oncogenic JMML mutations that arose in utero [26,27]. It is important to make the distinction between germline and acquired mutations of these genes (ie, by comparison with nonhematopoietic tissue, such as fibroblasts) because the myeloproliferative disorder associated with some of the germline mutations may resolve spontaneously and not require hematopoietic cell transplantation. (See 'Germline RAS/MAPK pathway mutations and associated disorders' above.)

EPIDEMIOLOGY — JMML is a rare cancer with an incidence of approximately 1.2 per million children 0 to 14 years of age per year [28-30]. The disease incidence is similar across several studies, and there is no clear effect of race, ethnicity, or geography on the incidence of JMML. The median age at presentation is two years (range 0.1 to 11.4) and there is a male predominance of 2 to 3:1 [31].

Patients with neurofibromatosis type 1 (NF1), Noonan syndrome, and germline CBL mutations have an increased likelihood of developing JMML. For patients with NF1, the risk of JMML is about 350 times greater than children without NF1 [31]. (See 'Germline RAS/MAPK pathway mutations and associated disorders' above.)

CLINICAL PRESENTATION — Clinical findings in JMML may be indistinguishable from other childhood leukemias and myeloproliferative disorders. Children with JMML typically present with symptoms related to infiltration of the bone marrow and other organs by the malignant myeloid and monocytic cells. One-third of affected children will have an acute illness with fever, signs of upper respiratory infection, organomegaly, and cutaneous findings. The remainder of JMML patients have a more indolent course, and symptoms typically precede establishment of the diagnosis by months [32].

The most common symptoms at diagnosis are [31]:

Pallor (64 percent)

Fever (54 percent)

Bleeding (46 percent)

Infection (45 percent)

Cough (40 percent)

Malaise (35 percent)

Common clinical signs at diagnosis include:

Hepatomegaly (97 percent)

Splenomegaly (97 percent)

Lymphadenopathy (76 percent)

Skin rash (36 percent)  

Children should be examined carefully for clinical evidence of congenital syndromes that are associated with mutations that cause JMML, including the following:

NF1 (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis")

Noonan Syndrome (see 'Noonan syndrome (NS)' below and "Noonan syndrome")

PATHOLOGIC FEATURES — The bone marrow and peripheral blood of children with JMML may display features of both myeloproliferative and myelodysplastic disorders (ie, immature and dysplastic forms), as well as cytopenias due to marrow infiltration and/or splenomegaly. These findings may be challenging to distinguish from nonspecific features that can be associated with bacterial or viral infections, other forms of leukemia, myelodysplastic syndromes, or myeloproliferative neoplasms. Further testing, including karyotypic analysis, genetic/molecular testing, and other laboratory studies may be required to formally establish the diagnosis of JMML. (See 'Diagnosis' below.)

Peripheral blood — The peripheral blood may be more informative than the bone marrow morphology. Important findings from examination of the peripheral blood include [32]:

Complete blood count will reveal prominent monocytosis (exceeding 5000/microL), but white blood cell (WBC) counts tend to remain less than 50,000/microL; fewer than 8 percent have WBC counts >100,000/microL.

Thrombocytopenia <50,000/microL is present in one-half of children with JMML, and may be severe and associated with bleeding.

Hemoglobin (Hb) level is usually low, and is <8 g/dL in approximately one-third of children.

Peripheral blood smear will typically reveal circulating immature myeloid cells, erythroblasts, nucleated red blood cells, and a few blasts (<3 percent).

Elevated fetal Hb (HbF), corrected for age, is present in two-thirds of children [33]; the altered HbF pattern affords a reliable marker in JMML, and remains a minor criterion for diagnosis in those patients without a known underlying molecular defect [29]. (See 'Diagnosis' below.)

Bone marrow

Morphology — The bone marrow in patients with JMML is typically hypercellular, with the vast majority of cells belonging to the myeloid series at all stages of maturation. Monocytes account for 5 to 10 percent of all myeloid cells and, by definition, the bone marrow must contain fewer than 20 percent myeloblasts (in contrast to acute leukemias in which more than 20 percent of bone marrow cells are blasts). There may be varying degrees of dysplasia (ie, aberrant myelopoiesis, erythropoiesis, and/or megakaryopoiesis) [32]. The immunophenotype is not diagnostic but will highlight the aberrant myelomonocytic differentiation.

