Myeloid leukemia associated with Down syndrome (ML-DS)

INTRODUCTION — Down syndrome (DS; constitutional trisomy 21, OMIM #190685) is the most common chromosomal abnormality among live-born infants. DS manifests as a developmental delay with a characteristic spectrum of congenital malformations, which may include the heart (eg, atrioventricular septal defect), gastrointestinal (eg, duodenal stenosis or atresia, imperforate anus, Hirschsprung disease), musculoskeletal, and complications in other organ systems. Hematologic abnormalities are common in children with DS. Among other hematologic disorders, neonates with DS may exhibit transient abnormal myelopoiesis (TAM; previously called transient leukemia or transient myeloproliferative disorder of DS), a preleukemic condition that is unique to infants with DS or mosaic trisomy 21.

Myeloid leukemia associated with DS (ML-DS) is a unique form of childhood leukemia that arises before age four years in a child with DS or with trisomy 21 mosaicism. The clinical presentation, pathogenesis, response to treatment, and excellent prognosis distinguish ML-DS from other acute leukemias in children [1]. ML-DS is usually manifest as acute megakaryocytic leukemia and diagnosis often follows a myelodysplastic syndrome (MDS)-like phase with prolonged cytopenias. ML-DS can arise in a child with a history of TAM, but most cases develop in children who were not documented to have TAM.

This topic discusses ML-DS.

TAM is discussed separately. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

Also discussed separately are:

●Clinical features and diagnosis of DS, including other DS-associated hematologic manifestations. (See "Down syndrome: Clinical features and diagnosis".)

●General management of children with DS. (See "Down syndrome: Management".)

DESCRIPTION

●Myeloid leukemia associated with Down syndrome (ML-DS) – ML-DS is a unique type of acute myeloid leukemia (AML) that arises in children with DS. ML-DS typically manifests as acute megakaryocytic leukemia, which is often diagnosed following a myelodysplastic syndrome (MDS)-like phase with prolonged cytopenias. In contrast with AML that arises in children who do not have trisomy 21, ML-DS has an excellent prognosis.

ML-DS can develop in children with constitutional trisomy 21 (ie, Down syndrome) or who are mosaic for trisomy 21; affected children may have had transient abnormal myelopoiesis (TAM; described below) as newborns, while other cases of ML-DS develop in children who were not documented to have TAM.

●Transient abnormal myelopoiesis (TAM) – TAM is a preleukemic disorder unique to infants with DS or trisomy 21 mosaicism that is manifest with circulating and/or tissue-infiltrating myeloid blasts. TAM resolves spontaneously in most patients, but some affected children experience early death from complications (eg, liver failure/fibrosis, coagulopathy). Approximately one-fifth of children with TAM subsequently develop ML-DS.

Clinical presentation, natural history, diagnosis, and management of TAM are discussed separately. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

PATHOGENESIS — Central to the pathophysiology of both ML-DS and transient abnormal myelopoiesis (TAM) is the presence of trisomy 21 and an acquired GATA1 mutation in a progenitor cell of fetal (liver) hematopoiesis.

●Trisomy 21 and GATA1 mutation – In the setting of constitutional trisomy 21, there is an expansion of megakaryocyte-erythroid progenitor cells (MEPs) in the fetal liver [2]. Development of TAM and/or ML-DS can occur when a fetal long-term hematopoietic stem cell in a child with trisomy 21 acquires a mutation that encodes an amino-terminally truncated GATA1 transcription factor (GATA1s, for short) [3]. GATA1s is associated with disordered fetal erythropoiesis/megakaryopoiesis. TAM resolves spontaneously within months of birth in most affected children; however, a minority of children experience early death from liver failure or other complications. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

●Development of ML-DS – Approximately 20 percent of children with TAM develop ML-DS months to years after resolution of TAM; ML-DS usually arises within the first four years of life. No specific clinical, hematologic, or molecular features predict the risk of transformation to ML-DS.

Although blasts disappear clinically in most children with TAM, they may persist subclinically for years. The presence of the same patient-specific GATA1 mutation in blasts of both TAM and ML-DS within the same individual indicates that ML-DS develops from a subclone of TAM [4-6]. Compared with TAM blasts, those of ML-DS contain additional genetic abnormalities that contribute to transformation (figure 1). Current understanding is that somatic mutations of GATA1 during fetal hematopoiesis function are the initiating event and result in the development of TAM. In a subset of patients (approximately 20 percent), ML-DS arises when additional mutations are acquired by a dormant TAM clone during the first four years of life.

