Transient leukaemia – a benign form of leukaemia in newborn infants with trisomy 21

Transient Leukaemia (TL) occurs frequently in newborn infants with Down Syndrome. Because in most cases the disease disappears spontaneously, it has been difficult to accept it as leukaemia, and as a result it has been referred by a variety of names including Transient Myeloproliferative Disorder and Transient Abnormal Myelopoiesis, suggesting that it is not leukaemia. In this review I shall present evidence that the disease is leukaemia and that although in most cases the course of the disease is transient in others it is life threatening. Also, I shall explore the nature of the leukaemic cell, its association with trisomy 21 and its relationship to other forms of leukaemia frequently found in children with Down Syndrome. The original description of transient leukaemia (TL) and other early reports described this disorder as one in which there were no overt signs or symptoms of the disease. Indeed in most cases that is true. Children with Down Syndrome are found to have an elevated white blood count and primitive cells (‘blasts’) in the peripheral blood. Usually the blood count has been performed either as a routine study or because of an illness unrelated to the abnormal haematology. Upon examination there may either be no signs of the disease or there may be some enlargement of the liver and spleen or a skin rash (see below) in a minority of such cases. Usually the patient remains well and the leukaemic cells (‘blasts’) gradually decrease in number and disappear completely within the first 3 months of life. It has been recently reported in a prospective series that 19% of TL cases are complicated by life-threatening complications (Al-Kasim et al, 2002). There are two major forms. Liver disease. This manifests as progressive obstructive jaundice with terminal liver failure (Miyauchi et al, 1992). Histologically there is hepatic fibrosis with evidence of infiltration by megakaryoblasts (Becroft & Zwi, 1990; Ruchelli et al, 1991). Approximately 50% of the cases will be progressive and fatal (Miyauchi et al, 1992; Al-Kasim et al, 2002). Others patients appear to recover completely with no long-term sequelae. Low-dose chemotherapy may be an effective treatment of the disease (Al-Kasim et al, 2002). It has been suggested that the hepatic fibrosis is caused by the release of platelet-derived growth factor (PDG-B), which has been found in the tissues of these patients together with the infiltrating leukaemic cells (Terui et al, 1990; Hattori et al, 2001). Cardio-pulmonary disease. This manifests as hydrops-like symptoms with pericardial effusions and ascites (Hendricks et al, 1993; Zipursky et al, 1996; Al-Kasim et al, 2002). The cause of this disorder is unknown, although there is evidence of leukaemic cell infiltration of the cardiac muscle (Zipursky et al, 1996). The disease manifests as pulmonary oedema and/or pericardial effusion; the disease may be progressive and fatal. There is evidence that low-dose chemotherapy may be curative (Doyle et al, 1995; Al-Kasim et al, 2002). Pericardial effusions are seen frequently in TL as isolated findings with no evidence of the cardio-pulmonary syndrome. In addition, isolated ascites has been reported (Shiffer & Natarajan, 2001). Leukaemic cells are found in both effusions. In one case studied by the author, basophils were the predominant cell in the effusion (Zipursky et al, 1997). We described a series of four newborns with hydrops fetalis due to TL (Zipursky et al, 1996). Two of the infants were stillborn, one died after birth and one recovered. These four cases were among 40 Down Syndrome children born in one hospital. The incidence in the group was 10%. Smrcek et al (2001) reported a study of 79 Down Syndrome fetuses examined in utero using two-dimensional echocardiography. They found 11 (14%) of the cases had fetal hydrops. An isolated pericardial effusion has also been observed in a fetus of 34 weeks gestation (Hirashima et al, 2000). At birth there was haematological evidence of ‘Transient Abnormal Megakaryocytopoiesis’. Skin lesions are seen frequently in TL. There is a description of three cases of vesiculopustular eruptions in Down Syndrome-related neonatal TL (Nijhawan et al, 2001). The skin lesions were described as vesiculo-papular and on biopsy leukaemic cells were found in both in the lesion leukaemic infiltrate and fluid. As noted below, approximately 20% of TL cases that recover completely in the first months of life will subsequently develop acute megakaryoblastic leukaemia (AMKL) in the first 4 years of life (Doyle & Zipursky, 1994). In some cases, however, there is not a complete remission of the leukaemia. We have described one case in which TL improved with therapy, but