Rudolph's Pediatrics, 22nd Ed.

CHAPTER 450. Myeloid Malignancies

Soheil Meshinchi, Robert J. Arceci, and Howard J. Weinstein

Acute myeloid leukemia (AML) accounts for about 20% of cases of acute leukemia in children and 80% of cases of acute leukemia among adults. Further, although AML is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, the survival for children with AML is current between 50% and 60% compared to nearly 85% of children with ALL. In addition, the treatment for children with AML remains particularly toxic and includes multiple, near myeloablative courses of treatment with chemotherapeutic agents and often hematopoietic stem cell transplantation (HSCT). As chemotherapeutic regimens have achieved higher cure rates in selected patients with good prognostic characteristics, HSCT is currently recommended primarily for patients with very high-risk disease characteristics or those who relapse and achieve a second remission. Insights into stem cell physiology and the molecular basis of AML have demonstrated some of the fundamental molecular changes driving the behavior of the leukemia, revealed their extensive heterogeneity, and have begun to provide new therapeutic targets and strategies.

The chronic myeloid forms of leukemia are extremely rare in children. These myeloproliferative syndromes most commonly include the adult type of Philadelphia-chromosome-positive (Ph+), chronic myelogenous leukemia (CML), and juvenile myelomonocytic leukemia (JMML). The clinical course, biologic characteristics, and molecular pathogenesis of CML and JMML are quite different. Until recently, allogeneic bone marrow transplant (BMT) from either a related or an unrelated donor was the management of choice for children with Ph + CML but the kinase inhibitor imatinib has changed the treatment paradigm for that disease in both children and adults, although hematopoietic stem cell transplantation (HSCT) is still the only know curative therapy for CML. An allogeneic HSCT remains the only know curative option for children with JMML.



The annual incidence of acute myeloid leukemia (AML) in children remains constant, with the exception of a slight peak in infants and during adolescence. After age 20 years, the incidence of AML slowly increases with age. Infants with congenital leukemia are more likely to have AML than acute lymphoblastic leukemia (ALL). Although the incidence of AML in children in the United States is approximately 7 cases per million children per year or approximately 600 new cases per year, there is a slightly higher incidence in Hispanic children of 9 per million per year. The incidence also appears slightly higher in Japan, Australia, and Zimbabwe. Of note, the incidence of AML has been increasing slightly although steadily.

The cause of AML is unknown, and most children have no known predisposing factors. Known risk factors include exposure to high-dose ionizing radiation, previous chemotherapy (especially with alkylating agents and epipodophyllotoxins), Down syndrome, congenital bone marrow failure syndromes (Diamond-Blackfan anemia and Kostmann agranulocytosis; see Chapter 430), chromosome fragility and impaired DNA repair mechanisms (such as Fanconi anemia), and inherited disorders, such as neurofibromatosis type I (NF1), which is due to mutations in neurofibromin, a RAS-directed GTPase (see Chapter 182). Children with NF1 are at increased risk of malignant disease, including myelodysplastic and myeloproliferative syndromes. The increased concordance of leukemia in identical twins (approximately 15%) appears to result from transplacental transfer of a single leukemic clone rather than from a genetic predisposition and approaches 100% for infant leukemia.

