The Management of Neoplastic Disorders of Haematopoeisis in Children with Down's Syndrome

Down's syndrome (DS) is the most common factor predisposing to childhood leukaemia. Children with DS have a 10- to 20-fold excess risk of developing leukaemia ( Table I) ( Krivit Stewart et al, 1958 ; Wald et al, 1961 ; reviewed in Fong Levitt et al, 1990 ; Robison, 1992; Zipursky et al, 1992 ; Avet-Loiseau et al, 1995 ). Roughly 1% of children with DS develop one or more of the following distinctive types of leukaemia: (i) a spontaneously regressing congenital or neonatal myeloproliferative disorder (TMD) (also known as transient myeloproliferative syndrome, congenital transient leukaemia, congenital leukaemoid reaction, transient leukaemoid proliferation and transient abnormal myelopoiesis); (ii) acute myeloid leukaemia (AML), usually acute megakaryoblastic leukaemia (AMKL) (or erythro/megakaryoblastic leukaemia before the age of 5 years); or (iii) common B-lineage acute lymphoblastic leukaemia (ALL) (for a review, see Zipursky et al, 1987 ; Robison, 1992; Avet-Loiseau et al, 1995 ). The current management strategy for these disorders, with few exceptions and considerable caution, is simple: in TMD, 'do nothing'; in AML, 'do less'; and in ALL, 'do more'. The rationale for this approach is the subject of this review. Table II lists seminal contributions to our understanding of leukaemia in DS. The full anatomical, physiological and functional expression of DS derives from trisomy of chromosome 21 ( Lejeune et al, 1959 ). Predisposition to leukaemia is common not only in the 90% of children with typical DS features and trisomy 21 but also in phenotypically normal or abnormal children with trisomy 21 mosaicism (5%), Robertsonian translocations (1%), partial trisomy of 21 (0·5%) or ring 21 (0·5%) ( Fong Iselius et al, 1990 ). There may even be an excess of leukaemia in those with DS mosaicism, perhaps because of a survival advantage in mosaics ( Iselius et al, 1990 ). The trisomy is caused by non-disjunction during the first or, less often, the second meiotic division, or in the case of a DS mosaic during a post-zygotic division (for a review, see Hassold et al, 1995 ). Mapping of centromeric genes to determine parental origin of non-disjunction indicates that in over 90% of cases the non-disjoined chromosome 21 is the maternal chromosome ( Abe et al, 1989 ; Lorber et al, 1992 ; Hassold et al, 1995 ). The non-disjoined maternal chromosome 21 is almost always present in the leukaemia blasts ( Heaton et al, 1981 ; Ferster et al, 1986 ; Lorber et al, 1992 ). The association of DS with advancing maternal age has been appreciated for over a century ( Fraser DenOttolander et al, 1979 ; Bain et al, 1981 ; Lewis, 1981,1984; Sulton et al, 1981 ; Bevan et al, 1982 ; Chan et al, 1983 ; Mirchandani Huang et al, 1984; and others) led to the French–American–British (FAB) criteria for diagnosis of megakaryoblastic leukaemia ( Bennett et al, 1985 ). Recognition of AMKL as a biologically distinct form of leukaemia that mimics FAB L2 ALL resolved most issues about the cell of origin of leukaemia in children with DS. Gene dosage or disomy of a leukaemia predisposition gene or haematopoiesis regulatory gene on chromosome 21 has been the presumed mechanism of leukaemogenesis in DS ( Abe et al, 1989 ; Lorber et al, 1992 ; Rogan et al, 1995 ; Huret Berger, 1997 ; Belkov et al, 1999 ; Heerema et al, 1999 ). However, overexpression of the known genes on chromosome 21 has not identified the leukaemia predisposition gene. Moreover, gene mapping and genotypic–phenotypic correlations on chromosome 21 in DS indicate that anomalies as complex as mental retardation in DS span a large part of the chromosome ( Korenberg et al, 1992 , 1995; Delabar et al, 1998 ; Yamakawa et al, 1998 ). Similarly, predisposition to leukaemia, spontaneous regression and response to cytotoxic therapy may be polygenic phenomena. Superoxide dismutase ( Druzhyna et al, 1997 ), tumour invasion and metastasis factor ( Ives et al, 1998 ), multiple genes involved in the immune response such as CD18 and the DS cell adhesion molecule ( Yamakawa et al, 1998 ) and genes predisposing to precocious