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Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)

Transient abnormal myelopoiesis (TAM) of Down syndrome (DS)
Literature review current through: May 2024.
This topic last updated: Nov 18, 2022.

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 tract (eg, duodenal stenosis or atresia, imperforate anus, Hirschsprung disease), musculoskeletal system, and other organs.

Hematologic abnormalities are common in children with DS. Among other hematologic disorders, neonates with DS may exhibit transient abnormal myelopoiesis (TAM), a preleukemic condition that is unique to infants with DS or mosaic trisomy 21. TAM was previously called transient leukemia or transient myeloproliferative disorder (TMD) of DS. TAM generally manifests as circulating blasts and is often accompanied by hepatomegaly; some children also have infiltration of blasts into skin or other organs. In a minority of cases, liver fibrosis/failure or other organ dysfunction causes early death. Some children with TAM later develop myeloid leukemia associated with DS (ML-DS) within the first four years of life.

TAM poses diagnostic challenges and requires an individualized approach to management that is stratified according to the risk of early death. The pathogenesis, natural history, and management of TAM are different from other DS-associated hematologic disorders, such as ML-DS and acute lymphoblastic leukemia (ALL).

The pathogenesis, clinical features, diagnosis, and management of TAM are presented in this topic.

Myeloid leukemia associated with DS is discussed separately. (See "Myeloid leukemia associated with Down syndrome (ML-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".)

PATHOGENESIS — TAM is a preleukemic disorder unique to infants with DS or mosaic trisomy 21 that is manifest with circulating and/or tissue-infiltrating blasts that usually resemble megakaryoblasts [1]. TAM resolves spontaneously in most patients, but 5 to 20 percent of affected children experience early death from complications. In addition, approximately one-fifth of children with TAM later develop myeloid leukemia associated with DS (ML-DS), a disorder that may present with cytopenias and low blast counts or as acute megakaryoblastic leukemia (AMKL) with higher blast counts (figure 1).

Central to the pathophysiology of both TAM and ML-DS is the presence of trisomy 21 and an acquired GATA1 mutation in a progenitor cell of fetal (liver) hematopoiesis. Key aspects of the pathophysiology of TAM and ML-DS include:

Trisomy 21 and GATA1 mutation – In the setting of constitutional trisomy 21, there is expansion of megakaryocyte-erythroid progenitor cells (MEPs) in the fetal liver [2-5]. Acquisition by a long-term hematopoietic stem cell of a somatic mutation of GATA1 (which encodes a key transcription factor for erythropoiesis and megakaryopoiesis) appears to initiate development of TAM [6]. GATA1 mutations in TAM and ML-DS typically encode a patient-specific short insertion/deletion or point mutation in exon 2 (or, rarely, in exon 3) [7,8]. The mutated gene encodes an amino-terminally truncated protein (GATA1s for short) that impairs megakaryocytic differentiation and leads to uncontrolled proliferation of a population of TAM blasts in the context of constitutional trisomy 21 [3,9-11].

The observation that TAM blasts are typically found in greater percentages in blood than in the bone marrow (the site of postnatal blood formation) is consistent with the origin of TAM in fetal liver hematopoietic cells [12,13]. While the typical sequence of events underlying TAM and ML-DS is acquisition of a somatic GATA1 mutation in the context of constitutional trisomy 21, rare instances of TAM or ML-DS have been described in which hematopoietic cells with a germline GATA1 mutation subsequently acquired somatic trisomy 21 [14,15].

Liver failure/fibrosis occurs in a minority of patients and can cause early death in children with TAM. Liver fibrosis appears to be caused by secretion of fibrogenic cytokines (eg, PDGF-alpha and -beta, TGF-beta) by TAM blasts and/or expression of PDGFR-beta or MCP-1 in fibrotic tissue [16,17].

Spontaneous resolution of TAM – TAM resolves spontaneously within the first three months of life (or before birth) in the vast majority of affected children. The mechanisms that account for its regression are uncertain. Hypotheses for the disappearance of TAM blasts include the developmental transition from prenatal fetal liver hematopoiesis to postnatal bone marrow hematopoiesis, a response by the developing immune system, and/or a high rate of spontaneous apoptosis [18].

Development of ML-DS – Approximately 20 percent of children develop ML-DS months to years after resolution of TAM (usually before age four years). Subclinical persistence of TAM blasts, together with additional mutations (eg, in signaling molecules, cohesin complex, epigenetic modifiers) are required for development of ML-DS [19]. Details of the pathogenesis of ML-DS are described separately. (See "Myeloid leukemia associated with Down syndrome (ML-DS)".)

TRANSIENT ABNORMAL MYELOPOIESIS (TAM)

Incidence — TAM occurs predominantly in children with DS or with mosaicism for trisomy 21. The incidence of TAM varies according to the method and timing of evaluation and the diagnostic criteria, which vary among research groups. (See 'Diagnostic criteria' below.)

The incidence of TAM has been estimated at 10 percent, based on small studies that reviewed blood smear morphology of newborns with DS [20-25]. However, TAM may go undetected if a blood smear is not obtained within days of birth [26].