Children with Down syndrome have a greater than 15-fold increased risk of leukemia compared to infants without Down syndrome. During the first three years of life, acute myeloid leukemia (AML), especially the megakaryoblastic subtype, predominates, but thereafter the ratio of acute lymphoblastic leukemia (ALL) to AML follows the usual childhood distribution. Besides being at risk for acute leukemia, children with Down syndrome or trisomy 21 mosaicism are at risk of transient myeloproliferative disorder (TMD). This syndrome is usually diagnosed during the first several days to weeks after birth and cannot be reliably differentiated from congenital AML. Infants with TMD often have elevated leukocyte counts (> 50,000/μL) with circulating blasts, hepatosplenomegaly, effusions, and may have hydrops. Bone marrow aspirations from these children usually have a lower blast percentage compared to peripheral blood. Unlike congenital AML, TMD usually resolves spontaneously within several weeks to months in about 80% of cases without cytotoxic therapy. However, 5% to 10% of neonates with TMD die from hepatic failure or multiorgan failure. In some of these patients, hepatic fibrosis has been associated with megakaryoblast infiltration of the liver. The blasts from infants with TMD have been shown to be clonal, have cell surface antigens characteristic of megakaryo-blasts, and have mutations in the GATA-1 gene, an erythroid/megakaryocytic restricted transcription factor. Recent data indicate that up to 30% of neonates who have spontaneous regression of TMD will develop AML before age 3 years. It is usually of the megakaryoblastic subtype and the blasts have been shown to harbor the same GATA-1 mutation as found in the transient blast population of TMD. Interestingly, these children respond well to chemotherapy and have about an 80% likelihood of overall survival. At present, the only neonates with TMD who are recommended to be treated include those with hepatic manifestations or very high white blood cell counts at diagnosis (> 50,000/μl). Treatment for these neonates usually includes low doses of cytosine arabinoside.

The risk of secondary AML among children and adults previously treated with alkylating agents and topoisomerase-II inhibitors, especially epipodophyllotoxins, is well established. Leukemia associated with use of an alkylating agent occurs within 4 to 10 years after initial therapy, is usually associated with abnormalities of chromosomes 5 and 7, and carries a grave prognosis. Leukemia associated with use of an epipodophyllotoxin (etoposide and teniposide) has a shorter latency (2–4 years) and usually is of the myelomonocytic or monocytic subtype; characteristically, translocations involving chromosome 11q23 with rearrangement of the MLL gene are noted. Children with the latter forms of leukemia often achieve complete remission with chemotherapy but invariably relapse and die unless they are treated by means of bone marrow transplant.


Acute myeloid leukemia (AML) is a clonal disorder that is the consequence of acquired molecular alterations in hematopoietic progenitor cells that cause differentiation arrest and confer proliferative growth advantage to the affected clone. Early studies using X-linked polymorphism and more recent molecular techniques have demonstrated clonal origin of AML, showing that leukemic cells share common genetic composition and are believed to have been derived from a common ancestral cell.  One major contributor to AML pathogenesis is acquisition of cyto-genetic abnormalities, including balanced or unbalanced chromosomal translocation, deletion or duplication of a region, or the entire gene. In childhood AML, approximately 80% of the patients have one of more than 300 identified cytogenetic abnormalities ranging in prevalence from less than 1% to greater than 15%. In addition, somatically acquired mutations in genes involved in AML pathogenesis have been identified that cooperate with specific cytogenetic alterations to cause AML phenotype.

During a morphologic remission, the clone is no longer detectable except with molecular methods. During hematologic relapse, the original clone reappears. The transforming event in acute myeloid leukemia (AML) could occur at any point in hematopoiesis from the pluripo-tent stem cell to a committed precursor, such as the myeloblast or erythroblast. Both animal and human data, however, provide evidence that the leukemic stem cell in AML is a primitive hematopoietic stem cell in most instances.


Cytogenetic abnormalities are identified in nearly 80% of childhood AML, many of which are unique to AML. Nearly 300 recurrent cyto-genetic abnormalities including translocations, deletions, or duplications have been identified. The most common chromosomal abnormalities in children and young adults with AML include inv16, t(15;17), (8;21), and chromosome 11q23 abnormalities (Fig. 450-1), which account for nearly half of the AML cases, and occur at a higher rate in pediatric populations compared to adults. Other cytogenetic abnormalities, including monosomy 5 or deletion 5q, monosomy 7, and trisomy 8, are less common in children and have a higher prevalence in adults. The molecular events associated with many of the structural chromosomal changes have now been elucidated.


