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Myelodysplastic syndromes and myeloproliferative disorders
Myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by varying degrees of cytopenias secondary to ineffective and dysplastic hematopoiesis and increased propensity to evolve into acute myeloid leukemia (AML). In contrast to adult MDS patients, who usually present with a hypercellular bone marrow (BM), the majority of pediatric MDS patients present with a hypocellular BM, making them difficult to distinguish from acquired and inherited BM failure syndromes (IBMFS) (see Chapter 6 , Bone Marrow Failure).
Diagnostic criteria and classification
Table 17.1 provides diagnostic criteria for pediatric MDS.
Table 17.1
Minimal diagnostic criteria for myelodysplastic syndromes.
Modified from Hasle, H., 2003. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17 (2), 277–282 with permission.
At least two of the following:
|
The classification of MDS has been updated over the years to accommodate newer diagnostic findings. Table 17.2 provides the historical evolution of the MDS classification and compares the French–American–British (FAB) classification with the 2001, 2008, and 2017 World Health Organization (WHO) classifications and diagnostic criteria. The 2008 WHO classification introduced a pediatric MDS classification for the first time. Refractory cytopenia of childhood (RCC) was proposed in the 2008 classification and maintained as a provisional entity in the 2017 classification. RCC is the most common subtype of pediatric MDS, accounting for more than 50% of cases. The majority of RCC patients have normal cytogenetics and present with a hypocellular BM with varying degrees of dysplasia resembling BMF. Higher grade pediatric MDS includes MDS with excess blasts [also known as refractory anemia with excess blasts (RAEB)] and RAEB in transformation (RAEB-T) as designated by the early classification of the FAB Group which is not maintained as a pediatric entity in the 2017 WHO classification. For all high-grade (advanced) MDS cases the adult classification scheme has been adapted.
Table 17.2
Historic and current 2017 World Health Organization Classifications of myelodysplastic syndromes.
Modified from Nguyen, P., 2009. The myelodysplastic syndromes. Hematol. Oncol. Clin. North Am. 23 (4), 675–691 with permission.
| FAB (1982) | WHO (2001) | WHO (2008) | WHO (2017) | WHO (2017) diagnostic criteria |
|---|---|---|---|---|
| RA | RA | RCUD (includes RA, RN, RT) | MDS-SLD | SLD, 1–2 lineage cytopenia (Hb <10 g/dL, absolute neutrophil count <1.8×10 9 /L, platelet count <100×10 9 /L), <15% RS or<5% RS with SF3B1 mutation, Blasts <1% (blood) and less than 5% BM, no Auer rods, unequivocal dyserythropoiesis in ≥10% erythroid precursors; ≥10% dysplastic neutrophils; ≥10% dysplastic megakaryocytes of ≥30 megakaryocytes, respectively |
| n/a | n/a | RCMD | MDS-MLD | Dysplasia 2–3 linages, 1–3 lineage cytopenia, <15% RS or<5% RS with SF3B1 mutation, Blasts <1% (blood) and less than 5% BM, no Auer rods |
| RARS | RARS | RARS | MDS-RS-SLDMDS-RS-MLD | Similar to MDS-SLD but with ≥15% RS or ≥5% RS with SF3B1 mutation, Similar to MDS-MLD but with ≥15% RS or ≥5% RS with SF3B1 mutation |
| RAEB | RAEB-1 | RAEB-1 | MDS-EB-1 | Cytopenia(s); <1×10 9 /L circulating monocytes; 2–4% circulating blasts; 5–9% medullary blasts; dysplasia involving ≥1 lineage(s); no Auer rods |
| RAEB | RAEB-2 | RAEB-2 | MDS-EB-2 | Cytopenia(s); <1×10 9 /L circulating monocytes; 5–19% circulating blasts; 10–19% medullary blasts; dysplasia involving ≥1 lineage(s); ±Auer rods a |
| n/a | n/a | RAEB-F | MDS-EB-F | Similar to RAEB-1 or RAEB-2, with at least bilineage dysplasia and with diffuse reticulin fibrosis (WHO grade 2 or 3), with or without collagenous fibrosis |
| RAEB-T a (blasts 20–29%) | (AML) | (AML) | (AML) | n/a |