GM-CSF hypersensitivity — Hematopoietic precursor cells of JMML often demonstrate hypersensitivity in colony-forming assays to granulocyte-macrophage colony-stimulating factor (GM-CSF), or spontaneous proliferation in vitro without the addition of exogenous growth factor. Spontaneous proliferation and hypersensitivity to GM-CSF may be used as a minor criterion of JMML diagnosis in the 10 percent of JMML patients who do not have identifiable molecular abnormalities affecting the Ras-MAPK pathway. However, the assay is not standardized across diagnostic laboratories and other diagnoses that can mimic JMML, such as viral infections, have also been reported to cause GM-CSF hypersensitivity [34,35].

Phosphospecific flow cytometry to detect hyperphosphorylation of STAT5 in bone marrow (or peripheral blood) cells in response to low doses of GM-CSF has been validated to rapidly and accurately diagnose JMML, and may contribute to diagnosis for those patients without a molecular marker of their disease [36], but is not considered one of the criteria to establish the diagnosis of JMML. (See 'Diagnosis' below.)

Genetic features

Cytogenetics — Cytogenetic studies demonstrate a normal karyotype in about two-thirds of cases. Monosomy 7 is the most frequent cytogenetic abnormality, and is found in 25 percent [31,37]. Progression of disease, especially following treatment with 6-mercaptopurine and other therapeutic agents, may reveal the acquisition or emergence of additional subclonal mutations.

Molecular abnormalities — More than 90 percent of patients with JMML have somatic and/or germline mutations of genes involved in a RAS/MAPK signaling pathway. The most commonly encountered abnormalities are:

Neurofibromin (NF1; 10 to 15 percent)

PTPN11 (non-receptor tyrosine phosphatase, SHP2; approximately 35 percent)

RAS (NRAS or KRAS; 20 to 25 percent)

CBL (E3 ubiquitin ligase; 10 to 15 percent)

ALK/ROS1 tyrosine kinase fusion genes have been identified in some patients who lack RAS/MAPK mutations [11].

DIAGNOSIS

Evaluation — The diagnosis of JMML should be considered in an infant or child with fever, hepatosplenomegaly, lymphadenopathy, rash, and/or bleeding in association with monocytosis, cytopenias, and/or circulating dysplastic cells (table 1). These clinical findings may be indistinguishable from those of children with viral or bacterial infections, or other more common forms of childhood leukemia. (See 'Differential diagnosis' below.)

Establishing the diagnosis of JMML and distinguishing it from other disorders requires:

History and physical examination

Complete blood count

Examination of the peripheral blood smear for (picture 1 and picture 2):

Increased monocytes

Abnormal myeloid forms, including immature myeloid cells and myelo/monoblasts

Abnormal erythroid cells, including nucleated red blood cells

Thrombocytopenia

Bone marrow aspirate and biopsy

Cytogenetic analysis (karyotype and/or fluorescent in situ hybridization) of blood and/or bone marrow

Molecular analysis of blood or bone marrow:

PTPN11

KRAS

NRAS

NF1

CBL mutation (or loss of heterozygosity)

Ancillary laboratory studies (eg, quantitation of fetal hemoglobin, hypersensitivity of myeloid precursors to GM-CSF) in select cases (see 'Diagnostic criteria' below)  

Genetic testing of non-hematopoietic cells (eg, fibroblasts, cells associated with hair follicles) should be performed to determine if abnormalities of PTPN11, KRAS, NRAS, NF1, and CBL represent germline or acquired mutations. Germline mutations should be found in both hematopoietic and non-hematopoietic tissues, and acquired mutations should be found only in hematopoietic cells. This distinction is important because germline mutations can cause a transient myeloproliferative disorder that may resolve spontaneously. (See 'Congenital versus acquired mutations' below and 'Clinical presentation' above.)

Diagnostic criteria — The diagnosis of JMML is made using the World Health Organization criteria. The clinical and laboratory criteria for the diagnosis of JMML are shown below and in the table (table 1).  