blasts did not disappear completely and mild thrombocytopenia persisted (Al-Kasim et al, 2002). By 6 months of age the blast numbers increased, then a cytogenic abnormality (in addition to trisomy 21) appeared in the leukaemic cells and it was evident that the TL had merged directly into AMKL. As noted above, some cases of TL have life-threatening complications. There are no controlled trials of therapy; however, in a small series it was suggested that treatment with low-dose cytosine arabinoside (10 mg/m2, twice a day for 7 d) can be curative (Al-Kasim et al, 2002). The use of low-dose therapy was based on experience in the treatment of AMKL in Down Syndrome in which low-dose cytosine arabinoside was curative (Tchernia et al, 1996; Zipursky, 1996). In a small series it was found that 10% of newborn infants with Down Syndrome had blasts in their blood (Doyle & Zipursky, 1994). As screening was done by microscopic examination of blood films, it is possible that some cases with relatively few blasts would have been missed. It is likely that the incidence may be higher because it does not include fetuses with disease who died or who recovered in utero. As noted above, 14% of Down Syndrome fetuses, studied by ultrasound, had TL (Smrcek et al, 2001). We reported that in one hospital there were four cases of hydrops fetalis among 40 Down Syndrome newborns (Zipursky et al, 1996). These two reports suggest that the incidence of TL in fetuses, most of which died in utero, is approximately 10%. As screening of live newborns with Down Syndrome revealed an additional 10% of cases with TL, it may be concluded that approximately one in five fetuses with Down Syndrome have TL; many die before birth, many are asymptomatic, and some have severe disease in the neonatal period. There are many reports of TL occurring in phenotypically normal children who have trisomy 21 mosaicism (Doyle et al, 1995; Slayton et al, 2002). When leukaemia occurs in these children, all the leukaemic cells have trisomy 21; in these patients assessment of skin biopsy fibroblasts or of PHA-stimulated lymphocytes, usually reveals a small percentage of cells that are trisomy 21. The percentage of trisomy 21 cells varies greatly and may be so low that they are not found in the non-leukaemic cells; in these cases mosaicism is restricted to the haematopoietic system. Slayton et al (2002) described a child with trisomy 21 mosaicism and TL in which only cells of the haematopoietic system had trisomy 21. A skin fibroblast culture and PHA stimulation of lymphocytes revealed no trisomy 21 cells. In children with trisomy 21 mosaicism and TL, all the leukaemic cells contain trisomy 21. This provides evidence that TL arises only in cells that have a third chromosome 21. Although it has been stated that TL in patients with phenotypically normal trisomy 21 mosaics did not progress to AMKL, we have reported a case of TL in a phenotypically normal trisomy 21 mosaic with progression to AMKL (Doyle et al, 1995). The corollary of these observations is that TL (and probably AMKL) with trisomy 21 in a phenotypically normal child is likely to be the same form of leukaemia found in children with Down Syndrome. The incidence of trisomy 21 mosaicism in newborn infants is approximately 1/2000–1/3000 (Hsu & Perlis, 1984; Worton & Stern, 1994). As the prevalence of Down Syndrome in newborn infants is 1/700, it is likely that TL occurs as readily in infants mosaic for trisomy 21 as in Down Syndrome. There are however, no definitive data to confirm this speculation. The classic presentation of TL is one in which the haematology is normal except for the presence of primitive cells (‘blasts’) in the peripheral blood. These ‘blasts’ vary in number, from a very small percentage of the total leucocyte count to greater than 200 × 109/l (Zipursky et al, 1997). The blasts vary in size from 15 to 20 microns in diameter. They contain a small amount of basophilic cytoplasm with some cytoplasmic budding. The nuclei show minimal condensation and contain one to three nucleoli. The blasts are considered to be megakaryoblasts although, as discussed below, features of other cell lineages may be found. This is discussed in the next section. Neutrophil and haemoglobin levels are normal. Platelet counts are usually normal; however, both thrombocytopenia and thrombocytosis are present in some cases with counts as low as 10 × 109/l to greater than 1000 × 109/l (Zipursky et al, 1997). In addition, macrothrombocytes and megakaryocyte fragments are found in blood films (Zipursky et al, 1999). TL leukaemic cells express the thrombopoietin receptor (c-mpl). The plasma levels of thrombopoietin are low in TL (Bonno et al, 1998) and are inversely related to the number of blasts in the peripheral blood. Presumably