ageing such as Alzheimer's disease amyloid-associated A4 protein precursor ( Hol et al, 1998 ) may all contribute to the predisposition to leukaemia. Although gene dosage has not yet explained leukaemia, it may in part explain response to therapy. There are on chromosome 21 at least five genes involved in nucleic acid synthesis: phosphoribosyl aminoimidazole synthetase, phosphoribosyl glycinamide synthetase, cystathionine β synthetase, superoxide dismutase and reduced folate carrier ( Taub et al, 1996 , 1999; Belkov et al, 1999 ). Overexpression of cystathionine β synthase appears to confer exquisite sensitivity to cytosine arabinoside in the blasts of children with DS and AMKL, but not necessarily in direct proportion to the number of copies of chromosome 21 ( Taub et al, 1996 , 1999). In contrast, expression of reduced folate carrier confers sensitivity to methotrexate in direct proportion to the number of copies of chromosome 21 ( Belkov et al, 1999 ). Niebuhr et al (1974) localized the Down's syndrome critical region to chromosome 21q22, a region of interest for leukaemia as well. Within the 21q22.1–22·2 region is the CBFA2 (AML-1) gene. CBFA2 is translocated in t(8;21) FAB M2 myeloid leukaemia, in t(3;21) chronic myeloid leukaemia in blast crisis, in treatment-associated myelodysplastic syndrome (MDS) and in the molecular t(12;21) in favourable childhood ALL (reviewed in Nucifora McLean et al, 1996 ; Downing, 1999). Also CBFA2/AML-1 is implicated in the familial platelet disorder (FPD)/AML syndrome ( Legare et al, 1997 ; Song et al, 1999 ): in five families with this disorder, subtle deletions in CBFA2/AML-1 led to the haploinsufficiency of this gene and loss of function ( Song et al, 1999 ). Because CBFA2 is involved in megakaryocyte differentiation, MDS, AML and ALL, it is an attractive candidate gene for the DS 'leukaemia predisposition' gene. Although trisomy of a putative leukaemia-predisposition gene on chromosome 21 offers an intuitive mechanism for the frequency of leukaemia in DS, there is some evidence that loss of heterozygosity through deletion may be the critical event. Kempski et al (1997) have noted interstitial deletions on part of the long arm of chromosome 21 in the leukaemic cells in four of five DS patients with AMKL. Cavani et al (1998) found significantly increased crossover in pericentric regions of 21q in DS AML cases compared with DS with ALL and DS without leukaemia. Seghezzi et al (1997) described a case of chronic myeloid leukaemia in a DS patient in which maternal allelic loss was present in the leukaemic clone. Despite intense interest in the biology and epidemiology of leukaemia in DS, there was for many years a universal reluctance to treat leukaemia, particularly AML, and other lethal diseases in children with mental deficiency ( Churchill, 1989). In 1982, Baby Doe, a neonate with DS and multiple potentially lethal anomalies, was allowed to die in a nursery in Indiana ( Pless, 1983). Baby Doe's death engendered legislation mandating full access to medical care for all children in the USA. Thereafter, more or less systematic inclusion of children with DS in clinical trials became the standard. Only then were the unique features of leukaemia in DS revealed. Transient myeloproliferative disorder is a form of self-limited leukaemia that occurs almost exclusively in neonates with DS. The mean maternal age of children with TMD is 29 years and that of mothers with DS children with AML 33 years ( Iselius et al, 1990 ) . This difference probably reflects the older age of DS children with leukaemia rather than a predisposition of younger mothers to give birth to infants with TMD. Zipursky et al (1992, 1997, 1999) estimated that at least 10% of DS newborns have TMD. TMD may be present at birth or in stillborns. It usually is diagnosed by 3 weeks of age. TMD may be an incidental finding on a complete blood count (CBC). Typically, TMD regresses spontaneously by the age of 2 or 3 months. The peripheral white blood cell (WBC) count is relatively low in most cases of TMD and profound cytopenias are rare ( Zipursky et al, 1992 ). Often the percentage of blasts in the peripheral blood is higher than in