Formal diagnosis of JMML requires the presence of all of the following Category 1 criteria:

Peripheral blood monocyte count of >1000/microL

Blast percentage in peripheral blood and bone marrow <20 percent

Splenomegaly

Absence of t(9;22) BCR-ABL1 fusion gene

In addition, the child must have at least one of the following Category 2 criteria:

Somatic mutation of PTPN11, KRAS, or NRAS

Clinical diagnosis of neurofibromatosis-1 or NF1 mutation

Germline CBL mutation or loss of heterozygosity of CBL

Monosomy 7

If none of the Category 2 criteria are met, the child must have at least two of the following Category 3 criteria:

Clonal cytogenetic abnormality other than monosomy 7

White blood cell >10,000/microL

Increased fetal hemoglobin (HbF) for age

Circulating myeloid precursors

GM-CSF hypersensitivity (see 'Pathogenesis' above)

DIFFERENTIAL DIAGNOSIS — The clinical and laboratory manifestations of JMML are protean and often nonspecific. The clinical presentation may be indistinguishable from certain infectious and malignant disorders. Since it is a rare disorder of infants and children, the clinician should maintain a high degree of suspicion for the diagnosis of JMML and be mindful of the defining diagnostic features. (See 'Clinical presentation' above and 'Diagnosis' above.)

Among the disorders in infants and children that must be distinguished from JMML are:

Infections – Disseminated infection with Epstein-Barr virus [38], cytomegalovirus (CMV) [39], and human herpesvirus 6 (HHV-6) [35], which may present with fever, hepatosplenomegaly, and failure to thrive, and mimic JMML in young patients. Blood cells in these infections may also exhibit hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in in vitro colony forming assays, and hyperphosphorylation of STAT5 in leukocytes by flow cytometry [34,39]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Overview of cytomegalovirus infections in children" and "Human herpesvirus-8 infection".)

JMML can be distinguished from these infectious diseases by clinical findings suggestive of a congenital syndrome (eg, neurofibromatosis-1, Noonan syndrome) and by certain diagnostic tests (eg, characteristic chromosomal and/or genetic abnormalities). Discriminating between these infections and JMML is particularly challenging in children without genetic findings that are typically associated with JMML [40,41]. Such infections and JMML may present concomitantly [40,42], further contributing to this diagnostic dilemma. (See 'Bone marrow' above.)

Leukemoid reaction describes a high white blood count (as high as 50,000/microL) with neutrophilia, prominent left shift, and toxic granulations, usually in response to infection. If the distinction cannot be made clinically, molecular and/or cytogenetic testing should distinguish JMML from a leukemoid reaction. (See 'Diagnosis' above.)

Chronic myelomonocytic leukemia (CMML) – CMML is a myeloproliferative/myelodysplastic disorder of older adults (that is not seen in infants or children), which can also manifest as persistent peripheral blood monocytosis (>1000/microL) that accounts for >10 percent of peripheral white blood cells. CMML bone marrow cells often have chromosome 7 abnormalities or trisomy 8, and may have mutations in epigenetic modifiers and RNA splicing apparatus that differ from those associated with JMML; however, some cases of CMML do have mutations in NRAS, KRAS, or CBL. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Pathogenesis'.)

Chronic myeloid leukemia (CML) – CML is a myeloproliferative neoplasm characterized by prominent neutrophilia, with the entire spectrum of myeloid cells present in the peripheral blood, including immature myeloid forms, monocytosis, eosinophilia, and/or basophilia; thrombocytosis; splenomegaly; hyperplastic bone marrow with myeloid predominance; and often reticulin fibrosis. Infants and children can have typical CML, but that disorder will be distinguished from JMML by the presence of the characteristic BCR-ABL1 rearrangement (by reverse transcription polymerase chain reaction), or t(9;22)(q34;q11.2) chromosomal rearrangement (ie, the Philadelphia chromosome; by karyotype or fluorescence in situ hybridization [FISH] analysis). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

Transient myeloproliferative disorder (TMD) of Noonan syndrome (TMD-NS) – TMD-NS presents an elevated white blood cell count that may resolve spontaneously over several months; close observation is an appropriate strategy for these children [21,22]. Children with NS exhibit facial dysmorphism, short stature, webbed neck, cardiac anomalies, and variable levels of impaired cognition. Germline mutations in PTPN11 (SHP2) are found in one-half of children with NS. The same molecular defects are found in up to 35 percent of patients with JMML, but these somatic defects can be distinguished from the germline lesions of NS by examination of non-hematologic tissues (eg, fibroblasts), which will lack the PTPN11 mutations. (See 'Germline RAS/MAPK pathway mutations and associated disorders' above and "Noonan syndrome".)