A prospective study detected circulating blasts in 98 percent of 200 neonates with DS (blasts ranged from 1 to 77 percent of nucleated blood cells) [27]. This study also reported somatic GATA1 mutations in 29 percent of newborns with DS; the presence of >20 percent blasts on a blood smear was invariably associated with GATA1 mutation, but GATA1 mutations were detected in only 8.5 percent of patients with >10 percent circulating blasts. The additional 20 percent of DS neonates who had a GATA1 mutation, but no clinical or hematologic features of TAM, were described as having "silent TAM." This entity is relevant because affected newborns are at risk of subsequent development of myeloid leukemia associated with DS (ML-DS). (See "Myeloid leukemia associated with Down syndrome (ML-DS)".)

Neonates with trisomy 21 mosaicism, who may not manifest clinical findings of DS, account for 7 to 16 percent of all cases of TAM [28-31]. In rare instances, trisomy 21 may even be limited to the population of blast cells [32].

Clinical presentation — Most cases of TAM are detected soon after birth. The presentation can range from asymptomatic to life-threatening complications. Blood and liver are most often affected, but other organs can be involved.

Most newborns with TAM display features associated with DS; others may have trisomy 21 mosaicism, as described above. Clinical features of DS are described separately. (See "Down syndrome: Clinical features and diagnosis".)

Asymptomatic – Asymptomatic presentation (ie, laboratory abnormalities alone) has been reported in 10 to 38 percent of children with TAM.

The Children's Oncology Group (COG) A2971 study reported that 38 percent of the infants with TAM were asymptomatic [12], the Berlin-Frankfurt-Münster (BFM) group reported 10 percent of 146 newborns with TAM did not have clinical findings [2], and the Pediatric Oncology Group (POG) 9481 study of 48 infants reported that 25 percent of neonates with TAM were asymptomatic [33].

Organ involvement – TAM often presents with involvement of liver, which can manifest as hepatomegaly, ascites, or liver failure. Less often, TAM affects spleen, skin, or other organs and may present with splenomegaly, pleural or pericardial effusions, vesicular skin rash, or other findings.

Liver – Liver is most often affected, with hepatomegaly present in more than half of cases; massive hepatomegaly (extending below the umbilicus) is seen in 10 percent [2,12,33]. The high frequency of liver involvement is thought to reflect the origin of TAM from fetal liver hematopoiesis. (See 'Pathogenesis' above.)

Hepatomegaly is a result of megakaryoblast infiltration and/or megakaryoblast-induced hepatic fibrosis. Hepatic involvement can be severe, with liver failure/fibrosis reported in 7 to 15 percent of cases [2,12]. Conjugated bilirubin was elevated in 13 to 63 percent of affected neonates, while alanine transaminase (ALT) was less frequently increased [2,12,33]. Bile stasis can be seen in the bile canaliculi and hepatocytes [5], which corresponds with the frequent elevation of conjugated bilirubin. (See 'Evaluation' below.)

Skin – Skin involvement was reported in 5 percent of cases in the POG 9481 study [33]. The rash most often involves the face, but there can be variable involvement anywhere on the body.

The rash is initially vesiculopustular, but it can become confluent and crusted with an erythematous base and it may resemble neonatal varicella-zoster virus (VZV) infection [5]. Biopsy reveals perivascular or dermal blasts and immature myeloid cells with infiltration into the epidermis [34-37].

Other organs – Spleen, kidney, lungs, and heart can be affected. Splenomegaly was reported in 36 to 44 percent of neonates with TAM, pericardial and pleural effusions in 10 to 23 percent, and ascites in 8 to 21 percent [2,12,33]. Pleural or pericardial effusions due to TAM must be distinguished from those due to heart failure.

TAM-associated complications – Severe, life-threatening complications have been reported in 22 to 42 percent of children with TAM [2,11,12,33,38,39]. Hyperleukocytosis, liver failure with coagulopathy, hydrops fetalis, multiorgan failure, ascites, and pleural or pericardial effusions are risk factors for early death, as described below. (See 'Criteria for risk stratification of TAM' below.)

Hyperleukocytosis – White blood cell (WBC) count >100,000/microL (>100 x 109/L) can cause respiratory distress or neurological symptoms due to leukostasis. Hyperleukocytosis constitutes a medical emergency and is an indication for urgent treatment.

Liver failure – Liver failure or complications of liver enlargement (eg, respiratory failure from diaphragmatic elevation or renal failure from hepatorenal syndrome) are the most common cause of fatal complications from TAM [5]. Liver fibrosis can occur in newborns with few circulating blasts [11]. In one study, none of the patients with documented liver fibrosis survived [2].

Hepatomegaly alone does not constitute an indication for treatment, unless it is accompanied by abnormal liver function.

Heart failure – Cardiopulmonary failure may be associated with pericardial and pleural effusions and is more prevalent in children with DS and a congenital heart defect [2,11,12,33,38]. Infiltration of the myocardium with myeloblasts has been described in post-mortem studies [20,38].

Only effusions that are not explained by a cardiac cause are an indication for treatment.