| n/a | MDS, U | MDS, U | MDS, U | MDS with 1% circulating blasts OR pancytopenia with unilineage dysplasia OR<1×10 9 /L circulating monocytes, ≤1% circulating blasts, <5% circulating blasts, dysplasia in <10% cells of ≥1 lineage(s) and demonstration of MDS-associated chromosomal abnormality(ies), exclusive of +8, del(20q), and loss of chromosome Y (−Y) |
| MDS, isolated del(5q) | MDS, isolated del(5q) | MDS, isolated del (5q) | Anemia; platelet count may be normal or increased; <1% circulating blasts; <5% medullary blasts; megakaryocytes with characteristic nuclear hypolobulation; isolated del(5q) cytogenetic abnormality involving bands q31–q33 | |
| CMML | (MDS/MPN) | (MDS/MPN) | (MDS/MPN) | n/a |
| n/a | n/a | RCC | RCC | Thrombocytopenia, anemia, and/or neutropenia; <2% circulating blasts; <5% medullary blasts; unequivocal dysplasia in ≥2 lineages, or in >10% cells of one lineage; no RS |
Abbreviations: AML , Acute myeloid leukemia; CMML , chronic myelomonocytic leukemia; FAB , French–American–British; Hb , hemoglobin; MLD , multilineage dysplasia; MPN , myeloproliferative neoplasm; n/a , not applicable; RA , refractory anemia; RAEB-F , refractory anemia with excess blasts with fibrosis; RAEB-T , refractory anemia with excess blasts in transformation; RARS , refractory anemia with ringed sideroblasts; RCC , refractory cytopenia of childhood; RCMD , refractory cytopenia with multilineage dysplasia; RCUD , refractory cytopenia with unilineage dysplasia; RN , refractory neutropenia; RS , ring sideroblasts; RT , refractory thrombocytopenia; SLD , single lineage dysplasia; U , unclassifiable.
a In the FAB Classification, the presence of Auer rods is one of the criteria for RAEB-T regardless of the number of blasts.
In addition, a new category of hematologic malignancies (including MDS) due to germline predisposition was introduced, which includes secondary MDS following IBMFS.
Juvenile myelomonocytic leukemia (JMML) and MDS associated with Down syndrome (DS), previously grouped under MDS, are now recognized as distinct entities and are, therefore, classified and discussed separately. Table 17.3 provides the current diagnostic categories of MDS and myeloproliferative neoplasms (MPN) in children.
Table 17.3
Diagnostic categories of myelodysplastic and myeloproliferative diseases in children.
Modified from Hasle, H., 2003. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17 (2), 277–282 with permission and the 2017 WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues.
|
Abbreviations: CMML , Chronic myelomonocytic leukemia; DS , Down syndrome; JMML , juvenile myelomonocytic leukemia.
Epidemiology
Incidence: 1.8 per million children per year in age group 0–14 years.
Constitutes 4% of all hematological malignancies.
Table 17.4 provides constitutional and acquired abnormalities associated with secondary pediatric MDS. Primary MDS occurs de novo without an apparent underlying cause.
Table 17.4
Inherited and acquired conditions associated with pediatric myelodysplastic syndrome (MDS) leading to secondary MDS.
| Conditions associated with MDS |
|---|
| INHERITED CONDITIONS |
| IBMFS: |
| Fanconi anemia |
| SDS |
| Severe congenital neutropenia |
| Dyskeratosis congenita and telomere biology disorders |
| Diamond Blackfan anemia |
| GATA2 haploinsufficiency (MonoMac syndrome, Emberger syndrome, familial MDS/AML) |
| SAMD/SAMD9L mutations |
| Familial nonsyndromic MDS due to mutations in ETV6, RUNX1/AML1 , ANKRD26, DDX41 , or CEBPA |
| Other familial MDS (at least one first degree relative with MDS/AML) without identified genetic cause a |
| ACQUIRED CONDITIONS |
| Prior chemotherapy |
| Prior radiation therapy |
| Acquired aplastic anemia b |
Abbreviations: AML, Acute myeloid leukemia; IBMFS, inherited bone marrow failure syndromes; MDS, myelodysplastic syndrome; SDS, Shwachman Diamond syndrome .
a Familial cases of MDS not due to GATA2, ETV6, RUNX1/AML1, CEBPA.
b A subset of cases currently classified as acquired aplastic anemia might be due to an underlying genetic predisposition and may in the future be considered an inherited condition.