TMD of Down syndrome (TMD-DS) – TMD-DS is generally seen in the first weeks of life, and can exhibit leukocytosis, circulating blasts, hepatosplenomegaly, and skin lesions that resemble JMML. Children with TMD-DS may range from asymptomatic to gravely ill. Cytogenetic analysis of blasts from TMD-DS should demonstrate trisomy 21, and further testing may reveal mutation of GATA1. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)", section on 'Diagnosis'.)  

Non-Down syndrome TMD – TMD has rarely been reported in patients without Down syndrome and should be considered in neonates presenting with leukemia cutis, hepatosplenomegaly, and hyperleukocytosis. Germline THPO mutation, somatic trisomy 21, t(8;16)(p11.2;p13.3), and GATA1 mutations have been described with transient myeloproliferative disease [43-46].

Infantile malignant osteopetrosis Infantile malignant osteopetrosis often presents with hepatosplenomegaly (caused by extramedullary hematopoiesis from replacement of the marrow cavity), and may exhibit anemia, thrombocytopenia, and leukocytosis. Although GM-CSF hypersensitivity has been reported in this disorder, characteristic bony findings, elevation of alkaline phosphatase, and hypogammaglobulinemia distinguish it from JMML [47]. (See "Skeletal dysplasias: Specific disorders", section on 'Infantile malignant osteopetrosis'.)

Wiskott-Aldrich syndrome (WAS) – WAS is a rare, recessive X-linked disease characterized by microthrombocytopenia, eczematous skin disease, and recurrent infections that may be difficult to distinguish from JMML. Patients with WAS may present without the characteristic microthrombocytopenia or leukocytosis/monocytosis. Testing for WASP (the gene affected in WAS) should be performed in any male patient without mutations of the RAS signaling pathway [48]. (See "Wiskott-Aldrich syndrome".)

PROGNOSIS/MANAGEMENT — JMML is an aggressive disease for most patients, and allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment; without HCT, the median survival is 10 to 12 months [31,49,50].

Prognostic factors — Certain clinical and/or laboratory factors that are associated with prognosis in JMML may influence a decision about whether to proceed to allogeneic HCT, and the timing of that treatment.

Clinical factors — Clinical factors that have been associated with reduced event-free survival (EFS) and overall survival (OS) in JMML, even following allogeneic HCT, include [31,51]:

Age >2 years

Increased fetal hemoglobin (HbF) for age

Platelet count <33,000/microL at presentation

Female sex

Molecular features — There is controversy regarding whether certain molecular factors influence prognosis in JMML.

Mutation status – In a study of 71 patients with JMML, mutation of PTPN11 (but not mutation of NF1, KRAS, or NRAS) was associated with older age (>2 years), increased HbF (>10 percent), reduced OS, and increased relapse following HCT [52]. However, another study of 100 patients did not identify PTPN11, NF1, or RAS as independent prognostic factors for survival [53].

Gene expression profile – In a study of 44 patients with JMML, those with gene expression signatures that resembled acute myeloid leukemia (AML) had worse OS (7 versus 74 percent) and EFS (6 versus 63 percent) at 10 years after HCT compared with those whose gene expression signatures did not resemble AML [54]. The AML-like gene expression signature correlated with poor prognosis clinical features (older age, higher HbF, and lower platelet count), but in multivariate analysis only the gene expression signature remained an independent marker of poor prognosis (although this study used different values for HbF and platelet count than other studies).  

DNA methylation status – DNA methylation patterns are associated with disease outcome; patients with the lowest methylation are most likely to experience spontaneous remission of disease [12,55,56]. Methylation subgroups in JMML may be incorporated into design of risk-stratified clinical trials [55].

Hypermethylation of four gene CpG islands (eg, BMP4, CALCA, CDKN2B, and RARB) was associated with a higher risk of relapse after transplant in a cooperative group study [12]. Hypermethylation was associated with clinical parameters that predict poor prognosis (older age and elevated HbF); PTPN11 mutations were over-represented in the hypermethylated group, whereas all children with CBL mutations exhibited absent or low hypermethylation.

Genome-wide hypermethylation profile that resembles that of acute myeloid leukemia (AML) was associated with poor outcomes in a study that included >100 patients with JMML [11]. Others observed that methylation of the RASA4 isoform-2 promoter correlated with older age and elevated HbF, with PTPN11 mutation, and with a higher rate of relapse after HCT [14]. Aberrant methylation status has been incorporated into a prognostic scoring system for JMML [57].