the marrow ( Nagao et al, 1970; Shinbo et al, 1977 ). Although TMD is by definition transient, it has many clinical and laboratory features of malignancy. Light microscopy, histochemistry, immunophenotyping and electron microscopy indicate that the blasts in TMD are dysplastic megakaryoblasts ( Lazarus et al, 1981 ; Kojima et al, 1990 ). Characteristically, the cells are pleomorphic, ranging in size from 7 µm to 20 µm ( Bennett et al, 1985 ). The blasts may manifest cytoplasmic blebbing and megakaryocytic cytoplasmic fragments may circulate in the peripheral blood. Cells are negative for peroxidase and Sudan black, but are sometimes focally positive for periodic acid–Schiff (PAS) and non-specific esterase (NSE), which is fluoride inhibited. They do not react with butyrate acetate esterase ( Bennet et al, 1985 ). Sometimes they contain basophilic granules. There is also one well-documented case of basophilic differentiation of TMD megakaryoblasts in vitro ( Suda et al, 1985 ). The leukaemic cell in AMKL and TMD is derived from a common erythroid and megakaryoblastic progenitor ( Zipursky et al, 1992 ; Tchernia et al, 1996 ). The cells express the transcription factor GATA -1 and erythroid-associated gamma-globin and delta-amino laevulinate synthase mRNA ( Ito et al, 1996 ). Immunological evaluation may be limited by difficulties in aspirating cells. Reactivity with platelet-related glycoproteins IIb/IIIa (CD41, CD42 or CD61) or, on biopsy sections, with factor VIII antigen supports the diagnosis of FAB M7, but their absence does not rule it out. As with other forms of AML, up to half the cells may express B-lineage- or T-lineage-related antigens ( Kuerbitz et al, 1992 ; Smith et al, 1992 ; Slordahl et al, 1993; Creutzig et al, 1996 ). They usually express the myeloid-related antigens CD13 or CD33 ( Creutzig et al, 1996 ). Slordahl et al (1993) described leukaemic megakaryoblasts displaying markers of four lineages in an infant with DS. TMD is clonal. Studies of female infants for X-linked phosphoglycerate kinase (PGK), hypoxanthine guanosine ribosyl transferase (HGPRT) or immunoglobulin heavy chain and T-cell antigen receptor (TCR) indicate that TMD is derived from a single cell ( Kurahashi et al, 1991; Miyashita et al, 1991 ). Occasionally, blasts have clonal cytogenetic abnormalities ( Lazarus et al, 1981 ; Barnett et al, 1990 ; Iselius et al, 1990; Bhatt et al, 1995 ). An acquired chromosome 21 (i.e. tetrasomy 21) t(21;21) and i21 are most common ( Barnett et al, 1990 ). It is not clear why a disease that has all the cellular properties of leukaemia regresses. Presumably, there are host factors that enable regression. Infants with TMD have thrombopoietin (TPO) levels lower than age-matched controls and their blasts have receptors from c-MPL, the ligand for TPO ( Bonno et al, 1998 ). TPO levels rise as the TMD wanes. TPO levels correlate inversely with blast number but not platelet number. No other host factors have been investigated in this context. A rising conjugated bilirubin is a sign of serious liver disease in infants with TMD. TMD is sometimes complicated by hepatic fibrosis which is life-threatening and often fatal ( Becroft for a review, see Ruchelli et al, 1991 ; Schwab et al, 1998 ). The frequency of hepatic fibrosis is not known. It may be the cause of stillbirth in DS. In one series of eight patients with the complication, two were long-term survivors ( Miyauchi et al, 1992 ). Infants may die of fulminant liver failure while the TMD is regressing. Autopsy shows profound sinusoidal lobular and intralobular fibrosis and mild to moderate haemosiderosis, often with evidence of extramedullary haematopoiesis with excess numbers of maturing megakaryoblasts. Pancreatic fibrosis was noted in 8 out of 18 cases in another series ( Ruchelli et al, 1991 ) . Extensive myelofibrosis and generalized visceral fibrosis are occasionally present ( Becroft Zipursky et al, 1992 ). Miyauchi et al (1992) offered an interesting theory: the signs and symptoms of hepatic fibrosis may dominate TMD because the leukaemic blasts arise from fetal hepatic blood-forming cells. Normally, the transition from hepatic to medullary myelopoiesis