Precise diagnosis and classification is essential to successful management and biologic investigation of childhood leukemia. In 1976, the French-American-British (FAB) Cooperative Group proposed a classification system based primarily on morphology and cytochemical features of the blasts and required at least 30% bone marrow blasts for the diagnosis of acute myeloid leukemia (AML). Although FAB classification provided a valuable tool for general classification of AML, it lacked the ability to predict accurately cytogenetic subclasses, and, in general, did not provide reliable prognostic information.

FIGURE 450-1. Molecular alterations in childhood acute myeloid leukemia (AML): (A) prevalence of cytogenetic abnormalities in childhood AML and (B) prevalence of mutations in patients with normal karyotype.

In 2002, the World Health Organization (WHO) proposed a new classification system that incorporated diagnostic cytogenetic information, which more reliably correlated with outcome into AML classification.  More recently, WHO expanded the number of cytogenetic abnormalities linked to AML classification, and for the first time included specific gene mutations (FLT3, CEBPA, and NPMmutations) in its classification system (Table 450-1). Such a genetically based classification system links AML class with outcome and provides significant biologic and prognostic information. With new emerging technologies aimed at genetic, epigenetic, proteomic, and immunophenotypic classification, AML classification will continue to evolve and provide informative, prognostic, and biologic guidelines to clinicians and researchers.


The initial signs and symptoms for most children with acute myeloid leukemia (AML) include anemia, thrombocytopenia, and neutropenia caused by bone marrow infiltration with leukemic blasts and decreased production of normal cells. Patients commonly present with pallor, fatigue, epistaxis, gum bleeding, petechiae, or purpura, as well as fever or infection that has not responded to antibiotic therapy. Children with AML may have bone or joint pain, but these symptoms occur more often in children with acute lymphoblastic leukemia (ALL). Bulky peripheral lymphadenopathy is not a common finding, and massive hepatosplenomegaly is rare with AML except among infants. Extramedullary leukemia can present as gingival hyperplasia, central nervous system (CNS) leukemia (headache, cranial nerve palsy), and skin nodules. Neonates and infants with AML frequently have leukemia cutis characterized by a papular or nodular rash that is salmon or bluish to slate gray in color. Clinical findings of CNS leukemia at diagnosis are rare. They include signs of increased intracranial pressure or cranial nerve palsy, seventh nerve palsy being the most common. Fewer than 5% of patients with AML have myeloblastomas (also known as granulocytic sarcoma or chloroma) at diagnosis or during the course of the illness. These are solid tumors of blasts and immature myeloid cells that typically occur in the bones and soft tissues of the head and neck (often involving the orbits), intracranial or epidural sites.

Peripheral blood counts at diagnosis in children with AML can be quite varied. The leukocyte count ranges from less than 1000/μL to more than 500,000/μL. Approximately 15% to 20% of children have an initial leukocyte count greater than 100,000/μL. Higher leukocyte counts are associated with the FAB, M4, and M5 subtypes, whereas lower leukocyte counts (< 5000/μL) are commonly seen in acute promyelogonous or M3 leukemia (acute promyelocytic leukemia [APL]). Most patients have a normocytic anemia (median hemoglobin concentration of 7 g/dL in one series), and approximately 50% of patients have platelet counts less than 50,000/μL. Disseminated intravascular coagulation is extremely common among almost all patients with APL and some infants with monocytic leukemia.

The characteristic bone marrow findings include hypercellularity with more than 20% blasts (usually 70–90% blasts). A bone marrow biopsy infrequently shows myelofibrosis (except for megakaryoblastic) and occasional multilineage dysplasia.