Congenital versus acquired mutations — Outcomes and management of children with JMML in the setting of certain congenital syndromes differ from children with acquired Ras pathway mutations. As an example, JMML in the neonatal period of children with Noonan syndrome (NS) spontaneously resolves in most patients (akin to the transient myeloproliferative disorder [TMD] of Down syndrome). (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

Allogeneic HCT remains the best option for curative therapy in patients with somatic mutations of PTPN11, NF1, KRAS, and a majority of patients with somatic NRAS mutations, with JMML [58]. However, spontaneous remissions of JMML and long-term survival without allogeneic HCT have been reported in some patients with somatic NRAS mutations [49,50,59]. High platelet count and low HbF may predict a more indolent course in such patients, warranting close observation without immediate HCT. However, HCT remains the treatment of choice for a majority of these patients [59].

Noonan syndrome (NS) — NS is an autosomal dominant disorder characterized by facial dysmorphism, short stature, webbed neck, cardiac anomalies, and variable levels of impaired cognition. Germline mutations in PTPN11 (SHP2) are found in one-half of children with NS, while other children may have germline mutations of NRAS or KRAS [20].

Patients with NS may present in early infancy with a TMD that can spontaneously regress. At times, infants with NS and TMD may develop life-threatening complications associated with prominent leukocytosis and organ infiltration, but cytoreductive therapy with 6-mercaptopurine can be effective in such cases [58]. The disease may also evolve into classical JMML with the gain of additional cytogenetic abnormalities. Careful monitoring for this possibility is warranted in any child with NS and transient myeloproliferative disease.

Germline mutations of CBL — JMML resolves spontaneously in a significant proportion of patients with germline CBL mutations [23]. Such patients should be monitored closely and proceed with HCT only if there is progressive disease and/or gain of chromosomal aberrations. (See 'Children who do not require HCT' below.)

In one report, four of six children with JMML and germline CBL mutation who did not receive HCT were alive without evidence of JMML 7.5 to 18 years from diagnosis [23]. Among 23 children with JMML and germline CBL mutation registered into the EWOG-MDS in Childhood database, the probability of survival was the same for children who underwent HCT (12 children) as for those who did not undergo HCT (11 children) [58].

Some children with a TMD in association with germline CBL mutations will acquire additional mutations (eg, loss of heterozygosity of CBL) and develop a more typically aggressive clinical course of JMML. [60]. There is no prognostic clinical feature or correlative laboratory marker to distinguish between these different outcomes.

Some patients with germline CBL mutations whose JMML resolves spontaneously will develop vasculitis later in life. HCT seems to abrogate the risk of vasculitis, since no reported patient with JMML and germline CBL mutations transplanted prior to the recognition of this genetic lesion developed vasculitis, in spite of a significant portion of those patients with stable mixed chimerism post-HCT [53,58].

RAS mutations — A majority of patients with RAS alterations require HCT, but long-term survival without allogeneic HCT has been observed in a small number of infants with JMML and G12S substitutions of KRAS or NRAS [49,50]. No specific mutational RAS type has been associated with JMML with a less aggressive course, but it has been observed that those who survived RAS-mutated JMML without HCT had normal HbF and higher platelet counts [59].

Even though no definitive studies are available to demonstrate the prognostic significance of these hematologic parameters, we offer close observation without immediate HCT for children with JMML and RAS mutation who have normal HbF and high platelet counts, rather than immediate HCT. (See 'Children who do not require HCT' below.)

TREATMENT — Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy of JMML, and this course should be pursued immediately in most children. Allogeneic HCT is recommended for all children with JMML associated with NF1 mutation, somatic PTPN11 and KRAS mutations, and for most children with somatic NRAS mutations. Median survival of children with JMML who do not undergo transplantation is as short as 10 to 12 months [31].

The minority of patients who do not require immediate HCT is described in more detail separately. (See 'Children who do not require HCT' below.)

Bridging to transplant — No specific approach has been shown to offer improved event-free survival in the period prior to HCT [61]. Molecular monitoring of JMML may be useful in this setting [62].