Coagulopathy – Bleeding in infants with TAM may be caused by a coagulopathy, thrombocytopenia, and/or disseminated intravascular coagulation (DIC). (See "Disseminated intravascular coagulation in infants and children".)

Abnormal coagulation is seen in 20 percent and DIC in <10 percent of affected children [2,12]. Management of hemorrhage may require platelet transfusions or coagulation factors (eg, fresh frozen plasma for coagulopathy and cryoprecipitate or fibrinogen concentrate for severe hypofibrinogenemia). (See "Disseminated intravascular coagulation in infants and children".)

Tumor lysis syndrome (TLS) – TLS, which is caused by massive cell death, can be seen in patients with TAM.

TLS is characterized by hyperphosphatemia, hypocalcemia, hyperuricemia, hyperkalemia, and renal insufficiency. TLS management includes hydration, allopurinol, and/or rasburicase, as described separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors".)

Management of infants with clinically severe/high-risk TAM is described below. (See 'High-risk TAM' below.)

Natural history — TAM resolves spontaneously for most children, but 5 to 20 percent of patients experience early death from a severe complication. An additional one-fifth of children with TAM later develop ML-DS.

Spontaneous resolution – For most affected children, TAM resolves spontaneously within three months of birth.  

In the COG A2971 study of 135 neonates with TAM, circulating blasts disappeared after a mean of 36 days (range 2 to 126 days) and all signs of TAM, including hepatomegaly, resolved after a median of 49 days (range 5 to 745 days) [12].

Prospective evaluation of 48 infants with TAM in POG 9841 reported that 89 percent spontaneously cleared circulating blasts, blood counts normalized in 74 percent, and a complete remission was maintained in 74 percent [33].

The AML-BFM study group reported 85 percent five-year overall survival (OS) and 63 percent five-year event-free survival (EFS) in 146 neonates with TAM [2].

Monitoring of children with resolved TAM is described below. (See 'Follow-up' below.)

Early death – Large prospective and retrospective studies have reported early mortality in 5 to 23 percent of children with TAM [2,12,33,39,40].

The predominant cause of TAM-related early death is progressive liver failure with cholestasis, hepatic fibrosis, DIC, and multiorgan failure [4]. Non-hepatic TAM-related deaths are most often due to cardiorespiratory failure associated with pericardial and pleural effusions, hydrops fetalis, renal failure, and infection. Other early deaths that are not directly attributable to TAM include severe heart disease or other congenital abnormalities associated with DS.

Features associated with early death are used to stratify management of TAM, as described below. (See 'Risk stratification' below.)

ML-DS – Approximately one-fifth of children develop ML-DS within the first four years of life, usually after complete clinical resolution of TAM, as described separately. (See "Myeloid leukemia associated with Down syndrome (ML-DS)".)

EVALUATION — Evaluation for TAM in a newborn suspected to have DS or trisomy 21 mosaicism requires microscopic examination of a blood smear for myeloid blasts, with confirmation of the immunophenotype by flow cytometry. Detection of a GATA1 mutation confirms the diagnosis, but in clinical practice, treatment decisions may be necessary before the sequencing results are available. (See 'Management' below.)

Bone marrow examination is not required to diagnose TAM.

All children with suspected trisomy 21 (either constitutional or mosaicism) and morphologic and immunophenotypic evidence of circulating myeloid blasts should be evaluated promptly for risk of death from TAM and treated urgently, if appropriate. These actions should not be delayed while awaiting results of mutation analysis, as early intervention has been associated with reduced TAM-related mortality [39]. (See 'Risk stratification' below.)

Blood smear and blood counts — All neonates with DS should have a blood smear reviewed and a complete blood count (CBC) soon after birth [4]. A CBC alone is not sufficient, as automated blast counts are not adequate and often fail to detect blasts

Blood smear – Within days of birth, a blood smear should be reviewed for the presence of blasts. Suspected blasts should be confirmed by a hematologist/oncologist, pathologist, or hematopathologist with experience in reviewing neonatal blood films. We refer all children with circulating blasts for flow cytometry, as described below. (See 'Flow cytometry' below.)

The blood smear typically reveals variable numbers of pleomorphic blasts that are medium to large in size, with large amorphous nuclei, prominent nucleoli, basophilic cytoplasm with coarse basophilic granules, and cytoplasmic blebs [1,27]. Blasts usually resemble megakaryoblasts, but morphology can vary. It is important to distinguish TAM blasts from immature cells in a markedly "left-shifted" granulocytic series that may be seen in a child with severe stress (eg, infection, sepsis, or other causes). (See 'Differential diagnosis' below.)

CBC – Abnormalities affecting red blood cells, white blood cells (WBC), and platelets are common in children with DS, as discussed separately. (See "Down syndrome: Clinical features and diagnosis", section on 'Hematologic disorders'.)

Moderate leukocytosis is common in TAM. The WBC count at presentation is 28,000 to 40,000/microL (28 to 40 x 109/L), but up to one-sixth of children present with hyperleukocytosis (WBC >100 x 109/L) [5,39,41]. Hyperleukocytosis is a risk factor for early death in children with TAM. (See 'Risk stratification' below.)