The most common additional molecular abnormalities are acquired loss-of-function mutations of cohesin complex genes (eg, STAG2, RAD21, SMC1A, CTCF) or epigenetic regulators (KANSL1, EZH2, SUZ12) and gain-of-function mutations of signal transducers (JAK2, JAK3, MPL, KIT, CSF2RB) or components of the RAS signaling pathway (NRAS, KRAS, NF1) [7-12]. These events appear to stop the spontaneous extinction of the GATA1 mutation-positive TAM clone(s) and result in transformation to ML-DS. The timing of the acquisition of the co-operating mutations and the prognostic impact of specific mutations in ML-DS remain to be determined.

●Sensitivity to chemotherapy – ML-DS blasts are highly sensitive to chemotherapy (especially cytarabine) and treatment usually results in excellent outcomes [13,14]. Reasons for the unique sensitivity of ML-DS myeloid blasts to chemotherapy are uncertain, although various hypotheses have been suggested [15,16].

EPIDEMIOLOGY — ML-DS is a unique form of childhood myeloid leukemia that occurs only in children with DS or mosaicism for trisomy 21 [17]. Estimates of the risk of ML-DS following transient abnormal myelopoiesis (TAM) vary from 5 to 30 percent [18-22]; more accurate estimates will require prospective studies of children with DS, with and without GATA1 mutations.

ML-DS occurs with a 150-fold higher incidence in young children with DS, compared with acute myeloid leukemia (AML) in children of the same age group who do not have DS [23]. Virtually all patients with ML-DS present by age four years (average age 1.7 years, compared with 7.5 years for AML in children without DS) [18]. In one study, only 1.3 percent of 2237 enrolled patients were ≥4 years (diagnosis of ML-DS in children ≥4 years in this study required AML with GATA1s) [24].

Prior history of TAM in children with ML-DS is discussed below. (See 'History of TAM' below.)

CLINICAL PRESENTATION — ML-DS comprises a spectrum of disease. Most patients present with symptoms consistent with de novo acute myeloid leukemia (AML). However, up to one-third of patients initially have a myelodysplastic syndrome (MDS)-like phase with prominent cytopenias and a modest percentage of blasts; this cytopenic phase is expected to progress to overt AML.

By definition, ML-DS is not diagnosed in the first 90 days of life or after age four years. During the first three months, an accumulation of myeloid blasts in infants with DS is likely due to transient abnormal myelopoiesis (TAM). (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)".)

Cytopenic prodrome — In up to one-third of patients, ML-DS presents with an MDS-like prodrome with prominent cytopenias.

In 20 to 33 percent of patients, the diagnosis of ML-DS is preceded by weeks or months of unexplained cytopenias; this phase was previously classified as MDS, but it is now recognized to be part of the spectrum of ML-DS [18,25,26]. In our experience, thrombocytopenia and neutropenia are most common, but the prevalence of involvement of various hematopoietic lineages is not well-described.

Leukemic presentation — The percentage of leukemic blasts in the bone marrow can be lower in ML-DS than AML (ie, <20 percent). Some children have extramedullary collections of blasts (chloroma), but central nervous system (CNS) involvement by ML-DS is very rare.

CNS involvement was detected in only 2 of 555 (0.4 percent) children with ML-DS in four clinical studies [24,26,27]. The low incidence of CNS involvement with ML-DS contrasts with 13 percent CNS involvement by AML in children without DS [28].

History of TAM — One-third of patients with ML-DS have a prior history of TAM.

Prior history of TAM was documented in 31 to 35 percent of children with ML-DS, according to clinical studies [24,27]. Conversely, ML-DS develops in 13 to 30 percent of children with TAM [17,19,29,30]. No clinical or routine laboratory finding at diagnosis of TAM reliably predicts subsequent development of ML-DS. The blasts of TAM completely resolve after a median of 36 days (range from 2 to 126 days) in the vast majority of patients [20]. However, occasional patients never lose their circulating blasts before they progress to ML-DS.

Persistence of measurable residual disease (MRD) after resolution of TAM is associated with development of ML-DS, as discussed separately. (See "Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)", section on 'Risk of developing ML-DS after TAM'.)

EVALUATION — Pretreatment evaluation must consider the special vulnerability of children with DS for cardiac and other toxicity.

Clinical and laboratory testing

●Clinical – History and physical examination should evaluate findings that suggest DS, including heart, gastrointestinal, musculoskeletal, and other abnormalities.