Familial MDS and germline mutations have been observed in more than 30% of children with MDS but are likely more frequent than previously considered. It is commonly associated with partial or complete loss of chromosome 7 (7q- or monosomy 7), particularly in association with GATA2 and SAMD9/SAMD9L mutations or haploinsufficiency.
Therapy-related myeloid neoplasms
In the 2008 and 2017 WHO classifications, this category includes therapy-related AML (t-AML) and therapy-related MDS (t-MDS). These disorders occur secondary to treatment with alkylating agents, topoisomerase II inhibitors, other chemotherapeutic agents, and radiation therapy.
- 1.
Alkylating agent- and ionizing irradiation–induced MDSs are characterized by deletions or loss of whole chromosome or complex cytogenetics. Latency period: 5–10 years.
- 2.
Topoisomerase II inhibitor–induced MDS is characterized by balanced translocations, commonly involving chromosome band 11q23, which harbors the KMT2A (formerly MLL ) gene. Latency period: 1–3 years.
Cumulative incidence of therapy-related MDS represents 5% of all childhood MDS and occurs in approximately 13% of children treated for malignancies.
Children with t-MDS or t-AML compared to children with de novo AML or MDS have the following characteristics:
- 1.
Older at presentation, have lower white blood cell (WBC) counts, and are less likely to have hepatomegaly or splenomegaly or hepatosplenomegaly.
- 2.
More likely to have trisomy 8 and less likely to have classic AML translocations.
- 3.
Less likely to attain remission after induction therapy (50% vs 72%) and less likely to have a longer overall survival (OS) (26% vs 47%), and event-free survival (21% vs 39%).
- 4.
Their disease-free survival (DFS) after attaining remission is similar to children with de novo AML or MDS (45% vs 53%).
Pathophysiology
MDS is a heterogeneous disease with different pathophysiologic mechanisms playing roles in its initiation and progression. Initially, apoptosis dominates the process and is responsible for the characteristic ineffective hematopoiesis. With time, as more genetic abnormalities accumulate in the MDS cells, arrest of maturation and enhanced proliferation occurs, resulting in transformation to AML. Recent evidence suggests that an underlying inherited predisposition (germline mutations, e.g., GATA2 or other inherited BM failure genes) is the disease-initiating event in a subset of patients with pediatric MDS. In those cases, secondary acquired somatic mutations may lead to disease progression.
Clinical features
The clinical presentation can be variable. A third of the patients are asymptomatic and come to medical attention because of an incidental finding of cytopenia. If symptoms occur, they are usually related to cytopenias, for example, pallor, bruises, petechiae, infections. In contrast to adults who frequently present with anemia, children typically present with thrombocytopenia, neutropenia, macrocytosis, and sometimes show an elevated fetal hemoglobin (HbF) levels. Lymphadenopathy or hepatosplenomegaly are uncommon and are associated with advanced disease.
Cytogenetics
- 1.
The presence of a clonal cytogenetic marker can confirm the diagnosis; however, about 61–67% of patients with RCC have normal cytogenetics.
- 2.
Monosomy 7 is the most common cytogenetic abnormality in childhood MDS followed by trisomy 8.
- 3.
Aberrations in chromosome 5, in particular the 5q-syndrome commonly seen in adults, are rare in children.
- 4.
Monosomy 7 and complex karyotype (≥ three abnormalities) have been associated with increased risk for leukemic transformation and poor prognosis.
The concept of monosomy 7 as a distinct syndrome has been abandoned. A subset of these cases ultimately fit the diagnosis of JMML. Another subset of cases initially reported as “monosomy 7 syndrome” were cases of familial MDS/AML and were likely due to GATA2 haploinsufficiency or SAMD9/SAMD9L mutations in a significant portion of the cases.