In most cases of AML, the diagnosis is straightforward after examination of the peripheral blood sample and a bone marrow aspirate. Other conditions that can cause diagnostic difficulty include the myeloproliferative disorders such as juvenile myelomonoctic leukemia, myelodysplastic syndromes, sepsis that causes a leukemoid reaction, or neutropenia caused by maturation arrest in granulocytic-monocytic precursors. In the presence of sepsis, the bone marrow findings may suggest acute promyelocytic leukemia because of a promyelocyte arrest with toxic granulation. However, normal granulocytic maturation ensues within a few days with resolution of the infection. As previously discussed, acute myeloid leukemia among neonates with Down syndrome is difficult, if not impossible, to differentiate from transient myeloproliferative disorder (TMD).


Substantial improvement in survival rate from less than 10% to approximately 50% of children with acute myeloid leukemia (AML) has occurred during the past 30 years. The improvement is the result of a higher percentage of children entering complete remission, a decrease in relapse rate because of more effective postremission strategies, including allogeneic hematpoietic stem cell transplantation (HSCT), and improvements in supportive care. All children with AML should be referred to pediatric oncology centers and treated on clinical trials.

Induction of Remission

The most widely used remission-induction regimen includes treatment with an anthracycline (usually daunorubicin) and cytarabine arabino-side with or without thioguanine or etoposide. With these regimens, 85% to 95% of children with acute myeloid leukemia (AML) enter complete remission after receiving 1 to 2 cycles of induction chemotherapy. Because the remission-induction phase of therapy is associated with prolonged cytopenias (3–5 weeks), 2% to 5% of patients may die of infectious or hemorrhagic complications before completing the induction phase. Deaths during the first several days after diagnosis are rare and often are caused by leukostasis or disseminated intravascular coagulation. Leukostasis, or plugging of blasts in vessels, is associated with elevated peripheral blast counts (more than 100,000/μL) and can cause hemorrhagic infarction of the brain or other organs. A greatly elevated leukocyte count is a medical emergency, and measures should immediately be taken to decrease the leukocyte count with chemotherapy (eg, hydroxyurea), exchange transfusion, or leukopheresis if the patient has symptoms, such as hypoxemia or mental status changes. Intensifying the doses or timing of chemotherapy during the remission-induction phase of treatment has not increased the percentage of children achieving complete remission but has resulted in a decrease in relapse rates and improvement in overall survival rates.

Table 450-1. WHO Classification of AML

Acute myeloid leukemia with recurrent genetic abnormalities

AML with t(8;21)(q22;q22), RUNX1-RunX1T1 (CBFA/ETO)

AML with inv(16)(p13q22) or t(16;16)(p13;q22), CBFB-MYH11

APL with t(15;17)(q22;q11-12), PML-RARA

AML with t(9;11)(p22;q23), MLLT3-MLL and other balanced translocation of 11q23 (MLL)

AML with t(1;22)(p13;q13), RBM15-MKL1

AML with t(9;22)(q34;q11), BCR-ABL1

AML with mutation of FLT3

AML with normal cytogenetics and cytoplasmic/mutated NPM

AML with mutation of CEBPA

Acute myeloid leukemia with myelodysplasia-related features

AML following a myelodysplastic syndrome

AML with multilineage dysplasia

AML with MDS-related cytogenetic abnormalities

Therapy-related acute myeloid leukemia, myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

Acute myeloid leukemia, not otherwise categorized

AML, minimally differentiated

AML without maturation

AML with maturation

Acute myelomonocytic leukemia

Acute monoblastic and monocytic leukemia

Acute erythroid/myeloid and pure erythroid leukemia

Acute megakaryoblastic leukemia

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis

Myeloid sarcoma

Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis

Other myeloid leukemias of Down syndrome

All-trans-retinoic acid (ATRA) has been shown to be a very effective drug for inducing remissions in patients with acute promyelocytic leukemia. All-trans-retinoic acid used alone is not curative but when ATRA is combined with induction chemotherapy, usually with an anthracycline, the combination is effective at achieving greater than 90% remission rates and with continued chemotherapy and ATRA, a 75% to 85% survival.