•Cardiac – Approximately half of children with DS have congenital heart disease, especially septal defects [31].

Prior to treatment, it is important to evaluate cardiac structure and function (eg, septal defects, valvular abnormalities) by echocardiography and obtain consultation from a pediatric cardiologist, as needed. (See "Down syndrome: Clinical features and diagnosis", section on 'Cardiovascular disease' and "Down syndrome: Management", section on 'Cardiac disease'.)

•Hematology – Many children with DS have hematologic abnormalities, such as polycythemia, macrocytosis (unrelated to vitamin B12/folic acid), and/or leukopenia. (See "Down syndrome: Clinical features and diagnosis", section on 'Hematologic disorders'.)

Importantly, treatment of ML-DS with even low doses of chemotherapy can cause profound and prolonged cytopenias. Coupled with other immunologic impairments in DS, treatment of ML-DS is associated with risk of severe infections or sepsis. (See 'Toxicity' below.)

●Laboratory – Laboratory studies should assess cytopenias and establish a baseline for assessment of tumor lysis syndrome (TLS).

Bone marrow examination is needed to establish the diagnosis of ML-DS. (See 'Diagnosis' below.)

•Hematology – Complete blood count (CBC) and blood smear to assess cytopenias and circulating blasts.

•Serum chemistries – Electrolytes, kidney and liver function tests.

•Bone marrow – Diagnosis of ML-DS requires bone marrow examination that includes histology, immunophenotype, and cytogenetics; molecular studies (eg, detection of a somatic GATA1 mutation) may also be performed.

Because megakaryoblastic leukemias, including ML-DS, are frequently associated with myelofibrosis and difficulty with bone marrow aspiration, we advise obtaining both a bone marrow aspirate and a trephine biopsy. Note that repeated bone marrow evaluations (eg, after an interval of several weeks) may be needed to definitively diagnose or exclude ML-DS in patients with prolonged cytopenias and a low percentage of blasts in the bone marrow.

Pathology — Bone marrow of a patient with ML-DS reveals distinctive leukemic blasts. ML-DS is unique among myeloid leukemias because there is no requirement for ≥20 percent blasts in the bone marrow to establish the diagnosis [32,33].

●Microscopy – Bone marrow microscopy reveals variable numbers of myeloid blasts.

Leukemic blasts resemble those of acute megakaryocytic leukemia (AMKL) in 30 to 96 percent of cases of ML-DS [24,25,27]. Blasts generally have round to slightly irregular nuclei and a moderate amount of basophilic cytoplasm with blebs or coarse granules. Erythroid precursors may exhibit megaloblastic changes and dysplastic forms (eg, multiple nuclei or nuclear fragments). The bone marrow biopsy may show reticulin fibrosis.

●Immunophenotype – Blasts typically manifest a megakaryocytic immunophenotype, but antigen expression varies.

Blasts were classified as megakaryoblasts (M7 category, in the French-American-British [FAB] classification), according to morphology or immunophenotype (ie, expression of CD41, CD42b, CD61) in 30 to 96 percent patients enrolled in clinical studies [24,25,27]. In other cases, the immunophenotype corresponds to various categories of AML [34]. Blasts may express CD33, CD34, CD117, CD36, and CD235a [9].

●Cytogenetics – Cytogenetic abnormalities (besides trisomy 21) are uncommon in ML-DS. Additional karyotypic abnormalities are not definitively associated with outcomes and they are not used to subcategorize ML-DS.

In a trial that enrolled 132 children, only 5.5 percent of cases of ML-DS had the favorable karyotypic abnormalities involving core binding factors [25], compared with 22 percent among more than 1000 patients with pediatric non-DS AML [35].

Some groups have reported an adverse prognostic impact of trisomy 8, isochromosome 7, monosomy 7, normal, or complex karyotype on patients with ML-DS [24,26,36,37]. Other studies did not report such associations [26,27,36]. In one report, for children with ML-DS and a complex blast karyotype, there was an increased risk of relapse despite no detectable measurable residual disease (MRD) when treatment did not include a course of high-dose cytarabine [26].

●Molecular – Somatic mutations of GATA1 (short insertions, deletions, or point mutations in exon 2, less frequently exon 3) are the hallmark of both TAM and ML-DS.

