**1. Introduction**

JMML is a rare aggressive clonal hematopoietic neoplasm of infancy and early childhood that combines excessive proliferation of the granulocytic and monocytic lineages with dysplasia making JMML analogous to chronic myelomonocytic leukemia (CMML). Therefore, the current WHO classification of myeloid neoplasms and acute leukemia envisages JMML as an overlap myeloproliferative/ myelodysplastic neoplasm. The diagnosis of JMML is mainly based on the clinical presentation in combination with morphology of the peripheral blood smears and the molecular analysis of leukemic cells. The peripheral blood and bone marrow of


• Hyperphosphorylation of STAT5.

*1 Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.* Blood*. 2016;127(20):2391–2405. doi:10.1182/blood-2016-03-643,544*

#### **Table 1.**

*The diagnostic criteria for juvenile myelomonocytic leukemia1 .*

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. Splenomegaly, lymphadenopathy, and skin rashes are common clinical features but the clinical picture of JMML can be somewhat non-specific. JMML is frequently confused with viral infections, immunodeficiency syndromes, myelodysplastic syndromes, myeloproliferative neoplasms or other forms of leukemia [1]. Moreover, JMML has diverse molecular subtypes with contrasting features and varied clinical outcomes. The broad overlap in clinical and laboratory features in combination with the heterogeneity of JMML itself made the diagnosis of JMML a hurdle to most hematologists. Consequently, the diagnosis of JMML almost always relies on the diagnostic criteria (**Table 1**). The chief backbone of the diagnostic criteria is the associated molecular and/or cytogenetic abnormalities. In particular, the genomic landscape of JMML had revolutionized our understanding of leukemogenesis of this greatly equivocal disease. JMML is a predominantly fatal disease but the clinical course can be highly variable. At both extremes of the disease, a third of patients follow a relatively indolent course while approximately 15% of cases develop AML, the so called 'blast crisis' [2].

#### **2. Clinical features**

• Patients present with splenomegaly, fever, thrombocytopenia, monocytosis, and elevated HbF.

**15**

*Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of* KMT2A*-Rearranged Acute…*

• Polyclonal hypergammaglobulinemia and presence of autoantibodies.

• The hallmark of the disease is the overproduction of myelomonocytic cells (monocytic and granulocytic cells) that infiltrate skin and vital organs (spleen,

liver, and lungs) leading to various clinical manifestations as follows [3]:

1.Lungs: dry cough, tachynoea and interstitial infiltrates on chest X-ray are

2.Skin: Cafe-au-lait spots might be indicative of an underlying germline conditions such as Neurofibromatosis type 1 (NF1) or Noonan syndrome-like disorder. Neurofibromas occur in patients with NF1. About 25% of patients

3.Gut infiltration may predispose patients to diarrhea—sometimes with bloody

4.Lymph nodes: About half of all patients have lymphadenopathy. Leukemic

○ Approximately 7–10% of JMML patients will not have splenomegaly at diagnosis but virtually all patients will develop splenomegaly within weeks to months of initial presentation (spleen size rapidly increases with

The peripheral blood (**Figure 1**) is the most important specimen for diagnosis [4]. It typically shows leukocytosis and thrombocytopenia. The vast majority of JMML patients have thrombocytopenia with the exception of children with NF1- mutated JMML, who show platelet counts within the normal range in most cases. The median

of neutrophils, with some immature cells (e.g. promyelocytes and myelocytes)

/L. The leukocytosis consists mainly

• Anemia is generally not a leading symptom and rarely requires red blood cell

• Most patients present with evidence of infection or constitutional symptoms

*DOI: http://dx.doi.org/10.5772/intechopen.94537*

that may mimic viral infections.

signs of pulmonary infiltration.

have pleomorphic skin rashes in the forms of:

○ Indurated raised lesions with central clearing.

infiltrates may give rise to markedly enlarged tonsils.

5.There is generally marked splenomegaly/hepatosplenomegaly:

○ Hepatomegaly is generally less prominent than splenomegaly.

features—and gastrointestinal infections.

○ Eczematous eruptions (cradle cap).

○ Sweet syndrome.

time).

**3. Pathologic features**

reported white blood cell counts are 25–30 x 109

**3.1 Peripheral blood**

(RBC) transfusion.

• Leukocytosis is common in JMML, but a presenting white blood count <10 x 109 /L is occasionally noted.

*Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of* KMT2A*-Rearranged Acute… DOI: http://dx.doi.org/10.5772/intechopen.94537*

	- Eczematous eruptions (cradle cap).
	- Indurated raised lesions with central clearing.
	- Sweet syndrome.

*Acute Leukemias*

**JMML diagnostic criteria**

• Splenomegaly.

*1*

**Table 1.**

• PB monocyte count ≥1 x 109

• Blast percentage in PB and BM <20%.