the low levels of thrombopoietin result from its binding to blast c-mpl and subsequent removal (Bonno et al, 1998). Dysplastic nucleated red cells have been observed in the peripheral blood (Bozner, 2002) and some of these erythroid precursors have an abnormal morphology (i.e. dyserythropoietic). Of considerable interest is the presence of basophils in the peripheral blood. In one reported case of TL, the number of basophils in the peripheral blood was as high as 56 × 109/l (Worth et al, 1999). The number of blasts declines during the first three post-natal months along with abnormalities in platelet number and morphology. Temporary increases in blast numbers may be seen during this time; however, it is rare for blasts to be found after 3 months of age. A case illustrating these changes is described elsewhere (Zipursky et al, 1997). The leukaemic cells have been found to be negative when stained for peroxidase, Sudan Black, PAS and chloracetate esterase, but positive for acid phosphatase and non-specific esterase (with variable by et al, 2001). The of the cell many features of megakaryoblasts et al, Zipursky et al, 1995). The cells may vary from primitive cells with no evidence of megakaryocyte to cells that contain and megakaryocyte as by There have been many of the on the of TL cells. have that the megakaryocyte and was by by et al, 1992; et al, 1992; et al, et al, 2001). microscopic with that the most blasts may not express these (Zipursky et al, 1995). The a of a primitive haematopoietic cell, is also on the of TL The leukaemic cells express the which is a and which is a There is no in of in the evidence only of basophilic and The of these is also seen on primitive haematopoietic cells et al, et al, which may their presence in the leukaemic cells of TL. there is evidence that these cells express erythroid As discussed below, of erythroid and have been observed by et al, 1995). the is are present in the and their numbers are and directly related the percentage of blasts in the peripheral blood (Zipursky et al, 1997). This is most other forms of leukaemia, because when the peripheral blood a numbers of the is by leukaemic cells. The erythroid precursors may be abnormal in may be in number, although this is of in A few may be A of the in TL is found in the An of this is in the biopsy of a newborn with TL and thrombocytopenia The numbers of a to that of the observed in the early of acute megakaryoblastic leukaemia of Down Syndrome patients (Zipursky et al, 1994). The presence of numbers of many of which are in the presence of thrombocytopenia is of abnormal platelet evidence of abnormal is the presence of and megakaryocyte fragments in the peripheral blood (Zipursky et al, 1999). A biopsy from a Down Syndrome child with Transient Leukaemia and and section. There are numbers of most of which are small or contain or The findings are to the of the acute megakaryoblastic leukaemia of Down Syndrome. The the and that the leukaemic cells of TL have the of a cell of megakaryocyte a the TL leukaemic cells also have of other cell An of the nature of the leukaemic cell is in a of this the leukaemic cells in TL of Down Syndrome patients or in phenotypically normal children with trisomy 21 mosaicism are for chromosome 21. In the of cases there are no other There however, reports of abnormalities in the leukaemic cells of TL. These include 21 et al, additional and et al, of a chromosome et al, et al, an chromosome et al, and with et al, The abnormalities and leukaemic cells disappear the same in cases in which AMKL in the first 4 years of the abnormality seen in TL does not in the leukaemic cells of AMKL have usually other There however, to that of the abnormalities found in TL, as noted et al, et al, et al, were present in the AMKL that appeared in life. These findings evidence that the AMKL had in one or cells of the original TL leukaemic There has been one of an of chromosome 21 in TL leukaemic cells et al, 1998). This may be of because the of chromosome 21 was the same as that in which were found in five cases of megakaryoblastic leukaemia in Down Syndrome patients et al, 1997). leukaemia a rare group of A review of the cases reported in the et al, 2002) found cases of which were acute and were acute There was one case of to a and one case of trisomy 21. There have been no cases to TL other than in patients with Down Syndrome or trisomy 21 It be however, that there are case reports in which phenotypically normal children have TL with trisomy 21 in the leukaemic cells but not in skin fibroblasts or PHA-stimulated lymphocytes et al, Presumably these children had mosaicism for chromosome 21 but this was restricted to cells of the haematological as noted As there have been no reports of a disease in the of trisomy it