Molecular genetics
In adult MDS, somatic mutations in splicing factors ( SF3B1, U2AF1, ZRSR2 ) and epigenetic regulators ( TET2, ASXL1, EZH2, DNMT3A, IDH1/IDH2 ) are present in about 75% of cases, followed by isolated TP53 mutations and mutations in a variety of other genes, including transcription factors ( RUNX1, ETV6, GATA2, PHF6 ), kinase signaling ( NRAS, KRAS, JAK2, CBL ), and cohesin complex genes. Interestingly, mutations commonly found in adult MDS, particularly genes controlling the RNA splicing machinery and epigenetics, are only rarely present in pediatric MDS, suggesting different pathogenic mechanisms between the two groups. This evidence and the recent discovery of germline mutations in RUNX1/AML1, GATA2 , SAMD9/SAMD9L , and ETV6 suggest that pediatric MDS is more frequently due to an inherited genetic predisposition.
Recent studies suggest a role for epigenetics in both adult and pediatric MDS, resulting in gene silencing through methylation or histone deacetylation.
Differential diagnosis
- 1.
It is to be noted that dysplastic features may be seen in non-MDS diseases, such as immunologic, rheumatologic, metabolic, mitochondrial (e.g., Pearson syndrome) and nutritional disorders, viral infections, and drug or toxin exposure.
- 2.
Some degree of dyspoiesis/dysplasia can be seen in IBMFS. Given the different treatment strategies and clinical implications, these need to be ruled out by appropriate testing in all patients with suspected MDS.
- 3.
It is difficult to distinguish hypocellular RCC from acquired aplastic anemia. The 2008 and 2017 WHO classifications have established criteria to discriminate between both entities (summarized in Table 17.5 ). It is important to note that RCC currently remains a provisional entity for which the clinical and prognostic implications remain under investigation.
Table 17.5Histopathologic criteria of hypocellular refractory cytopenia of childhood and severe aplastic anemia as outlined in the World Health Organization Classification.Adapted from the 2017 WHO classification.Lineage characteristics RCC SAA Erythroid Patchy, left-shifted erythropoiesis with increased mitoses Lacking foci or left-shifted erythroid cells or only showing single small focus of <10 cells of erythroid cells with maturation Myeloid Markedly decreased, left-shifted myelopoiesis Lacking or markedly decreased myelopoiesis with very few small foci of granulopoiesis with maturation Megakaryocytes Markedly decreased megakaryopoiesis Lacking or only very few megakaryocytes present Dysplastic changes (micromegakaryocytes) a No dysplastic changes or micromegakaryocytes a Lymphoid Lymphocytes, PC, MC may be focally increased or dispersed Lymphocytes, PC, MC may be focally increased or dispersed CD34+ cells Not increased Not increased Abbreviations: MC, mast cells; PC, Plasma cells; RCC, refractory cytopenia of childhood; SAA, severe aplastic anemia .a Immunohistochemistry with CD61 staining is required for the detection of micromegakaryocytes.
- 4.
The majority of children who develop MDS following a diagnosis of acquired aplastic anemia present with MDS within the first 3 years from the diagnosis of aplastic anemia.
- 5.
Patients with mild-to-moderate aplastic anemia may be more likely to develop a clonal disease than a patient with severe aplastic anemia. Repeated evaluation for both conditions, including BM examinations, may become necessary to reach a diagnosis.
- 6.
If ringed sideroblasts are observed in a pediatric BM with concern for MDS or BMF, a search for other etiologies, particularly nutritional deficiencies, drug toxicity, congenital sideroblastic anemias, especially those related to mitochondrial cytopathies, including Pearson marrow-pancreas syndrome, should be considered since MDS with ring sideroblasts is rare in children.
- 7.
Clinical course and the response to therapy for de novo AML are different from advanced MDS with excess blasts (MDS-EB, RAEB in previous classifications). For this reason, it is important that these conditions are diagnosed accurately.
Table 17.6 highlights some investigations and other diagnostic possibilities in patients suspected of having MDS.