Concordance of the identical GATA1 mutation in blasts of both ML-DS and TAM in a given individual demonstrates that ML-DS evolves as a subclone of TAM. However, while TAM blasts typically contain only GATA1 mutations, the mutational landscape of ML-DS blasts is more complex and diverse [7,9].

Mutations in blasts of ML-DS differ from those of non-DS AML [7,9]. The predominant mutations of ML-DS inactivate cohesin complex genes (eg, STAG2, RAD21; 47 percent), epigenetic regulators (eg, EZH2, KANSL1; 36 percent), and CTCF (CCCTC-binding factor transcriptional repressor; 20 percent), or activate signal transducers (eg, CSF2RB, JAK1, JAK2, JAK3, MPL, SH2B3; 48 percent) and RAS pathway genes (N-RAS, K-RAS, PTPN11; 14 percent). The prognostic relevance of these molecular subgroups of ML-DS remains to be determined.

DIAGNOSIS — ML-DS should be suspected in a child with DS who is >3 months of age (ie, outside the age range of transient abnormal myelopoiesis [TAM]) with unexplained new cytopenias (eg, thrombocytopenia, neutropenia) or who has persistence or an increase of circulating blasts. ML-DS should also be considered in children <4 years with an apparent diagnosis of acute megakaryocytic leukemia without phenotypic DS; such children may be mosaic for trisomy 21.

ML-DS is a clinicopathologic diagnosis that requires all of the following:

●Trisomy 21 – Diagnosis of DS (constitutional trisomy 21) or trisomy 21 mosaicism.

●Age – 3 months to 4 years.

●Myeloblasts – Characteristic myeloblasts in blood or bone marrow. Importantly, there is no requirement for ≥20 percent blasts in the bone marrow to make a diagnosis of ML-DS [32]. Microscopy and immunophenotype of ML-DS blasts are described above. (See 'Pathology' above.)

●Somatic GATA1 mutation – Detection of a mutation in GATA1 exon 2 (occasionally exon 3) confirms the diagnosis of ML-DS, but it is not required in all cases.

In clinical practice, age <4 years in a child with DS and myeloid leukemia is used as an acceptable proxy for an underlying GATA1 mutation; documentation of a GATA1 mutation in a child <4 years with DS and myeloid leukemia has not been required for enrollment in therapeutic trials for ML-DS.

However, GATA1 mutation analysis can detect the exceptional patient who, despite age >4 years, is eligible for treatment according to an ML-DS protocol (eg, 3 of 237 patients in one trial) [24]. (See 'AML in an older child with DS' below.)

MANAGEMENT — Management of ML-DS differs from that of transient abnormal myelopoiesis (TAM) and treatment of acute myeloid leukemia (AML) in children without DS.

Treatment should be delivered in a center with expertise in managing pediatric leukemias. If that is not possible, management should be in consultation with and/or incorporating input from a clinician who has substantial experience with ML-DS and DS. We encourage enrollment in a clinical trial, when possible.

Assessment of measurable residual disease (MRD) is an important aspect of management of ML-DS [38], but there are unique aspects of MRD assessment in ML-DS that require special expertise. Even outside of a clinical trial, we strongly suggest use of a reference laboratory for accurate MRD assessment in ML-DS.

Distinctive aspects of MRD assessment in ML-DS are discussed below. (See 'Response monitoring' below.)

When to start treatment — The timing for initiating treatment should be individualized; the type of presentation of ML-DS (ie, AML-like versus myelodysplastic syndrome [MDS]-like), concurrent infections, and family circumstances should all be considered when weighing this decision.

●Clinical presentation – As described above, ML-DS comprises a spectrum of disease; in most patients, it presents as de novo leukemia, but in a minority of cases, it may first be recognized in a child who appears well and has few circulating blasts and only modest cytopenias. (See 'Clinical presentation' above.)

•AML-like – For children with an AML-like presentation (≥20 percent marrow blasts) we generally initiate treatment promptly to hasten the resolution of cytopenias and avoid other disease-related complications.

•MDS-like – For an otherwise well child with mild or moderate cytopenias due to ML-DS, it is acceptable to either promptly initiate treatment or modestly delay the start of treatment.

We explain to families that, in contrast to TAM, spontaneous improvement of cytopenias and resolution of blasts cannot be expected in ML-DS. Earlier treatment of ML-DS avoids disease progression (eg, increasing blasts in blood or marrow, emergence of a cytogenetic clonal abnormality, or transfusion-dependence) and complications (eg, progressive neutropenia with infections). For children with ML-DS, the marrow blast percentage at the start of chemotherapy (ie, <20 percent versus ≥20 percent) was not associated with prognosis [27].