would appear that TL occurs only in newborn infants with either Down Syndrome or trisomy 21 There is a of newborns who both had a form of leukaemia birth with complete of and evidence of leukaemic infiltration of et al, 2000). The disease during the first of life. These two cases that Syndrome leukaemia in newborns can does not the of leukaemia, which is an in the nature of TL in Down Syndrome. In the review described et al, of cases of neonatal As noted above, most cases of TL have a course in which the disease remission and the patient is in approximately 20% of the cases that Leukaemia (AMKL) within the first 4 months of life et al, 1993; & Zipursky, 1994). Although the incidence of is higher in Down Syndrome than in there is no evidence that TL to the of or other form of leukaemia in Down other than AMKL. than TL, AMKL is the form of leukaemia in Down Syndrome It occurs during the first 4 years of life and the incidence of AMKL in Down Syndrome is to be approximately greater than in (Zipursky et al, Although it is a form of megakaryoblastic leukaemia the disease is from the two other forms of AMKL, which in form occurs in and is with a with of a et al, disease a course and a to The other form of leukaemia, found in also has a to chemotherapy et al, 1990; and usually does not have the of Down Syndrome AMKL et al, 1993; Zipursky et al, 1994). It can be concluded that the AMKL of Down Syndrome is from other forms of megakaryoblastic leukaemia of The leukaemic cell in Down Syndrome AMKL is to the leukaemic cell of TL in of and et al, et al, 2001). The of the leukaemic cell of TL is very to that in however, the TL cell has evidence of megakaryocyte et al, Zipursky et al, 1995). abnormalities are in AMKL than in TL. In AMKL most cases have a abnormality et al, et al, the trisomy (Zipursky et al, et al, 2001). The nature of the abnormalities in AMKL were considered by et al They studied the in AMKL patients and found that the abnormalities than trisomy 21) were present only in a small number of suggesting that the changes from a trisomy 21 They suggested that the abnormalities seen in AMKL were a or Although the leukaemic cells of TL and AMKL are the course of disease is very As noted above, most cases of TL are and AMKL is a disease with no with either therapy or low-dose the of Down Syndrome AMKL is very high (Zipursky et al, 1996; 2000). The and of TL and AMKL are in of cell and is an that and is found in the of leukaemia cases in both children and In one was found in 50% of cases of AMKL it was rare in the leukaemic cells of TL et al, 2002). that are found in the of cases of leukaemia were not found in the leukaemic cells of TL but were present in two cases of AMKL et al, 2000). In most cases of TL the disease is a AMKL is a leukaemia in which the course of the disease is and the cells have features of the of and of The evidence that TL and AMKL only in trisomy 21 cells. it is likely that AMKL occurs only in children who have had TL (see These observations suggest that TL and AMKL are of a which is from other form of leukaemia, described as 21 The leukaemic cell of AMKL is to that of TL in and cells show features of however, both have erythroid and basophilic as noted In both TL and AMKL, is a of the disease. The incidence of TL and of AMKL in Down Syndrome patients is with the that all cases of AMKL in children who have had TL. the incidence of TL in Down Syndrome live is approximately 10%. of children will develop AMKL, that children with Down Syndrome will develop AMKL. The incidence of AMKL in Down Syndrome is to be cases (Zipursky et al, These are however, they are with the that all cases of AMKL in children who with TL There are reports of three children in the same abnormalities were found in TL and in the leukaemic cells of AMKL that et al described a patient in the leukaemic cells of TL and AMKL both an evidence that AMKL is from a of TL is by the study of et al They a case of TL, in a phenotypically normal that 3 months a that the blast count had to peripheral blood trisomy a an of chromosome By months there were no cells and in no evidence of either trisomy 21 or the of At 20 AMKL with a of the trisomy 21; the leukaemic cells the of chromosome and a abnormality of chromosome et al described a case of TL in which the leukaemic cells had a abnormality which months of in the leukaemic cells of AMKL. It is likely that AMKL arises in some cells of the TL leukaemic cell by this then to the other TL leukaemic cells The during the early months and years of life as AMKL. It has been difficult to accept TL as leukaemia because it disappears as noted in the on other forms of leukaemia can disappear in the newborn period. the that a leukaemia be leukaemia is not is not a to TL as a leukaemia. There in addition, the