Table 17.6
Investigation for the diagnosis of myelodysplastic syndrome and pertinent differential diagnosis.
| Blood a |
| Hemoglobin level and red cell indices: |
| Macrocytosis D/D—drugs, folate, or B 12 deficiency (including abnormalities in their metabolic pathways), IBMFS, MDS, JMML |
| Microcytic and ring sideroblasts: unlikely to be MDS, exclude mitochondrial diseases, copper deficiency, vitamin B 6 deficiency |
| Normocytic D/D—anemia of chronic diseases/inflammation, IBMFS or acquired aplastic anemia (some cases) |
| White cell count, differential count, platelet count |
| Blood film for morphologic review |
| Fetal hemoglobin concentration D/D—MDS, JMML, IBMFS |
| Immunodeficiencies: Occasionally, immunodeficiency may be associated with MDS or vice versa |
| Pertinent tests to be performed on blood in the context of above D/D: |
| Fetal hemoglobin |
| Cytogenetics (mitomycin C or diepoxybutane study for excessive chromosomal breakage) b |
| Erythrocyte adenosine deaminase activity |
| Vitamin B 12 and folate levels |
| Quantitative immunoglobulin levels and T- and B-lymphocyte quantitation |
| Flow cytometry studies for paroxysmal nocturnal hemoglobinuria using standard panel for granulocytes, monocytes, and red blood cells (particularly for hypocellular marrow). Recommended panels include a combination of fluorescent aerolysin, CD14, CD16, CD24, CD59, CD33, CD15 for granulocytes and monocytes |
| Bone marrow |
| Aspirate and trephine biopsy, including appropriate immunohistochemical studies, such as CD34 and CD61 c |
| Iron stain |
| Cytogenetics: conventional and fluorescent in situ hybridization for chromosomes 7, 8, 20, and BCR/ABL (Ph chromosome) |
| Molecular analysis: RT-PCR for BCR/ABL and FLT3 ITD |
| Additional specialized tests (not routinely performed) |
| Neutrophil function |
| Platelet function |
| Colony-forming unit assay for various lineages on bone marrow cells |
If bone marrow is hypocellular aplastic anemia and/or paroxysmal nocturnal hemoglobinuria should be considered. Hepatomegaly or splenomegaly or hepatosplenomegaly favors diagnosis of JMML or acute myeloid leukemia.
Abbreviations: D/D, differential diagnosis; IBMFS, Inherited bone marrow failure syndromes; JMML, juvenile myelomonocytic leukemia; MDS, myelodysplastic syndrome .
a Draw blood for hemoglobin fractionation studies, paroxysmal nocturnal hemoglobinuria panel, and adenosine deaminase (if macrocytosis), before transfusing patient with red blood cells.
b Patients with Fanconi anemia may present with MDS. The significance of this observation is that all patients with MDS should have chromosomal breakage analysis performed to exclude Fanconi anemia because Fanconi anemia is a recessive disorder and warrants genetic counseling. Additionally, preparative regimen for hematopoietic stem cell transplantation is different for patients with Fanconi anemia.
c Bone marrow trephine biopsy: biopsy may help differentiate refractory cytopenia of childhood from acquired aplastic anemia. Two additional types of MDS have been recognized recently, (1) hypoplastic MDS and (2) MDS with myelofibrosis. Also, in some reports, emphasis is placed on recognizing abnormal location of immature precursor cells, that is, presence of blasts in intertrabecular areas in bone marrow biopsy specimens, since it may have prognostic significance. However, no significance has been found thus far, in the major reports of pediatric MDS series.
Prognosis
- 1.
Monosomy 7 and complex karyotype (≥3 abnormalities) are known to be associated with increased risk for disease progression to leukemia.
- 2.
The International Prognostic Scoring System (IPSS) and the revised IPSS that are frequently used in adult MDS have less value in children and their applicability in pediatric MDS has not been verified and a designated pediatric MDS prognostic scoring system does not exist.
- 3.
An analysis by the European Working Group of Childhood MDS (EWOG-MDS) suggested a poor prognosis in patients with two- to three-lineage cytopenia and a blast count >5% in BM.
Patients with low-grade pediatric MDS, in particular hypocellular RCC, can have relatively stable disease for months to years.
Studies in children undergoing myeloablative hematopoietic stem cell transplantation (HSCT) for MDS demonstrated highly variable outcomes and contain a heterogeneous group of patients and treatments. A 3-year OS ranges between 18% and 74% depending on stage (RCC, 74%; RAEB, 68%; RAEB-T, 18%).