Supportive care measures during all phases of therapy for AML are critical. They include providing indwelling central venous access, antiemetic agents, psychosocial support for the child and family, monitoring for the metabolic consequences of leukemic cell lysis (tumor lysis syndrome), empiric therapy for fever and neutropenia with broad-spectrum antibiotics, prophylactic platelet transfusion, administration of allopurinol or rasburicase in situations of very high leukemic counts, and prophylaxis of Pneumocystis jiroveci pneumonia and fungal infections. Use of hematopoietic growth factors has not increased remission rates or overall survival rates among children with AML. In some studies, use of these factors has been associated with slightly less infectious morbidity during periods of neutropenia. All blood products should be irradiated to prevent transfusion-associated graft-versus-host disease (GVHD).

Central Nervous System Therapy

Unlike for acute lymphoblastic leukemia (ALL), management of occult central nervous system (CNS) leukemia with intrathecal chemotherapy alone or combined with cranial irradiation has not been shown to improve overall survival among children with acute myeloid leukemia (AML). Most AML protocols, however, include intrathecal chemotherapy because isolated CNS disease has been found in approximately 20% of children who receive no CNS-directed therapy. Between 3% and 20% of children with newly diagnosed AML have been reported to have leukemic blasts in the cerebrospinal fluid; they are treated with weekly intrathecal chemotherapy until the cerebrospinal fluid is cleared of leukemic blasts. Cranial radiation is not required. The presence of leukemic blasts in the spinal fluid at diagnosis does not appear to have an adverse impact on prognosis.

Treatment in Remission

Unlike therapy for acute lymphoblastic leukemia (ALL), the use of modestly myelosuppressive combination chemotherapy after remission has had little effect on reducing the relapse rate among patients with acute myeloid leukemia (AML). With intensification or consolidation chemotherapy that has included high doses of cytarabine, the 5-year leukemia-free survival rates have increased from 10% to 50% overall, but up to 75% in some groups with good risk AML. The optimal intensity and duration of postremission chemotherapy remain under active investigation.

Bone Marrow Transplantation

The use of marrow ablative doses of chemotherapy with or without total body irradiation, followed by hematopoietic stem cell transplantation (HSCT) from a histocompatible family donor, in the care of children with acute myeloid leukemia (AML) in initial remission, was first attempted in the mid-1970s (see Chapter 133). Although there is a statistically significant disease-free survival advantage for allogeneic HSCT compared with chemotherapy, this has not translated into increased overall survival, in part because of HSCT-related mortality. Currently, patients in the United States will be offered allogeneic HSCT during their first remission if they have standard or high-risk AML, but only after relapse and achieving a second remission for patients with favorable-risk AML. In several large, prospectively randomized pediatric trials, it has been shown that autologous bone marrow transplant (BMT) is comparable to intensive chemotherapy in the first remission of AML.


Prognostic factors include host factors and response to therapy, as well as disease characteristics. These factors are generally interdependent, the sum of which ultimately determine disease response and patient outcome. In addition, prognostic factors may change as treatment changes, thus necessitating the evaluation of all established and putative prognostic markers within the framework of a defined therapy. Efforts to identify risk factors in acute myeloid leukemia (AML) are directed to define populations who may benefit from alternative therapies.  Although some host factors including race5 and nutritional status6 have been linked to clinical outcome, currently their correlation has not been strong enough to justify alteration of therapy.

Disease characteristics inherent to AML include factors such as diagnostic white blood cell (WBC) count, morphologic classification (French-American-British—FAB subtype), and biological characteristics, such as cytogenetics or gene mutations. Although WBC count has been demonstrated to be a prognostic factor in AML, where those with high WBC count have a worse outcome,7 it has been determined that WBC count reflects the underlying biology of the disease and in the context of cytogenetics and other molecular alteration, it is not an independent predictor of relapse.8

FIGURE 450-2. A: Prognostic significance of FLT3/ITD with high and low allelic ratio (AR) compared to those with no FTL3 mutations (FLT3/WT). (Source: Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. 2006;108(12):3654-3661.) B: Overall survival for patients with CEBPA mutations compared to those with CBF AML[inv(16) or t(8;21)], or neither. (Source: Ho PA, Alonzo TA, Gerbing RB, et al. Prevalence and Prognostic Implications of CEBPμ Mutations in Pediatric AML. Blood (ASH Annual Meeting Abstracts) 2007;110:1441.)