**II. Genetic studies (1 finding sufficient):**

syndrome- need to be excluded). • Clinical diagnosis of NF1 or *NF1* mutation.

• Hemoglobin F increased for age.

• GM-CSF hypersensitivity in colony assay. • Hyperphosphorylation of STAT5.

*The diagnostic criteria for juvenile myelomonocytic leukemia1*

**I. Clinical and hematologic features (all 4 features mandatory):**

• Germ line *CBL* mutation and loss of heterozygosity of CBL.

**features listed under I, the following criteria must be fulfilled:**

• Myeloid or erythroid precursors on peripheral blood smear.

**III. For patients without genetic features, besides the clinical and hematologic**

/L.

• Absence of Philadelphia chromosome (*BCR/ABL1* rearrangement).

• Somatic mutation in *PTPN11* or *KRAS* or *NRAS* (Germ line mutations -indicating Noonan

• Monosomy 7 or any other chromosomal abnormality or at least 2 of the following criteria:

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. Splenomegaly, lymphadenopathy, and skin rashes are common clinical features but the clinical picture of JMML can be somewhat non-specific. JMML is frequently confused with viral infections, immunodeficiency syndromes, myelodysplastic syndromes, myeloproliferative neoplasms or other forms of leukemia [1]. Moreover, JMML has diverse molecular subtypes with contrasting features and varied clinical outcomes. The broad overlap in clinical and laboratory features in combination with the heterogeneity of JMML itself made the diagnosis of JMML a hurdle to most hematologists. Consequently, the diagnosis of JMML almost always relies on the diagnostic criteria (**Table 1**). The chief backbone of the diagnostic criteria is the associated molecular and/or cytogenetic abnormalities. In particular, the genomic landscape of JMML had revolutionized our understanding of leukemogenesis of this greatly equivocal disease. JMML is a predominantly fatal disease but the clinical course can be highly variable. At both extremes of the disease, a third of patients follow a relatively indolent course while approximately 15% of cases develop AML, the so called 'blast crisis' [2].

*.*

*Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.* Blood*. 2016;127(20):2391–2405. doi:10.1182/blood-2016-03-643,544*

• Patients present with splenomegaly, fever, thrombocytopenia, monocytosis,

• Leukocytosis is common in JMML, but a presenting white blood count

**14**

**2. Clinical features**

<10 x 109

and elevated HbF.

/L is occasionally noted.

	- Hepatomegaly is generally less prominent than splenomegaly.
	- Approximately 7–10% of JMML patients will not have splenomegaly at diagnosis but virtually all patients will develop splenomegaly within weeks to months of initial presentation (spleen size rapidly increases with time).

#### **3. Pathologic features**

#### **3.1 Peripheral blood**

The peripheral blood (**Figure 1**) is the most important specimen for diagnosis [4]. It typically shows leukocytosis and thrombocytopenia. The vast majority of JMML patients have thrombocytopenia with the exception of children with NF1- mutated JMML, who show platelet counts within the normal range in most cases. The median reported white blood cell counts are 25–30 x 109 /L. The leukocytosis consists mainly of neutrophils, with some immature cells (e.g. promyelocytes and myelocytes)

#### **Figure 1.**

*Peripheral blood of a 13 months old boy with PTPN11-mutated JMML. Photomicrograph shows leukocytosis with neutrophilia and monocytosis. There is left shift, toxic granulation and vacuolation. Occasional primitive cells (~ 2%) are present. No nucleated RBCs are seen.*

#### **Figure 2.**

*Bone marrow aspirate demonstrates a hypercellular marrow (100 – Age = %normal cellularity) with left shift and increased myeloid and monocyte lineages. Blast count is about 4%. There is occasional evidence of hemophagocytosis and mild erythroid dysplastic features.*

and monocytes. Although most cases show a striking monocytosis, often with dysplastic forms, the absolute monocyte count can be <1 x 109 /L. Blasts (including promonocytes) usually account for <5% of the white blood cells, and always <20%. Eosinophilia and basophilia are observed in a minority of cases. Nucleated red blood cells are often seen. Red blood cell changes include macrocytosis (particularly in patients with monosomy 7), but normocytic red blood cells are more common.

**17**

JMML [8].

*Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of* KMT2A*-Rearranged Acute…*

Bone marrow (**Figure 2**) findings are consistent with the diagnosis of JMML but are not per se diagnostic. However, bone marrow aspiration is necessary to exclude AML M4. The most consistent finding in bone marrow specimens is the reduced number or absence of megakaryocytes in about two third of cases. The bone marrow aspirate and biopsy are hypercellular with granulocytic proliferation, although in some patients erythroid precursors may predominate. Monocytes in the bone marrow are often less prominent than in the peripheral blood, generally accounting for 5–10% of the bone marrow cells. The marrow blasts (including promonocytes) can be moderately elevated, but does not reach the level seen in acute leukemia (account for <20% of the bone marrow cells). Auer rods are never present. Dysplasia is usually minimal; however, dysgranulopoiesis (including pseudo-Pelger-Huet neutrophils and hypogranularity) may be noted in some cases, and erythroid precursors may be enlarged. No specific immunophenotypic abnormalities have

Unlike in AML, the bone marrow in patients with JMML demonstrates no blockage of differentiation of myeloid elements. Rather, as is seen in chronic myeloid leukemia (CML), the bone marrow in JMML displays myeloid hyperplasia with increased production of monocytic cells along the full spectrum of differentiation, including blast forms, promonocytes, monocytes, and macrophages. The marrow blast count may be slightly elevated but in classic JMML it does not reach the counts seen in AML. Nevertheless, differentiating JMML from AML is nearly impossible on clinical grounds alone as significant hepatosplenomegaly and respiratory failure can occur in both. Moreover, blood counts and hematologic features may mimic AML. This especially holds true for infants with the lysine methyltransferase 2A (*KMT2A*) rearrangements who occasionally present with hepatosplenomegaly and low blast count resembling JMML [5]. A puzzling interface between *KMT2A*-rearranged AML and JMML therefore exists. Recent reports have validated the close mimicry between *KMT2A*rearranged AML and JMML [6]. Unless unveiled by cytogenetics, JMML can conceal the clinical diagnosis of *KMT2A*-rearranged AML. Age of susceptibility (infancy or early childhood) and abnormal monocytosis have blurred the line between these distinct entities. Specifically, JMML may mimic AML with t(9;11). t(9;11) is the most frequent molecular subtype involving the *KMT2A* gene (*KMT2A-MLLT3*) in AML. t(9;11)-positive AML/JMML overlap was well-characterized in the medical literature [7]. Both conditions have increased immature monocytes and blasts. I reported a 14-month-old girl with t(9;11)-positive AML who died as she received JMML-directed therapy. The clinical picture, peripheral smear and the suboptimal blast count of only 10% had stealthily impersonated

Chromosomal rearrangements involving the *KMT2A* gene do not exist in the genomic landscape of JMML. KMT2A gene rearrangements are common genetic mutations in pediatric AML with an incidence of 15–25% (50–60% in children younger than two years). However, both KMT2A-rearranged AML and JMML share common morphologic features. *KMT2A*-rearranged AML is usually AML M4 or M5, and both are characterized by increased numbers of monoblasts or abnormal

*DOI: http://dx.doi.org/10.5772/intechopen.94537*

**3.2 Bone marrow**

been reported in JMML.

**4. Differential diagnosis**

**4.1** *KMT2A***-rearranged AML masquerading as JMML**

*Juvenile Myelomonocytic Leukemia (JMML): A Mimicker of* KMT2A*-Rearranged Acute… DOI: http://dx.doi.org/10.5772/intechopen.94537*

#### **3.2 Bone marrow**

*Acute Leukemias*

**Figure 1.**

*cells (~ 2%) are present. No nucleated RBCs are seen.*

**16**

**Figure 2.**

and monocytes. Although most cases show a striking monocytosis, often with

*Bone marrow aspirate demonstrates a hypercellular marrow (100 – Age = %normal cellularity) with left shift and increased myeloid and monocyte lineages. Blast count is about 4%. There is occasional evidence of* 

promonocytes) usually account for <5% of the white blood cells, and always <20%. Eosinophilia and basophilia are observed in a minority of cases. Nucleated red blood cells are often seen. Red blood cell changes include macrocytosis (particularly in patients with monosomy 7), but normocytic red blood cells are more common.

*Peripheral blood of a 13 months old boy with PTPN11-mutated JMML. Photomicrograph shows leukocytosis with neutrophilia and monocytosis. There is left shift, toxic granulation and vacuolation. Occasional primitive* 

/L. Blasts (including

dysplastic forms, the absolute monocyte count can be <1 x 109

*hemophagocytosis and mild erythroid dysplastic features.*

Bone marrow (**Figure 2**) findings are consistent with the diagnosis of JMML but are not per se diagnostic. However, bone marrow aspiration is necessary to exclude AML M4. The most consistent finding in bone marrow specimens is the reduced number or absence of megakaryocytes in about two third of cases. The bone marrow aspirate and biopsy are hypercellular with granulocytic proliferation, although in some patients erythroid precursors may predominate. Monocytes in the bone marrow are often less prominent than in the peripheral blood, generally accounting for 5–10% of the bone marrow cells. The marrow blasts (including promonocytes) can be moderately elevated, but does not reach the level seen in acute leukemia (account for <20% of the bone marrow cells). Auer rods are never present. Dysplasia is usually minimal; however, dysgranulopoiesis (including pseudo-Pelger-Huet neutrophils and hypogranularity) may be noted in some cases, and erythroid precursors may be enlarged. No specific immunophenotypic abnormalities have been reported in JMML.