Platelet counts are variable in TAM. Thrombocytopenia is not more common in newborns with TAM compared with other newborns with DS. Anemia is rare in TAM [2,12,33].

Flow cytometry — Flow cytometry is performed to confirm the myeloid lineage of blasts and to exclude other causes for circulating immature myeloid cells, such as sepsis or leukemia. TAM blasts generally have a myeloid or megakaryocytic morphology and immunophenotype, but findings are variable and there is no single pathognomonic finding or combination of findings.

TAM blasts are typically positive for CD33, CD117 (c-KIT), CD13, CD34, HLA-DR, CD4 (dim), CD41, CD42, CD110 (TPOR), IL3R, CD36, CD61, and CD71 [1]. Expression of CD7, CD56 and CD235a (glycophorin) may be present, whereas cells are negative for myeloperoxidase (MPO) [2,42,43].

GATA1 mutation testing — Detection of a somatic GATA1 mutation provides useful confirmation of the diagnosis of TAM, but failure to detect GATA1 mutation does not exclude the diagnosis. The role of GATA1 mutation in diagnosing TAM is discussed below. (See 'Diagnostic criteria' below.)

If the clinical scenario and laboratory findings are consistent with TAM, management decisions should be made promptly after detection of myeloid blasts, rather than waiting for the result of the GATA1 mutational analysis because early treatment of newborns with high-risk TAM is associated with improved survival [39]. (See 'Management' below.)

GATA1 mutations in TAM/ML-DS blasts consist of short insertions/deletions or point mutations in exon 2 (less often in exon 3) [7]. The mutations result in N-terminal truncation of GATA1 protein and expression of a short form, termed GATA1s. However, not all children with blasts have a detectable GATA1 mutation [27]. A negative sequencing result in a child with TAM may be caused by a low percentage of blasts, a large genomic deletion or deletion of a primer binding site, low sensitivity of the sequencing assay, and other reasons.

Other testing — Diagnostic tests for TAM can typically be performed on a peripheral blood sample. A bone marrow aspirate is not routinely needed for evaluation and diagnosis of TAM.

Karyotype – The blast karyotype confirms the presence of trisomy 21 and screens for additional chromosomal abnormalities. In the majority of newborns with TAM, no additional karyotypic abnormalities (other than trisomy 21) are seen in the blasts [42].

Medical genetics consultation should be obtained for all children with trisomy 21, whether features of DS are detected or not (eg, in a child with trisomy 21 mosaicism).

Bone marrow examination is not required – Since TAM is a disorder of fetal hematopoiesis (which occurs outside the bone marrow), the percentage of circulating blasts is typically higher than the percentage in marrow [12]. Thus, bone marrow examination is not required for diagnosis of TAM.

When bone marrow examination was performed, abnormal megakaryocytic maturation was seen in 75 percent and dyserythropoiesis in 25 percent of patients [2,12,33].  

DIAGNOSIS

When to suspect TAM — TAM should be suspected in newborns with possible DS who have blasts detected on blood smear, hydrops fetalis, ascites, hepatosplenomegaly, unexplained abnormal liver dysfunction/failure, coagulopathy, or pericardial or pleural effusions.

TAM should also be considered in newborns who have no evident features of DS but have one of the findings listed above; in such cases, trisomy 21 mosaicism should be evaluated.  

Diagnostic criteria — Diagnosis of TAM is based on demonstration of myeloid blasts in blood (or another tissue) in a child with trisomy 21; however, diagnostic criteria vary among pediatric trial groups (described below).

We diagnose TAM based on:

Age – Under 3 months.

Trisomy 21 – Documented in blood cells by karyotype or fluorescence in situ hybridization (FISH).

For a child with a presumptive diagnosis of TAM, but without clinical features of DS, it is important to determine if the child has genetic mosaicism [44]. We obtain medical genetics consultation for all children with trisomy 21, including children with possible genetic mosaicism. (See "Down syndrome: Clinical features and diagnosis".)

Blasts – Circulating or tissue-infiltrating myeloid and/or megakaryocytic blasts, based on morphology and immunophenotype:

Morphology – The blood smear typically reveals blasts with prominent nucleoli and blebbed basophilic cytoplasm; however, TAM blasts are pleomorphic and morphology varies [27]. (See 'Blood smear and blood counts' above.)

TAM is occasionally diagnosed based on cytological or histological detection of TAM blasts in an affected organ (eg, liver) or an umbilical cord blood sample [2].

Immunophenotype – Flow cytometry typically reveals blasts with variable co-expression of stem cell markers (CD34, CD117), myeloid markers (CD33, CD13), megakaryocytic and platelet antigens (CD41, CD42, CD61, CD36), erythroid markers (glycophorin A/CD235a) [42], and aberrant expression of CD56 and CD7 [2,45-47]. However, no specific lineage-specific antigen or combination of antigens is required to diagnose TAM-related blasts, as described above. (See 'Flow cytometry' above.)

Blast percentage – There is no consensus for the minimal percentage of circulating blasts required to diagnose TAM.