In order to minimize complications of JMML prior to transplant, we suggest treatment with azacitidine or 6-mercaptopurine, with or without cis-retinoic acid, for children with organ congestion or high white blood cell counts. Other options include low-dose cytarabine, high-dose cytarabine with fludarabine (for children who are ill or who progress on less intensive therapy), induction therapy used for acute myeloid leukemia (AML), and close observation for children who are clinically stable [1,63]. In addition to chemotherapy, pre-transplant splenectomy has been attempted to reduce the disease burden prior to transplant, without definitive evidence of benefit [53].

Azacitidine is approved by the US Food and Drug Administration (FDA) for treatment of children ≥1 month with newly-diagnosed JMML; the dose varies with age and weight, per the FDA label; specific dosing is available in the azacitidine drug monograph [64]. A multicenter study (AZA-JMML-001) reported 61 percent partial remission and successful bridge to HCT in 17 of 18 patients treated with azacitidine (75 mg/m2) once daily for 7 days [65]. In a retrospective analysis, azacitidine induced clinical and molecular responses in patients with relapsed JMML pre-transplant and post-transplant [66].

Hematopoietic cell transplantation (HCT) — A variety of donor sources and conditioning regimens have been examined for HCT in JMML. Outcomes from allogeneic HCT in JMML are comparable between grafts from HLA-identical sibling and HLA-identical unrelated donors, but greater degrees of HLA mismatch are associated with worse outcomes. Chemotherapy-based approaches are preferred over radiation-based conditioning. (See 'Conditioning regimen' below and 'Donor source' below.)

Efficacy — HCT is the only therapy that has the potential to cure JMML. Examples of studies of allogeneic HCT in JMML include:

In the largest prospective trial of allogeneic HCT in JMML, the EWOG-MDS/European Blood and Marrow Transplantation (EBMT) group transplanted 100 children (67 boys and 33 girls) with bone marrow, peripheral blood, or umbilical cord grafts (79, 14, and 7 children, respectively) from HLA-identical relatives (48 children) or unrelated donors (52 children) [53].

The estimated overall survival (OS) was 64 percent (54 to 74 percent) at five years. The estimated event-free survival (EFS) at five years for recipients of grafts from HLA-matched relatives and HLA-matched unrelated donors were not significantly different (55 and 49 percent, respectively).

The cumulative incidences of transplant-related mortality and leukemia recurrence were 13 and 35 percent, respectively.

Female sex and age >4 years predicted poorer outcomes in multivariate analysis.

A study from Japan examined 27 children with JMML transplanted with grafts from HLA-matched siblings (12 children), HLA-matched unrelated donors (10 children), and other sources (5 children) [67]. Total body irradiation (TBI) was used for conditioning in 18 of the children.

EFS and OS at four years after HCT were 54 and 58 percent, respectively.  

Children <1 year old had better OS compared with older children, while those with abnormal karyotypes had lower OS compared with those with normal karyotypes.

Conditioning regimen — Chemotherapy-based preparative regimens are preferable to radiation-based approaches, because of better efficacy and avoidance of late effects of TBI on the young children who are predominately affected by JMML. Ongoing trials are comparing various chemotherapy myeloablative regimens. (See "Preparative regimens for hematopoietic cell transplantation".)

A retrospective study evaluated 43 children from the EWOG-MDS database who underwent conditioning with a busulfan-cyclophosphamide-melphalan myeloablative preparative regimen (21 patients) or TBI (22 patients) and received HLA-identical or one-antigen mismatched grafts from related donors (25 children), mismatched relatives (4 children), or matched unrelated donors (14 children) [68]. EFS was better for those who received the chemotherapy-based conditioning regimen versus TBI (62 versus 11 percent, respectively).

Another retrospective study reported 73 percent five-year OS, 26 percent relapse, and 9 percent transplantation-related mortality among 129 patients; the most commonly used conditioning regimen (59 patients) was busulfan-fludarabine-melphalan [69].

Busulfan-fludarabine-melphalan conditioning was used in 30 recipients of HLA-matched related donors (six patients) or alternative sources (including 13 mismatched donors) [70]. Outcomes were better in recipients of HLA-matched grafts (EFS 71 percent; 95% CI 49-92 percent) compared with those with HLA-mismatched donors (EFS 29 percent; 95% CI 3-55 percent). Primary engraftment failed in five patients, all of whom received mismatched grafts. This conditioning regimen may not be suitable for patients without an HLA-matched donor.