●Concurrent viral infection – In children who are ill with a significant viral infection (eg, pneumonia) at the time of diagnosis, we generally delay the start of treatment until clinical stabilization. Viral infections have been associated with early death in treatment of children with ML-DS [39], as described below. (See 'Toxicity' below.)

Similarly, we await count recovery between courses of chemotherapy to avoid exacerbating the anticipated treatment-related cytopenias. Starting subsequent cycles of chemotherapy prior to count recovery (ie, to increase dose intensity) was not beneficial in children with ML-DS and resulted in excessive treatment-related mortality [18].

●Patient/family circumstances – Given the lack of a prognostic benefit from early treatment, it is reasonable to individualize the time of start of chemotherapy after taking the patient's and family's circumstances into account.

Treatment — Management of ML-DS is complex, and outcomes are generally excellent, but treatment is associated with significant toxicity, including profound cytopenias and severe infections. We encourage enrollment in a clinical trial, when possible.

For all children with ML-DS, we suggest induction therapy and intensification therapy that includes a course of high-dose cytarabine, rather than eliminating high-dose cytarabine for selected patients, based on retrospective comparison of clinical studies.

Analysis of successive Children's Oncology Group (COG) studies (AAML0431 and AAML1531) reported superior outcomes when high-dose cytarabine was administered to all patients with ML-DS, rather than eliminating high-dose cytarabine for standard-risk patients (MRD-negative [<0.05 percent blasts by flow cytometry] at end of induction) [26]. For patients who had standard-risk ML-DS, elimination of high-dose cytarabine was associated with inferior two-year event-free survival (EFS; 86 versus 94 percent, respectively).

Treatment begins with remission induction therapy, which is followed by an intensification phase. Management should be guided by a contemporary treatment protocol. An outline of treatment in COG AAML0431 [27], which is considered a standard of care in North America, includes:

●Induction therapy – Induction therapy includes four cycles of chemotherapy; in three of these cycles, infusional cytarabine and daunorubicin is accompanied by oral thioguanine, while one cycle comprises high-dose cytarabine plus asparaginase; two of the induction cycles are accompanied by intrathecal (IT) cytarabine [27].

ML-DS blasts are highly sensitive to cytarabine and anthracyclines [13,14]. Excellent outcomes are achieved using lower intensity chemotherapy than that used for non-DS-associated AML [24,27,40-42], while reduced treatment-related mortality contributes to improved EFS (eg, 83 to 89 percent) compared with earlier studies [18].

Initial treatment of ML-DS is not stratified according to disease phase or other prognostic factors (eg, cytogenetic/molecular features). The course of chemotherapy is the same whether a child presents in the myelodysplastic phase of ML-DS (<20 percent marrow blasts) or the AML-like phase (≥20 percent marrow blasts). In contrast to MDS of children without DS, hematopoietic cell transplantation (HCT) does not play a role in the treatment of primary ML-DS.

There are no significant biological, therapeutic, or prognostic differences between children who have an AML-like presentation versus an MDS-like/cytopenic presentation [25,27,43]. Furthermore, available data show no significant differences in outcomes for children with various presentations of ML-DS [24,27]. (See 'Outcomes' below.)

●MRD assessment – After recovery of blood counts from the first cycle of induction therapy, bone marrow MRD is measured to assess treatment response and prognosis. (See 'Response monitoring' below.)

●Post-induction therapy – Intensification includes two cycles of standard-dose cytarabine and etoposide.

Five-year EFS of patients with ML-DS is approximately 90 percent [24,25,27,40,41,44,45]; these outcomes are considerably better than for treatment of AML in children who do not have DS. There is no current evidence that outcomes are improved by treatment stratification according to disease phase or MRD status, nor are there data to suggest benefits from intensification of treatment, routine HCT, or maintenance therapy after achieving remission [18]. Trial design in ML-DS has focused on reducing treatment-related mortality by lowering the intensity of treatment [26], as described above.

Further discussion of outcomes with ML-DS is presented below. (See 'Outcomes' below.)

Toxicity — Infections and cardiac toxicity are important adverse effects (AEs) of ML-DS management.

●Cardiotoxicity – Congenital heart disease is present in 40 to 55 percent of patients with DS [31]. It is important to evaluate cardiac structure and function prior to the start of anthracycline-containing chemotherapy cycles and to involve a pediatric cardiologist, as needed.