evidence to the that TL is The abnormal cell in TL is as a with to the megakaryoblasts of the AMKL that occurs in early in Down Syndrome. TL and AMKL cells have features of erythroid and lineages (see The disease may be described At (Zipursky et al, in et al, or skin (Nijhawan et al, there is evidence of leukaemic infiltration of As noted there are reports of abnormalities in TL this is with a (i.e. of of the on the revealed that the leukaemic cells of TL are from a cell, a with a leukaemic et al, et al, 1991). et al (2002) Leukaemia as a leukaemia that the in the first four weeks of of or erythroid cells; of these cells into d) of other that may the It is that TL all these in of the evidence we have concluded that TL is leukaemia (Zipursky & The morphology of the cell is with the features of megakaryoblasts in other forms of megakaryoblastic leukaemia. The of the cell is with that of a with of of platelet & by in the megakaryoblasts of TL et al, et al, that the cells were of megakaryocyte As noted above, platelet are on the of the cell as by The leukaemic cells express for the that is in cells et al, 1995). is not in or other As above, the and peripheral blood in TL contain abnormal erythroid precursors have been in TL these include (Bozner, as well as and et al, 1995). A case of TL with predominant erythroid cells has been reported (Bozner, 2002). of in the TL leukaemic cells is additional evidence of erythroid et al, A case of transient leukaemia has been described in which there were numbers of basophils in the peripheral blood (Worth et al, 1999). In that numbers on the day of life 56 × It be noted that in the same case with were also present in high numbers but were not considered to be et al also described a case in which there were high numbers of basophils and in the peripheral blood. As noted we have studied one case in which the cells of a TL pericardial effusion were In culture of TL leukaemic cells basophils et al, of TL cells revealed blasts which et al, Zipursky et al, 1995). The evidence that the leukaemic cell of TL is a cell with the for cells of the erythroid and series in It is not are also in in the leukaemic cells have not only the of cells of the erythroid and basophils but also cells of the and It be that the of basophils is et al reported the growth of cells and that the leukaemic cells and erythroid They also reported that approximately 50% of the cells in a culture of TL leukaemic cells were as by and The that a cell with for erythroid and is of normal is discussed in a section. There are reports of of TL leukaemic cells. of these reports that cells to normal et al, et al, et al described in there is no evidence that in growth are of either in of the of the TL or the subsequent of AMKL. It can be concluded from the culture that the leukaemic cells can that the normal of the will in and in the blasts can into and erythroid There is evidence that in the normal of there is a cell with the for both erythroid and cells et al, 1996). The leukaemic cells of TL and AMKL have features and the in of both these two cell The evidence for this is It is however, that the leukaemic cells of TL and AMKL also have the of in and in cells of the basophilic The evidence for a cell of is not is however, is that and are and for and et al, 1993; 2001). a in the for the factor has been found in patients with AMKL of Down suggesting that this may a in the of AMKL et al, 2002). is a factor which is for normal 2001). It has been that it is a negative of megakaryocyte 2001). In the of (in there is an in megakaryocyte and both a in and abnormalities of megakaryocyte with an small and cytoplasm that few platelet and 2001). It is of considerable interest that this also in AMKL and is with a of The abnormal in TL is to that in and in AMKL. it remains to be of are also present in TL. the would be related to the abnormal of TL and AMKL and not to a in a TL cell as it to the cell of AMKL. it may be that the is not in TL; this would suggest that the found in AMKL were with the of It can be concluded that the and leukaemic cells of TL and AMKL, are leukaemic of cells with the for megakaryocyte and The cells express factor for the of these three cell The from the leukaemia of TL to the form of this disease may be with changes in the for the normal of these cell Transient Leukaemia and acute megakaryoblastic leukaemia are two of a form of leukaemia that occurs only in cells that are for chromosome 21. This disease does not in other cell TL is from other forms of leukaemia and AMKL is from other forms of megakaryoblastic leukaemia in These two are of a leukaemia that from all other forms of leukaemia and occurs only in cells that are trisomy 21. Two found in the cells of patients with transient leukaemia & Zipursky, &