Diagnostic cytogenetics is widely recognized as one of the most significant prognostic factors in AML, distinguishing favorable risk patients from those at high risk of relapse. Two of the most commonly identified translocations in pediatric AML, t(8;21) and inv(16) leukemias, collectively account to 15% to 20% of childhood AML.  Numerous adult and pediatric studies have demonstrated that patients with t(8;21) or inv(16) have superior outcome compared to other AML patients.11,12 Acute promyelocytic leukemia (APL) is currently the most curable form of AML with cure rates of 70% to 90% in children and adults.13 The underlying t(15;17) translocation in APL, which leads to formation of the PML-RARalpha fusion protein, leads to maturational arrest in the promyelocyte stage. This maturation arrest can be overcome with pharmacologic doses of all-trans retinoic acid (ATRA). Due to its sensitivity to prodifferentiation therapy, (ATRA) APL is treated differently than other AML subtypes with excellent outcomes.14-16 More recently, addition of arsenic acid to ATRA and chemotherapy has provided further improvement in outcome.17

Karyotypes associated with poor outcome have been identified in a smaller proportion of pediatric patients with AML. Monosomy 7 (–7), monosomy 5 (–5) and deletion of q arm of chromosome 5 (del5q), which collectively account for approximately 5% of the cases of childhood AML, are strongly associated with poor remission induction and high relapse risk.11,18,19

Molecular alterations including mutations, deletions, insertions, or duplications in the genes involved in hematopoiesis have been associated with AML pathogenesis.  The presence of mutations in several genes has been associated with disease outcome and has been used to identify patients at high risk of relapse, as well as those expected to do well. Internal tandem duplication of the FLT3 gene (FLT3/ITD), a gene involved in regulation of stem cell differentiation, has been associated with high risk of relapse in children with AML.8,32 This mutation occurs in approximately 12% of childhood AML patients and is prevalent in patients with normal cytogenetics and those with high diagnostic WBC. Recent studies have linked allelic variation of FLT3/ITD to disease outcome, where those with high allelic ratio (∼80% of those with FLT3/ITD) have exceedingly high risk of relapse with conventional chemotherapy, whereas FLT3/ITD-positive patients with low allelic ratio have an outcome similar to those without FLT3/ITD(Fig. 450-2A).8 Mutations of other genes have been associated with favorable outcome. CEBPα is a transcription factor that regulates granulocytic differentiation. Mutations in CEBPα gene, which leads to neutrophilic maturation arrest, have been identified in approximately 5% of childhood AML. This mutation is mainly observed in patients with normal karyotype and is associated with extremely low relapse risk and favorable outcome (Fig. 450-2B)33 Nucleophosmin (NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar localization, regulates the ARF-p53 tumor-suppressor pathway. Mutations in the NPM gene have been reported in AML that lead to the abnormal cytoplasmic localization of the affected protein.34 NPM mutations have been reported in 30% to 50% of adult AML,35 with a prevalence of approximately 10% in children.36

Evaluation of the prognostic significance of NPM mutations suggests that presence of NPM mutations correlate with favorable outcome in adult AML patients with normal karyotype without FLT3/ITD.35,37,38


The prognosis is poor for children who do not enter remission with an anthracycline-cytarabine regimen or who have a relapse. Allogeneic hematopoietic stem cell transplantation (HSCT) offers these patients the best chance for long-term survival.