As examples, the Children's Oncology Group (COG) defines the diagnosis by the presence of any blasts (if blasts are confirmed with a second sample), Berlin-Frankfurt-Münster (BFM) requires >5 percent blasts, and the World Health Organization (WHO) does not specify a percentage. Investigators in the United Kingdom found that blasts were present in most blood samples from newborns with DS [11].

Mutation analysis – Detection of a somatic GATA1 mutation is useful for confirming the diagnosis of TAM, but it is not required; occasionally, a GATA1 mutation is not detected in a child who meets diagnostic criteria for TAM (ie, age, trisomy 21, and characteristic blasts).

We do not require a specific percentage of blasts to perform next-generation sequencing (NGS); however, some experts favor mutation testing only in those children with a certain threshold level of blasts (eg, >10 percent) [4]. Sanger sequencing or NGS of GATA1 can be used for mutation testing. (See 'GATA1 mutation testing' above.)

All children with trisomy 21 and circulating or tissue-infiltrating myeloid blasts must be promptly assessed for risk factors for early death and treatment initiated, if warranted. Risk stratification and management should not be delayed by waiting for mutation analysis (if performed). (See 'Risk stratification' below and 'Management' below.)

Diagnostic criteria for TAM are not universal and prospective studies have used different criteria to diagnose TAM:

Children's Oncology Group (COG) – In COG A2971, diagnosis of TAM was based on the detection of any non-erythroid blasts in blood and/or organs (eg, liver, pleural, pericardial effusions, bone marrow) of infants <90 days old with constitutional trisomy 21 (DS) or trisomy 21 mosaicism [12]. This definition required confirmation with a second blood sample or additional findings of >5 percent non-erythroid blasts in marrow, hepatomegaly or splenomegaly, lymphadenopathy, or pericardial/pleural effusions.

Berlin-Frankfurt-Münster (BFM) – In the BFM study, diagnosis of TAM required >5 percent myeloid blasts (by morphology) in blood or bone marrow aspirate within the first six months of life [2]. In a subsequent BFM study, the age criterion was reduced to the first three months of life [39].

Oxford-Imperial Down Syndrome Cohort Study (OIDSCS) – OIDSCS considers ≥10 percent blasts a threshold for diagnosis of TAM [4]. This group describes neonates who have DS and a GATA1 mutation, but have no clinical or hematologic features of TAM, as having "silent TAM."

Differential diagnosis — No single feature is entirely specific for TAM, as all can occur with other conditions. The differential diagnosis depends on the clinical features of the individual child. Nevertheless, suspicion for TAM should be high in a newborn with suspected DS who has non-lymphoid/non-erythroid blasts in blood, together with organomegaly, liver dysfunction, rash, pericardial or pleural effusions, extreme leukocytosis, or coagulopathy without a clear alternative explanation.

Other conditions can cause findings that resemble TAM:

Immature circulating cells – Circulating immature myeloid cells (eg, "left shift") or blasts in a newborn or young infant may reflect a reactive process or a hematologic malignancy.

Reactive processes may be due to infections (eg, sepsis, severe congenital infection [TORCH; ie, toxoplasmosis, rubella, cytomegalovirus, herpes simplex], syphilis, or parvovirus), severe hemolysis (eg, major blood group incompatibility, Rh disease), or other stress.

Although acute lymphoblastic leukemia (ALL) should enter the differential diagnosis of an infant with circulating blasts, there is a striking absence of ALL in infants (<1 year) with DS [48].

Heart failure – Heart failure due to a cardiac malformation in a newborn with DS needs to be distinguished from cardiorespiratory compromise due to pericardial or pleural effusions from TAM.

Elevated bilirubin – Causes of conjugated hyperbilirubinemia unrelated to TAM include bacterial sepsis, viral infections, metabolic diseases, abnormalities of the bile ducts (eg, biliary atresia), and neonatal hepatitis. (See "Approach to evaluation of cholestasis in neonates and young infants".)

Skin lesions – Skin lesions associated with TAM should be distinguished from infection with herpes simplex virus (HSV) or varicella-zoster virus (VZV), erythema toxicum, Sweet syndrome, and leukemia cutis associated with other types of acute leukemia [49].

Diagnosis may require cytological analysis of the vesicle content, polymerase chain reaction (PCR) for viral DNA, and electron microscopy. (See "Vesicular, pustular, and bullous lesions in the newborn and infant".)  

RISK STRATIFICATION — TAM undergoes spontaneous resolution within months in most children with TAM, but up to one-fifth of patients experience early death from a severe complication. (See 'Natural history' above.)

Prompt risk stratification and treatment, if warranted, should be performed.  

Testing — Testing used for risk stratification includes:

Hematology

Blood counts – Complete blood count (CBC) with differential count.

Coagulation – Prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT); other tests, including D-dimer and fibrinogen, are performed as clinically indicated.

Serum chemistries

Electrolytes, kidney function tests – Testing should include potassium, phosphate, and uric acid to detect tumor lysis syndrome (TLS).

Liver function tests (LFTs) – Including conjugated and unconjugated bilirubin, alkaline phosphatase, and transaminases.