Donor source — A variety of donor sources, including HLA-matched relative, HLA-matched unrelated, HLA-mismatched, and umbilical cord blood transplantation (UCBT) have been used in HCT for JMML. UCBT allows for timely transplant in potentially unstable patients without a suitable matched related donor. (See "Donor selection for hematopoietic cell transplantation".)

Examples of studies that examined this question include:

The EWOG-MDS/EBMT trial demonstrated no significant difference in EFS and transplant-related mortality when comparing matched-related to matched-unrelated donors [53].

A retrospective study of 110 children with JMML who received single-unit, unrelated UCBT revealed 44 percent five-year disease-free survival [71]. Only 16 percent of the umbilical cords were HLA-matched with the recipient, whereas 43 percent had one or two HLA disparities, and 35 percent had three HLA disparities.

Haploidentical allogeneic HCT using T cell-depleted grafts has been used for children without a suitable matched related donor, unrelated donor, or umbilical cord donor, but remains an investigational approach [71-74].

Post-transplant management — Relapse after HCT is the most common cause of treatment failure, so some clinicians offer post-transplant treatment, including rapid withdrawal of immunosuppression and/or administration of donor-lymphocyte infusion (DLI). However, DLI is often ineffective when relapse is overt [58,75,76]. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation".)

Children who do not require HCT — Close observation without immediate allogeneic HCT is often warranted for most children with JMML who have the following features (see 'Congenital versus acquired mutations' above):

Germline CBL mutation

Noonan syndrome

Acquired RAS mutations, with normal hemoglobin F and higher platelet counts

In this setting, we obtain weekly complete blood counts until resolution of hematologic and clinical signs of disease. There is no clear consensus regarding the optimal frequency of bone marrow examinations, but there is value in detecting early disease re-emergence and clonal evolution. For that reason, we perform bone marrow examination with cytogenetics every four to six weeks until clinical and hematologic symptoms resolve, and then every three to four months for one year. If the child is clinically stable and without evidence of cytogenetic progression, we gradually reduce the frequency of examination and testing over the following years.

These children should be offered HCT if the disease progresses or if chromosomal aberrations occur.

SUMMARY AND RECOMMENDATIONS

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative/myelodysplastic disorder of infancy and childhood that is manifest as increased infiltration of the peripheral blood, bone marrow, and viscera by abnormal myelomonocytic cells. (See 'Clinical presentation' above.)

Most children with JMML have somatic and/or germline mutations of NF1 (neurofibromin), PTPN11 (SHP2), KRAS, NRAS, or CBL that activate the RAS/MAPK signaling pathway and cause hypersensitivity of myeloid progenitor cells to the granulocyte-monocyte colony stimulating factor (GM-CSF). (See 'Pathogenesis' above.)

The diagnosis of JMML should be considered in an infant or child with fever, hepatosplenomegaly, lymphadenopathy, rash, and/or bleeding in association with monocytosis, cytopenias, and/or circulating dysplastic cells. (See 'Clinical presentation' above.)

The evaluation of suspected cases should include an analysis of the peripheral blood smear and a bone marrow aspiration and biopsy. (See 'Evaluation' above.)

The diagnosis of JMML is made using the World Health Organization criteria (table 1). (See 'Diagnostic criteria' above.)

JMML must be distinguished from other hematologic malignancies, infections, and transient myeloproliferative disorders that may present with similar clinical and laboratory findings. (See 'Differential diagnosis' above and 'Congenital versus acquired mutations' above.)

The choice of treatment is influenced by prognostic factors, including clinical, cytogenetic, and molecular features (see 'Prognostic factors' above):

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy of JMML. For most children with JMML, we recommend immediate allogeneic HCT rather than other therapies (Grade 1B). (See 'Efficacy' above.)

For most children with the following clinical syndromes and genetic features, we suggest observation rather than immediate HCT (Grade 2C) (see 'Children who do not require HCT' above):

-Germline CBL mutation

-Noonan syndrome

-Acquired RAS mutations, with normal hemoglobin F and higher platelet counts

For those undergoing transplant, we suggest using either HLA-identical sibling or HLA-identical unrelated donors rather than HLA-mismatched donors (Grade 2B). We suggest chemotherapy-based conditioning rather than radiation-based approaches (Grade 2C). (See 'Hematopoietic cell transplantation (HCT)' above.)

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Topic 96034 Version 14.0

References

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