HSCT results for 3-year OS for children with MDS:
| De novo MDS patients (all grades) | |
|---|---|
| HLA-matched family donor | 50% |
| Matched unrelated donor | 35% |
| Secondary MDS | 20–30% |
Abbreviation: HLA, human leukocyte antigen
Results of long-term (8-year) DFS after unrelated HSCT:
| RCC | 51% |
| RAEB | 35% |
| RAEB-T | 29% |
Probability of relapse after unrelated HSCT (8 years)
Adapted from Woodard, P., Carpenter, P.A., Davies, S.M., 2011. Unrelated donor bone marrow transplantation for myelodysplastic syndrome in children. Biol. Blood Marrow Transpl. 17 (5), 723–728.
| RCC | 4% |
| RAEB | 23% |
| RAEB-T | 29% |
Recurrence rate was similar between primary and secondary MDS. Abbreviations: DFS , Disease-free survival; HSCT , hematopoietic stem cell transplantation; MDS , myelodysplastic syndrome; OS , overall survival; RAEB , refractory anemia with excess blasts; RCC , refractory cytopenia of childhood.
A recent study of children with advanced primary MDS (RAEB, RAEB-T, and myeloid dysplasia–related AML) showed improved of a 5-year OS of 63% after HSCT (related and unrelated donors).
Treatment
HSCT remains the only curative therapy for pediatric MDS. Chemotherapy alone is ineffective. Therefore high-resolution HLA typing should be performed at diagnosis to expedite a matched related donor (MRD) or unrelated donor search. Given the clinical heterogeneity and lack of precise prognostic factors, guidelines on the optimal timing for HSCT for pediatric MDS and the need for upfront chemotherapy in advanced MDS remain controversial and, therefore, variable.
- 1.
RCC: children with RCC, in particular those without:
- a.
High-risk cytogenetic abnormalities, such as monosomy 7 or complex abnormalities
- b.
Need for transfusions
- c.
Severe neutropenia (absolute neutrophil count remains above 1000/mm 3 ) has a long and stable clinical course without treatment for months to years. For this reason, some investigators recommend a careful “watch-and-wait” strategy for this particular low-risk cohort of patients that fulfills the histologic criteria of hypocellular RCC
Recent reports have suggested that immunosuppressive therapy with antithymocyte globulin (ATG), corticosteroids, and cyclosporine may be effective in a subset of patients with RCC, for which an MRD is not available for HSCT. Nevertheless, patients with RCC remain at risk for progression to leukemia of ~30% over 5 years, with a median time to RAEB of 47 months. Therefore for the majority of RCC patients, HSCT with the best available donor is recommended. BM is the preferred stem cell source. Pre-HSCT chemotherapy is usually not indicated. Myeloablative-conditioning regimens are used for the majority of patients, although reduced intensity-conditioning regimens have been utilized in a subset of patients with low-risk hypocellular RCC.
- a.
- 2.
MDS-EB: debate exists as to whether patients with MDS-EB (previously RAEB) should receive cytoreduction prior to HSCT. Historically many investigators recommend AML-like induction chemotherapy before HSCT in children with MDS-EB, although there are no clear data that this improves outcomes. Therefore some investigators recommend proceeding directly to HSCT with the best available donor in patients with MDS-EB. The recommendation of cytoreduction prior to HSCT depends on multiple factors, including blast count, disease kinetics and risk of progression, cytogenetics, donor availability, and estimated time to transplant based on donor availability and molecular genetic studies. A suitable MRD is preferred for HSCT over an unrelated or alternate donor. Early molecular genetic testing is recommended for all patients with pediatric MDS, in particular for those where a related HSCT donor is considered it will impact donor choice, the conditioning regimen and follow-up.
Biological agents: hypomethylating agents (azacitidine, decitabine) have been shown to improve OS in high-risk adult MDS patients but have limitations as they are not curative and the time to treatment response can be several months. Other newer agents, including thalidomide analogs (used in 5q-syndrome in adults), multikinase inhibitors, and thrombopoietin receptor agonists, are being used more frequently in adult MDS. None of these agents have been extensively studied in pediatric MDS and the use of hypomethylating agents is often decided on a case-by-case basis and whenever possible should be offered as part of a clinical trial.