accompanies the regression of TMD. Failure to make a timely transition to medullary haematopoiesis and overproduction of cytokines, such as platelet-derived growth factor or transforming growth factor β, by megakaryoblasts may lead to overwhelming fibrosis ( Miyauchi et al, 1992 ; Schwab et al, 1998 ). The management of TMD is conservative, most often involving watchful waiting or supportive care. When the WBC count exceeds 200 × 109/l, exchange transfusion or leucapheresis may avoid the complications of hyperleucocytosis ( Nakagawa et al, 1988 ) . In the rare cases of TMD where cytopenias or hyperleucocytosis become life-threatening, cytotoxic therapy may be considered. Low dose cytosine arabinoside (Ara-C) may be an appropriately conservative measure as it is sometimes curative in AMKL in DS ( Tchernia et al, 1996 ). There are as yet no data in this situation. In the face of imminent death from liver fibrosis, therapy may also be indicated. Options include low dose Ara-C for its efficacy in AMKL ( Tchernia et al, 1996 ), or standard AML therapy because it can reverse myelofibrosis in AMKL ( et al, 1986 ). strategy be to proliferation with a response such as which has been to fibrosis in patients with fibrosis ( et al, 1999 ). there are no data for these Because some neonates with trisomy 21 mosaicism are phenotypically it is to rule out DS by or in before cytotoxic therapy for leukaemia in neonate with leukaemia. It is estimated that about of DS infants develop AMKL or an TMD ( et al, ; et al, 1985 ; Zipursky et al, 1992 ). Although the of the 10% of TMD and the AMKL were derived from the DS ( as they that one in infants with DS has these series of DS patients with AML, a of TMD ( et al, 1992 ; Zipursky et al, 1992 ; Creutzig et al, 1996 ). one that DS children AML, of have a of MDS, the frequency of be as low as to leukaemia following TMD, it is almost always AMKL and it usually occurs the of and 3 years ( et al, ; et al, 1983 ; et al, 1986 ; Barnett et al, 1990 ; Zipursky et al, 1992 ). TMD and AML are usually phenotypically AMKL that the second disease is derived from the In some the of the AML is more complex but features of the TMD, clonal ( et al, 1985 ; et al, 1988 ; Barnett et al, 1990 ). However, there are rare cases in which the AML has a or deletion to the in the TMD. The is not M7, and the age is usually over 5 years ( et al, 1985 ; et al, 1987 ; et al, 1997 ; et al, et al, 1998 ). cases host factors that to the of myeloid leukaemia rather than clonal of leukaemic cells. Infants with a of TMD with complete blood for years and parental the of AMKL. In their review, Barnett et al not or cytogenetic those infants with TMD on to develop AML and those Table lists the features of AML, most often AMKL, in DS patients compared with patients. of the proportion of AML that is AMKL in children with DS from to ( Table . The is probably an as or 20 children with DS and leukaemia have their leukaemia of their predisposing DS ( Table of the cases are In the and of children with AML DS ( et al, 1996 ) . In the proportion of children with AML have Down's syndrome has from to 10% ( Table ( Robison, 1992 ; et al, 1998 ). higher numbers of DS children with AML probably from (i) of children with DS and AML on large clinical trials Baby legislation ( et al, 1998 (ii) reduced death from congenital disease and other anomalies, the of DS children to develop leukaemia ( Levitt et al, 1990 (iii) reduced parental of therapy ( et al, 1996 and of AMKL as a distinct form of leukaemia that in the may have been as ALL ( Bennett et al, 1985 ; Zipursky et al, 1987 ). Only the factor for the in DS patients with AML ( Table and the relatively proportion of DS ALL patients. of the of ALL to AML have from the as in to ( Table I) ( Levitt et al, 1990 ; Robison, 1992; et al, 1998 ), and in the first 3 years of AML is more common than ALL ( Creutzig et al, 1996 ). The unique features of AML in DS patients are the an MDS, FAB or and the response to therapy. all AML in children with DS occurs the of and 5 with a of 2 years ( Table ( Zipursky et al, 1987 ; Kojima et al, 1990 ; Levitt et al, 1990 ; et al, 1992 ; Creutzig et al, 1996 ; et al, 1996 ; et