Contemporary protocols for ML-DS that use reduced cumulative doses of an anthracycline are associated with lower frequency and severity of cardiotoxicity, compared with earlier studies that used higher anthracycline doses:

•Contemporary protocols – In AAML0431, the cumulative dose of continuous-infusion daunorubicin was reduced by 25 percent (to 240 mg/m²), compared with earlier studies; there was no life-threatening cardiac toxicity and only 3 percent grade ≥3 cardiac AEs among 205 children [27]. In AAML1531, cardiac toxicity was observed in 3 percent of 114 patients on the standard-risk arm [26]. Treatment in ML-DS 2006 was associated with death from heart failure in 1 percent of 170 patients [24].

•Older studies – In contrast to contemporary studies, among 54 patients in POG 9421, symptomatic cardiomyopathy developed (during or soon after treatment) in 18 percent, and 6 percent died of heart failure [46]. Congenital heart disease, which was present in half of the patients who developed symptomatic cardiomyopathy, was not found to be a risk factor.

•Dexrazoxane – This cardioprotectant should be used to preserve cardiac function without compromising EFS or overall survival (OS) in children with non-DS AML [47]. In a study of ML-DS, there was no adverse effect of including dexrazoxane on risk of relapse [26]. Dexrazoxane is infused immediately prior to each bolus infusion of anthracycline during AML chemotherapy.

●Viral infections – Infection-related mortality occurred in 5 percent of 61 patients enrolled in AML-BFM 2004; all three deaths were due to viral infections (two with respiratory syncytial virus [RSV]; one with herpes simplex virus [HSV] encephalitis) [39].

In light of this risk of viral infection, initial stabilization after a significant viral infection (eg, pneumonia) is advised before initiating chemotherapy, if clinically feasible. In general, we also await count recovery between courses of chemotherapy, as described above. (See 'When to start treatment' above.)

Response monitoring — Assessment of MRD by flow cytometry and/or GATA1 mutation is used to monitor treatment response and for prognostic purposes [38]; MRD response is not used to stratify treatment. Whether enrolled in a clinical trial or not, we strongly encourage use of a reference laboratory (ie, a laboratory used in clinical trials for ML-DS) to perform MRD analysis for ML-DS (described below).

Treatment of ML-DS is not stratified according to MRD response; this contrasts with treatment of non-DS AML in children. In one study, reduction of treatment intensity in patients with optimal MRD response with ML-DS was associated with an unexpected increase of relapse rate [26].

Bone marrow of children treated for ML-DS contains DS-specific, non-malignant myeloid precursors that co-express CD56 and CD33/CD34 that are not found in normal, non-DS bone marrow [48-50]. There is a high risk of mistaking these normal cells in recovering bone marrow of children with DS for persistent ML-DS MRD. It is therefore important to base treatment decisions only on MRD results obtained from a ML-DS MRD reference lab to avoid potentially grave errors in management.

OUTCOMES — ML-DS has an excellent prognosis; this observation contrasts sharply with outcomes for acute myeloid leukemia (AML) in children without DS.

Studies of ML-DS have reported five-year event-free survival (EFS) of approximately 90 percent [24,25,27,40,41,44,45]. Examples of outcomes in larger studies of ML-DS include:

●COG AAML0431 – AAML0431 used high-dose cytarabine, a reduced cumulative dose of anthracycline, and fewer treatments with intrathecal (IT) chemotherapy, compared with an earlier COG study; measurable residual disease (MRD) was assessed after the first course of treatment [27]. Among 204 children, five-year overall survival (OS) was 93 percent and five-year EFS was 90 percent. Outcomes differed according to MRD status based on flow cytometry; for MRD-negative patients (blasts <0.01 percent), five-year disease-free survival (DFS) was 93 percent, compared with 76 percent for children who were MRD-positive. There were three non-relapse deaths (1.5 percent, due to human metapneumovirus, pneumonia and hepatic failure, and pneumonia). Five-year probability of survival after relapse was 21 percent [51].

●ML-DS 2006 – This multigroup study (NOPHO, DCOG, AML-BFM) reduced the cumulative dose of etoposide and the number of doses of IT chemotherapy, and it omitted the maintenance phase [24]. Despite the reduction of treatment intensity, five-year OS was 89 percent and five-year EFS was 87 percent. Trisomy 8 was reported to be an independent risk factor for survival. Treatment-related mortality (TRM) was 3 percent (two from heart failure, three with infection). Seven of nine children who relapsed died.