Imaging

Chest radiography – To detect abnormalities of the heart, lungs, and effusions.

Abdominal ultrasound – To identify ascites, hepatomegaly, or other findings, as clinically indicated.

Echocardiogram – To detect cardiac malformations and pericardial effusion.

Criteria for risk stratification of TAM — Management is based on the risk for early death from TAM. (See 'Management' below.)

High risk – Increased risk for early death from TAM is based on presence of one or more of the following features:

Hyperleukocytosis – White blood count (WBC) >100 x 109/L (100,000 leukocytes/microL)

Liver failure – Hepatomegaly alone is not a risk factor for early death. In the absence of abnormal liver function or liver enlargement that causes severe respiratory compromise from an elevated diaphragm, hepatomegaly, per se, is not an indication for treatment with low-dose chemotherapy.

Liver failure or life-threatening hepatic dysfunction was defined by either of the following in a study-specific management guideline by COG (AAML08B1):  

-Bilirubin – >10 times upper limit of normal (ULN).

-Transaminases – Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >20 times ULN.

Hydrops fetalis – Based on clinical evaluation. (See "Nonimmune hydrops fetalis".)

Effusions – Ascites, pericardial effusion, or pleural effusions not caused by heart failure, based on examination or imaging.

Coagulopathy – Bleeding diathesis or disseminated intravascular coagulation (DIC).

Low risk – Absence of all of the above findings.

MANAGEMENT — Management of TAM is guided by the risk for early death, which should be determined promptly after detection of myeloid blasts in a child with trisomy 21. Determination of risk status of a child with TAM is discussed above. (See 'Risk stratification' above.)

Early intervention for patients with high-risk TAM is associated with decreased risk for early death [2,12,39]. Treatment of a newborn with the clinical presentation of high-risk TAM should not be delayed by waiting for results of GATA1 testing.

High-risk TAM — For children with high-risk TAM, we suggest treatment with low-dose cytarabine, rather than exchange transfusion, leukapheresis, or supportive care alone. No randomized trials have been performed, but prospective and retrospective studies indicate that low-dose cytarabine is highly effective and is associated with improved survival. Although these doses of cytarabine appear low, this treatment has been associated with significant neutropenia, thrombocytopenia, and anemia in newborns with DS [2,5,12,38,42].

Administration, toxicity, and outcomes with low-dose cytarabine is presented below. (See 'Low-dose cytarabine' below.)

While exchange transfusion/leukapheresis can rapidly reduce white blood cell (WBC) counts in infants with leukostasis, this intervention is not be expected to improve complications caused by blasts in the extravascular compartment (eg, blasts infiltrating liver). While only limited reports are available, these approaches provide only temporary improvement and many require repeated procedures and/or cytarabine therapy [12,33,50].

Low-dose cytarabine — Low-dose cytarabine is administered to patients with high-risk TAM, but not to children with none of the risk factors for early death. (See 'Criteria for risk stratification of TAM' above.)

A course of low-dose cytarabine reduces the burden of blasts, severity of the symptoms, and the risk of early death from TAM. However, low-cytarabine can be associated with significant myelosuppression and it does not prevent later development of myeloid leukemia associated with DS (ML-DS).

Administration – Several regimens have been published. We use subcutaneous cytarabine 10 mg/m2/dose every 12 hours (equivalent to 0.33 mg/kg/dose). In patients with a prompt decrease of blast counts, we shorten the course from the published seven days [38] to five days, to reduce the risk of myelosuppression.

We suggest hospitalization until recovery of blood counts for all infants treated with low-dose cytarabine. Hospitalization enables close monitoring for treatment response and cytopenias, blood product support, and prompt management of febrile neutropenia.

Regimens that used higher doses (eg, 3.33 mg/kg/24 hours continuous infusion for 5 days [12]; 0.5-1.5 mg/kg for 3 to 12 days [2]; 1.5 mg/kg daily subcutaneously or intravenously for 5 to 7 days [4,39]) were associated with significant myelosuppression.

Toxicity – Treatment with low-dose cytarabine was associated with severe neutropenia (absolute neutrophil count [ANC] <500/microL) in one-third of children and severe thrombocytopenia (platelets <20,000/microL) in one-quarter of children with DS [39], despite the fact that these doses are a small fraction of doses used to treat acute myeloid leukemia (AML) in patients without DS.

Studies that employed higher or more prolonged cytarabine treatment were associated with even higher proportions of patients experiencing anemia, leukopenia, and thrombocytopenia [12].

Monitoring – Monitoring the child for complications of TAM, response to treatment, and adverse effects (AEs) is individualized according to clinical status.

Newborns with TAM are monitored closely in the days and weeks after treatment and should be hospitalized until recovery of blood counts, since they may develop profound and prolonged cytopenias after treatment with low-dose cytarabine.

In addition to physical examination, ANC, platelet count, and blast count are monitored until signs of blood count recovery. Liver function tests (LFTs) and other laboratory studies are repeated until recovery from critical abnormalities. Blood products, antibiotics, and other care are administered as needed during this period.