Myeloid proliferations in children with Down syndrome (DS)
Incidence
It has been suggested that ~1 in 150 children with DS develop MDS or AML by the age of 3 years. DS children are at 10–100 times risk of developing leukemia compared with non-DS children. Myeloid leukemia in children with DS is distinct from the disease in non-DS children. Transient abnormal myelopoiesis (TAM) often precedes myeloid leukemia associated with DS. The most common form of AML in DS children is acute megakaryoblastic leukemia (FAB M7). AML often follows a prolonged MDS-like phase. In patients with DS, there is no biological difference between MDS and AML; and therefore the 2017 WHO classification uses the term myeloid leukemia associated with DS to encompass both MDS and AML.
About 10% of DS infants develop TAM in the first 3 months of life. It is characterized by accumulation of immature megakaryoblasts in blood and liver, and to a much lesser degree in the BM. The majority of patients attain spontaneous remission in 3 months. However, 30% of TAM patients develop myeloid leukemia associated with DS by 3 years of age.
Biology
Acquired mutations in GATA1 (a hematopoietic transcription factor gene) are associated with M7 AML and TAM in DS. A subset of patients with myeloid leukemia associated with DS has mutations in JAK3 and FLT3 genes.
Treatment
DS patients with MDS or AML have improved survival rates (DFS at 4 years is 88%) compared to their non-DS counterparts. Nevertheless, DS patients do not tolerate (nor need) as intensive therapy as non-DS patients with AML or MDS since their blasts are very sensitive to chemotherapeutic agents, particularly Ara-C. DS patients are treated with similar agents as non-DS patients but with a less intensive schedule (see Chapter 19 , Acute Myeloid Leukemia).
Treatment of transient abnormal myelopoiesis in Down syndrome
Supportive treatment is given.
In the case of severe organ dysfunction, such as liver dysfunction, exchange transfusion, leukapheresis, and chemotherapy with cytarabine are used.
Uncommon complications of TAM: hydrops fetalis, renal failure, organ infiltration, pleural effusion, respiratory failure, hepatic fibrosis, disseminated intravascular coagulopathy.
Juvenile myelomonocytic leukemia
JMML is a rare and aggressive myeloid neoplasm of early childhood classified as an overlap MDS/MPN in the 2008 and 2017 WHO classifications. JMML is characterized by hyperproliferation of monocytic and granulocytic cells with infiltration of spleen, liver, lungs, and the gastrointestinal tract. The majority of patients carry a mutation in PTPN11, KRAS, NRAS, CBL , or neurofibromatosis type 1 ( NF-1 ) leading to hyperactive RAS signaling. Allogeneic HSCT remains the only curative therapy with a cure rate of about 50–60%.
Epidemiology
Incidence: 1.2 per million children per year comprises about 2% of all pediatric hematologic malignancies.
Median age at diagnosis: 1.8 years; 35% below 1 year of age, and only 4% above 5 years of age.
Male: Female ratio of 2:1.
Association with inherited syndromes due to germline mutations in PTPN11, NF1 , or CBL .
Increased risk of developing JMML in trisomy 8 mosaicism.
Children with NF-1 have a 200- to 500-fold increased risk of JMML.
Children with Noonan syndrome (NS) show multiple developmental defects and can develop a transient MDS/MPN with a JMML-like presentation due to germline mutations in PTPN11 . NS patients are also at higher increased risk of developing JMML.
Clinical features
Age: usually presents before 2 years of age.
Physical findings:
- 1.
Constitutional/general symptoms: fever, failure to thrive, poor weight gain, infections
- 2.
Skin: skin rash, xanthoma, café-au-lait spots, petechiae, bruising
- 3.
Hematologic: splenomegaly, hepatomegaly, lymphadenopathy, enlarged tonsils, bleeding, pallor
- 4.
Respiratory symptoms: tachypnea, cough, wheezing, respiratory distress
- 5.
Gastrointestinal: abdominal pain, distended abdomen, diarrhea (sometimes bloody)
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