Myelodysplastic syndrome (MDS) and myeloproliferative syndrome (MPS) represent heterogeneous groups of clonal hematopoietic disorders. Combined they represent less than 10% of myeloid malignancies in children.

MDS is characterized by ineffective hematopoiesis, dysplastic maturation of bone marrow progenitors, and increased apoptosis. Mild to severe cytopenias result from these changes that in turn lead to the need for red blood cell and platelet transfusions. These are accompanied by increased susceptibility of infection due to neutropenia. The bone marrow of patients with MDS is usually hypercellular and displays dysplastic changes of myeloid precursors. The hypercellularity, and common chromosomal abnormalities such as monosomy 7, deletion of chromosome 5q, or trisomy 8, distinguish it from severe aplastic anemia (SAA). MDS is a “preleukemic” syndrome in that a high proportion of patients progress to AML over months to years.

The outcome for patients with MDS is largely based on the disease characteristics including the degree and extent of dysplasia, the requirement for transfusions, the blast count, and cytogenetics. The DNA methyltransferase inhibitor, 5’azacytidine, has been approved by the FDA for the treatment of adults with MDS. This agent significantly improves hematopoiesis, and reduces the need for transfusions and the rate of conversion to AML. There are no strong data that this type of treatment can cure patients with MDS.

Juvenile myelomonocytic leukemia (JMML) is the most common disorder in children with some features of MDS, as well as MPS. Juvenile myelomonocytic leukemia is characterized by leukocytosis with an absolute monocytosis in addition to a high fetal hemoglobin level, a hypercellular, and often dysplastic bone marrow and myeloid progenitors that display granulocyte macrophage colony-stimulating factor (GM-CSF) hypersensitivity. The disease most commonly occurs in children under age 2 years and is frequently associated clinically with lymphadenopathy, hepatosplenomegaly, and skin changes that include xanthoma, café au lait spots, and eczematous rashes. Usually the karyotype is normal in JMML, although monosomy 7 is observed, but it does appear to be a poor prognostic factor in this situation compared to AML. There are no compelling data that any treatment other than allogeneic hematopoietic stem cell transplantation (HSCT) is curative in JMML. Approximately 50% of children with JMML have long term survival when treated with HSCT.49

In contrast, myeloproliferative syndromes (MPS) are characterized by increased proliferation and survival of hematopoietic progenitors, resulting in very high peripheral blood counts depending on the type of disorder. For example, in essential thrombocythemia (ET), the platelet count is extremely high while in polycythemia vera (PV) the red blood cell mass is expanded. These two disorders are characterized molecular-ly by mutations in signal transduction gene products, particularly JAK2. Chronic myelogenous leukemia (CML), characterized molecularly by the chromosomal translocation of t(9;22) and fusing the genes for bcr-abl, is by far the most frequently observed MPS in children and is characterized by chronic, accelerated, and blast crisis phases. A chronic phase, which usually lasts 3 to 5 years, typically presents with a profound leukocytosis with all stages of granulocytic differentiation present, frequently with thrombocytosis and a hypercellular bone marrow demonstrating normal granulocytic maturation. The accelerated phase is characterized by increasing percentages of leukemic blasts or immature progenitors in the peripheral blood and bone marrow, basophilia, and increased chromosomal abnormalities. Splenomegaly and thrombocytopenia usually develop or worsen. Blast crisis is when CML converts to a picture that is indistinguishable from acute leukemia.

Myeloablative HSCT has to date been the only accepted curative therapy for patients with CML. Children and adolescents with CML who receive an HLA matched, related, or unrelated donor HSCT have long-term survival of approximately 75%.53,54 However, ablative HSCT is associated with significant long-term adverse sequelae including chronic graft-versus-host disease, sterility, endocrinological problems, and secondary malignancies.  The optimal treatment for CML has not been agreed upon. Many pediatric oncologists still favor the use of HSCT, although an increasing number are favoring imatinib along with careful monitoring, especially in patients without a well-matched HLA donor.55