Outcomes – Low-dose cytarabine is effective for treatment of children at high risk for death from TAM. It is not administered to children without high-risk features. (See 'Risk stratification' above.)

Blast counts in peripheral blood respond quickly to cytarabine therapy, but liver disease may progress during the first weeks of life and hepatomegaly may persist for months [51]. Isolated hepatomegaly without significant liver dysfunction is not an indication for treatment with low-dose cytarabine, because it has not been associated with an increased risk of early death.

Treatment with low-dose cytarabine significantly improved survival of newborns with high-risk TAM, compared to management with supportive care alone. Reports of low-dose cytarabine treatment in children with high-risk TAM include:

In a BFM study, low-dose cytarabine treatment of 28 children with high-risk TAM (half of whom required intensive care and 10 percent had hepatic fibrosis) was associated with 78 percent five-year overall survival (OS) [2]. Among children with high-risk features, compared to those who received supportive care alone, low-dose cytarabine treatment was associated with fewer deaths (24 versus 72 percent) and superior five-year event-free survival (EFS; 52 percent versus 28 percent). Survival of children with high-risk TAM treated with cytarabine was similar to that of children with untreated low-risk TAM (78 versus 85 percent).

In the TMD Prevention 2007 study, 43 patients with high-risk features were eligible for the treatment with low-dose dose cytarabine (1.5 mg/kg/day for 7 days) [39]. Compared with an historical control group of 45 patients, the incidence of early death was lower (12 versus 33 percent) and there was a trend toward improved five-year OS (80 versus 67 percent) and five-year EFS (59 versus 44 percent).

COG A2971 reported 54 percent survival among 24 children with high-risk features who were treated with low-dose cytarabine [12]. The dose in this study (3.33 mg/kg/day for 7 days) was higher than currently suggested and 96 percent of patients experienced grade ≥3 toxicity.

In the Japanese TAM-10 study of 167 patients with TAM, low-dose cytarabine (1.0 to 1.5 mg/kg/day for a median of 6 days) was associated with reduced early deaths among the 36 children with WBC count ≥100 × 109/L [52]. Early death (<9 months) occurred in 13 percent of patients, four-year OS was 81 percent, and four-year EFS was 65 percent. No patients died of adverse effects associated with low-dose cytarabine therapy.

Repeat courses of low-dose cytarabine — TAM blasts are highly sensitive to cytarabine, but some children do not respond adequately to cytarabine. An inadequate response to cytarabine may be seen in infants with severe liver disease due to fibrosis, since low-dose chemotherapy can reduce tissue infiltration with TAM blasts, but cannot counteract the impact of organ fibrosis in the short term [2,5,12,33,38,41].

Retreatment with a second or even third course of low-dose cytarabine was reported in 25 and 21 percent of patients with TAM [39]. A treatment-free interval of at least five to seven days was recommended in one set of guidelines [43].

One instance of liver transplantation was described in an infant with TAM and progressive liver failure [53]. The infant underwent a living-donor liver transplant at 56 days of life without surgical complications. The explanted liver showed atrophy and severe fibrosis without leukemic cell infiltration. The post-transplant course was favorable with no hematologic abnormality and the infant was reported to be well eight months after transplantation.

Low-risk TAM — Low-risk TAM refers to children who lack high-risk features. (See 'Diagnostic criteria' above.)

Children with low-risk TAM have excellent outcomes and require only monitoring. In contrast to patients with high-risk TAM, in whom the risk of myelosuppression after low-dose cytarabine is outweighed by a survival benefit, treatment with low-dose cytarabine or other approaches is not indicated for patients with low risk TAM. As examples:

COG A2971 reported that 106 of 108 children with low-risk features spontaneously cleared circulating blasts at a median of 36 days (range, 2 to 126 days); the other two infants developed high-risk features and required treatment [12]. Three-year OS of untreated children was 84 percent.

In TMD-07, there were no deaths among the 59 children with low-risk TAM [39].

In POG-9481, 89 percent of 47 patients cleared circulating blasts in a mean of 58 days (range, 2 to 194 days); two children had transient recurrence of blasts without other symptoms [33].

Risk of developing ML-DS after TAM — The most important risk factor for development of ML-DS is detection of measurable residual disease (MRD).

Treatment with low-dose cytarabine does not appear to decrease the probability of developing AML [2,12,39]. This indicates that cytarabine is not sufficient to eradicate the preleukemic TAM clone. The role of cytarabine for reducing TAM-associated early death is discussed above. (See 'Low-dose cytarabine' above.)

Examples of variables that have been associated with development of ML-DS include:

Flow cytometry – ML-DS developed in 45 to 46 percent of children who had MRD detectable in blood by flow cytometry three months after the diagnosis of TAM, compared with 13 to 16 percent in those without detectable MRD [39,54]).

Cytogenetics – Chromosomal abnormalities (in addition to trisomy 21) in TAM blasts was associated with development of ML-DS [33].

GATA1 mutation – In a study of 368 infants screened for TAM, all 8 children who later developed ML-DS were among the 55 who had GATA1 mutations [54].