●AML-D11 – This study by the Japanese Pediatric Leukemia/Lymphoma Group reported that detection of MRD was associated with prognosis in ML-DS [45]. MRD was assessed prospectively by flow cytometry and targeted sequencing of GATA1 at the end of the first course of treatment. Among 76 standard-risk patients (by morphology), 8 percent were MRD-positive by flow cytometry and 12 percent were MRD-positive by sequencing. Three-year OS was 97 percent and three-year EFS was 95 percent in patients who were MRD-negative by flow cytometry, and three-year OS and EFS were both 98 percent in those MRD-negative by sequencing. In the flow cytometry MRD-positive group, three-year OS and EFS were 80 and 60 percent; for patients who were MRD-positive by sequencing, three-year OS and EFS were 71 and 57 percent, respectively.

●COG AAML1531 – This study stratified therapy according to MRD status; high-dose cytarabine was omitted for children with standard risk (ie, MRD-negative, <0.05 percent in bone marrow after the first course of treatment; 85 percent of patients), while treatment was intensified for patients who were MRD-positive (15 percent of patients) [26]. Interim analysis of the 114 patients in the standard-risk group showed that outcomes were inferior compared with an earlier study (AAML0431); two-year OS was 91 percent and two-year EFS was 86 percent. For 12 standard-risk patients who relapsed, one-year OS was 17 percent. A complex karyotype was associated with a higher risk of relapse in the standard-risk group.

●COG 2861 and 2891 – These studies reported that higher-intensity chemotherapy did not improve survival but resulted in excessive TRM during induction therapy (32 percent TRM) [18]. Similarly, allogeneic hematopoietic cell transplantation for primary ML-DS in first remission was not successful; two-year DFS was only 33 percent.

Other studies that used various treatment protocols have reported variable outcomes and toxicity [19,25,41,42,44,52-55].

SPECIAL SCENARIOS

AML in an older child with DS — Myeloid leukemia in an older child (ie, ≥4 years) with DS should be considered equivalent to acute myeloid leukemia (AML) in a child without trisomy 21 and should be treated accordingly. Only those older children with DS who have a GATA1 mutation should be treated according to an ML-DS protocol.

ML-DS with the typical disease mechanism (GATA1 mutation) of ML-DS is almost exclusively observed in children <4 years; AML rarely occurs in an older child with DS. Among 10 patients with DS who were ≥4 years old at diagnosis of myeloid leukemia (5 percent of all patients with myeloid leukemia and DS in a research database), only two (ages four and five years) had GATA1 mutations, whereas eight did not (age 6 to 12 years) [24,56].

Management of AML (ie, non-ML-DS) is discussed separately. (See "Acute myeloid leukemia in children and adolescents".)

AMKL in a young child without DS — Several genomic subsets of pediatric acute megakaryocytic leukemia (AMKL) in children without DS have been described [57]. Since what initially appears to be AMKL in a child <4 years of age without DS could also be ML-DS in a patient with trisomy 21 mosaicism, we advise analysis of blast cytogenetics and GATA1 mutational analysis before starting therapy, if clinical circumstances allow.

Relapsed/refractory ML-DS — The prognosis for relapsed or refractory (r/r) ML-DS is dismal; this is in striking contrast to the highly favorable outcomes of primary ML-DS.

There is no consensus treatment for r/r ML-DS and management varies among study groups and institutions. We strongly encourage participation in a clinical study, when possible.

Reported outcomes with r/r ML-DS include:

●Chemotherapy – In ML-DS 2006, seven patients died among the nine patients who relapsed [24]. In AAML0431, five-year overall survival (OS) after relapse was 21 percent [27] and was 25 percent in a retrospective study of patients treated on AML studies in Japan [58]. In AAML1531, even if primary treatment of ML-DS did not include high-dose cytarabine, one-year OS after relapse was only 16 percent [26].

There are case reports of reinduction therapy for r/r ML-DS using vorinostat [59], decitabine/vorinostat [60], and azacitidine [61].

●Hematopoietic cell transplantation (HCT) – Two studies have reported outcomes after allogeneic HCT.

•In a retrospective study of 29 patients with r/r ML-DS from Japan, 2 of 14 patients who underwent allogeneic HCT survived; remission status at the time of transplantation and duration of first remission were associated with prognosis [58]. Among patients transplanted in complete remission (CR), two of eight patients survived, while none of six patients survived who were transplanted without achieving CR. There were no survivors among those whose first remission was <6 months.