Expression level of GATA1sGATA1 mutations were classified in a cohort of 66 patients with TAM according to the predicted level of expression of the mutant protein GATA1s. The risk for ML-DS was associated with a predicted low expression level of GATA1s; 10 of 11 patients with TAM who progressed to ML-DS were in the group with low expression [55].

FOLLOW-UP — All children with TAM are followed to document resolution of blasts, normalization of blood counts, and to screen for evidence of transformation into myeloid leukemia associated with DS (ML-DS).  

Routine monitoring – We follow infants with a history of TAM every three months until their fourth birthday. Since most diagnoses of ML-DS are made in the first two years of life, longer intervals (eg, every six months) in the third and fourth years are also reasonable [4].

There is no clear evidence that follow-up for TAM has a beneficial impact on prognosis of subsequent ML-DS. In a BFM study of patients with ML-DS, event-free survival (EFS) was higher (91 percent) for 29 patients who had a history of TAM compared with patients with ML-DS who were never diagnosed with TAM (70 percent) [2]. Survival of patients with ML-DS was not better for those who were diagnosed early (with low bone marrow blast percentage), compared to those who presented with >20 percent blasts in the bone marrow [56,57].

Measurable residual disease (MRD) – We do not routinely monitor MRD in patients with TAM during follow-up, outside of a research setting, because the probability of detecting a mutation remains a function of the sensitivity of the assay used. There is no consensus about the role and preferred protocol for MRD monitoring in children with TAM.

Targeted sequencing/next-generation sequencing (NGS) [11,54], high-resolution melting curves [58], and intracellular flow cytometry [59] been used to detect GATA1 mutations or mutant GATA1s protein. Although persistent MRD has been associated with a higher risk for developing ML-DS [39], the probability of detecting a mutation remains a function of the sensitivity of the assay used. However, some investigators, using an NGS method with a sensitivity of 0.3 percent to detect GATA1 mutations, suggested use of this method to identify a GATA1 mutation-negative population of patients that could be excluded from further follow up [11].

MYELOID LEUKEMIA ASSOCIATED WITH DS (ML-DS) — ML-DS is discussed in detail separately. (See "Myeloid leukemia associated with Down syndrome (ML-DS)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Down syndrome" and "Acute myeloid leukemia: Children and adolescents".)

SUMMARY AND RECOMMENDATIONS

Descriptions

Transient abnormal myelopoiesis (TAM) – TAM is a preleukemic syndrome manifest as myeloblasts in blood or other organs that occurs only in neonates with Down syndrome (DS; trisomy 21) or mosaic trisomy 21.

Myeloid leukemia associated with DS (ML-DS) – Acute megakaryoblastic/myeloid leukemia that develops in some children with DS during the first four years of life.

Pathogenesis – TAM and ML-DS arise only in children with trisomy 21 who acquire a GATA1 mutation in fetal hematopoietic progenitor cells. (See 'Pathogenesis' above.)

Incidence – Approximately 10 to 30 percent of neonates with DS, but incidence varies according to case definition and timing of testing. (See 'Incidence' above.)

Presentation – Most children are diagnosed with TAM in the first week of life. Although some patients are asymptomatic, others have involvement of liver or other organs, and some have life-threatening complications. (See 'Clinical presentation' above.)

Natural history – TAM usually resolves spontaneously within months, but up to one-quarter of affected children die early with severe complications. (See 'Natural history' above.)

Initial evaluation – Microscopy of blood smear or other involved tissue for myeloid blasts, with confirmation of the immunophenotype by flow cytometry. (See 'Evaluation' above.)

Diagnosis – TAM is suspected in infants (<3 months) with DS or without findings of DS (ie, genetic mosaicism) who have circulating myeloid blasts, hydrops fetalis, liver dysfunction/failure, coagulopathy, or effusions. (See 'When to suspect TAM' above.)

Diagnosis requires (see 'Diagnostic criteria' above):

Morphology – Myeloid blasts in blood or other tissue.

Flow cytometry – Immunophenotype may be variable but generally includes stem cell, myeloid cell, and platelet antigens.

Karyotype – Trisomy 21 in blasts.

Detection of GATA1 mutation is useful to confirm the diagnosis but should not delay risk stratification and treatment, if warranted.

Differential diagnosis – TAM should be distinguished from immature cells or blasts associated with infections, stress, or leukemia, and other causes of liver failure or hydrops fetalis. (See 'Differential diagnosis' above.)

Risk stratification – Stratification is according to the risk for early death. High-risk features include leukocytosis >100,000/microL, liver failure/fibrosis, hydrops, effusions, and coagulopathy. (See 'Risk stratification' above.)

Management – Treatment is stratified according to the risk for early death:

High risk – For children with high-risk for early death, we suggest treatment with low-dose cytarabine, rather than observation or other approaches (Grade 2C). (See 'High-risk TAM' above.)

Low risk – For low-risk children, we suggest observation/supportive care based, rather than treatment (Grade 2C). (See 'Low-risk TAM' above.)

Monitoring – Clinical and laboratory evaluation is described above. (See 'Follow-up' above.)

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Topic 16914 Version 12.0

References

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