•A registry study of 28 patients with r/r ML-DS reported 19 percent three-year OS and 14 percent three-year disease-free survival [62]. All but one patient had received myeloablative conditioning and 43 percent of patients had been in remission at the time of transplantation. The main cause of treatment failure was subsequent relapse (61 percent at three years), rather than toxicity; treatment-related mortality at 100 days and three years was 14 percent and 25 percent, respectively.

FOLLOW-UP — Follow-up care includes surveillance for disease relapse and monitoring for cardiotoxicity.

●Schedule – There are no consensus guidelines for follow-up of children with ML-DS. One empiric schedule after completion of treatment for ML-DS includes monthly clinic visits with a physical examination and complete blood count (CBC)/differential count during the first year of follow-up, every three months in the second year, every six months until the end of year 5, and then annually [26].

●Relapse surveillance – In one study, all but one relapse occurred within one year from study entry [26].

●Cardiac toxicity – Cardiotoxicity of ML-DS chemotherapy has decreased with contemporary regimens, but it warrants monitoring [24,27,46]. We perform echocardiograms following a published schedule offered by the Children's Oncology Group.

SUMMARY AND RECOMMENDATIONS

●Description – Myeloid leukemia associated with Down syndrome (ML-DS) is a unique form of acute myeloid leukemia (AML) that occurs in children with Down syndrome (DS) or mosaicism for trisomy 21. ML-DS may arise in children who had the preleukemic condition, transient abnormal myelopoiesis (TAM), as newborns. (See 'Description' above.)

●Pathogenesis – Both ML-DS and TAM require trisomy 21 and a mutation of GATA1 that encodes a truncated form of the transcription factor (GATA1s). ML-DS is associated with additional genetic abnormalities that contribute to transformation (figure 1). (See 'Pathogenesis' above.)

●Presentation – ML-DS comprises a spectrum of disease. Most patients present with de novo AML (≥20 percent blasts in blood or marrow), but some have a myelodysplastic syndrome (MDS)-like phase with prominent cytopenias and fewer blasts in the bone marrow than overt AML.

●Evaluation – Evaluation must consider cardiac or kidney disorders that might affect treatment. Bone marrow aspirate and biopsy should be performed (aspiration often yields little material if the marrow is fibrotic). (See 'Evaluation' above.)

●Diagnosis – ML-DS should be suspected in a child with DS >3 months to 4 years of age with unexplained cytopenias and/or myeloid blasts and may occur in a child <4 years with unexplained cytopenias or myeloid blasts in the absence of features of DS (in association with mosaicism for trisomy 21). (See 'Diagnosis' above.)

The clinicopathologic diagnosis of ML-DS requires:

•Trisomy 21 – DS or trisomy 21 mosaicism.

•Age – Three months to four years.

•Myeloblasts – Characteristic myeloblasts in blood or bone marrow; diagnosis does not require ≥20 percent blasts in marrow.

•GATA1 mutation – Detection of a somatic GATA1 mutation in blasts supports the diagnosis, but it is not required. Testing should be performed for AML in a child with DS >4 years of age.

●Management – Treatment should be delivered in a center with expertise in managing pediatric leukemias or with input from a clinician with experience with ML-DS.

•Timing – Timing for initiating treatment should be individualized. We favor initiating treatment soon after establishing the diagnosis to hasten resolution of cytopenias and avoid disease complications. However, outcomes do not differ according to disease phase (ie, MDS-like versus AML-like). Treatment should be delayed to enable clinical stabilization after a significant viral infection (eg, pneumonia) and may be delayed for children with an MDS-like presentation with mild cytopenias for family/other circumstances. (See 'When to start treatment' above.)

•Treatment – Management of ML-DS is complex and associated with significant toxicity. Details of treatment should conform with a contemporary treatment protocol.

For all children with ML-DS, we suggest induction therapy followed by intensification therapy that includes high-dose cytarabine, rather than eliminating high-dose cytarabine for selected patients (Grade 2C). (See 'Treatment' above.)

●Outcomes – In contrast with AML in children who do not have DS, outcomes with ML-DS are excellent. (See 'Outcomes' above.)

●Special scenarios – Management of relapsed/refractory ML-DS and other special scenarios are described above. (See 'Special scenarios' above.)

●Follow-up – Our approach to monitoring for relapse and late toxicity is described above. (See 'Follow-up' above.)