al, 1998 ). The blasts express the myeloid antigens CD33 and/or CD13 or but only have the IIb/IIIa or factor VIII ( Table ( et al, 1992 ; et al, ) . As with other forms of AML and TMD, lymphoid antigens are ( Kuerbitz et al, 1992 ; Smith et al, 1992 ; Creutzig et al, 1996 ). It has been that of AML cases in DS present with ( Kojima et al, 1990 ; Zipursky et al, 1992 , Creutzig et al, 1996 ; et al, 1998 ) ( Table The is by of by and are rare ( erythroid and megakaryoblastic are dysplastic and increased numbers of in the of (for a review, see Zipursky et al, 1992 ). In the out of patients with AMKL The of to AMKL, to from to ( Creutzig et al, 1996 ). In the absence of to AMKL appears However, one patient diagnosed with at 22 of age two spontaneous at and before diagnosis of AMKL ( Creutzig et al, 1996 ). Although there is no evidence of an advantage to therapy during MDS, it is probably to therapy platelet or are to or to treat of in DS patients appears to be as favourable as the response of their AML ( et al, 1992 ). The of cytogenetic abnormalities is in DS and patients with AML ( Table ( et al, 1981 ; et al, 1986 ; et al, 1992 ; Creutzig et al, 1996 ; et al, 1998 ). of DS patients only trisomy The favourable and the translocations of AML are present in of the patients with AML, but are children with DS ( Table is a of the non-disjoined chromosome which may for the absence of translocations ( et al, 1987 ). most and in about of the DS as often as in the cases ( Creutzig et al, 1996 ; et al, 1998 ). and do not in DS AMKL, but Creutzig et al noted five translocations involving chromosome in their series of DS patients. less AML translocations such as and also ( et al, 1997 ). is not a factor in DS even patients with 7 have disease ( et al, 1991 ; et al, 1998 ). An acquired tetrasomy in DS AML is as favourable as other cytogenetic acquired in is a or cytogenetic ( et al, 1998 ). The most of AML in DS patients is its to AML therapy ( et al, 1992 ; Kojima et al, ; et al, 1996 ; et al, 1998 ). to therapy for DS infants with AMKL is the as that of DS patients with other FAB ( Creutzig et al, 1996 ; et al, 1998 ). In contrast, AMKL is the only FAB in AML ( et al, 1990 ; et al, 1997 ; et al, 1998 ). Table the and survival those with and without DS in In the DS patients to AML have significantly than those no or ( Levitt et al, 1990 ; et al, 1992 ; Creutzig et al, et al, 1996 ). There are two et al that out of DS patients with or megakaryoblastic leukaemia with Ara-C were of their ( Zipursky et al, 1992 ; in out of children with DS and with and In more excess rather than the most common those with DS and AML ( et al, 1998 ). found the in their DS as all 7 in patients were ( et al, 1998 ) . the only of therapy to standard AML therapy in DS, indicates that DS patients from therapy that is less than that for other children with AML ( et al, 1998 ). In in to the those with DS to the less standard significantly higher and survival than those an ( Table ( et al, 1996 ; et al, 1998 ). marrow a than Ara-C therapy the DS patients. The with AML therapy and the of to Ara-C in some patients with AMKL the AML therapy for patients with DS and of Ara-C may be the approach of Tchernia et al less than half the patients and the of Zipursky two out of patients with lower than those in the large standard AML therapy ( et al, 1992 ; et al, 1998 ). Taub et al , 1999) have that Ara-C for the relatively of DS patients with They in the DS are more to Ara-C than Ara-C is higher in DS than in cell from DS more Ara-C than normal cell ( Taub et al, 1996 ). from reduced folate and they with overexpression of the gene in DS cells ( Taub et al, 1999 ). of or AML in DS has not been the subject of systematic and that inclusion of DS patients in marrow trials at of the Although the no in in first cell may be a for therapy for those with et al found that DS patients with AML ALL or survival was and death to was with those with DS to be at risk of increased fatal complications and Although MDS, and in infants and children with DS are distinct there is no form of ALL in DS. white blood cell count and are in DS and patients ( Table age is higher in DS patients but of age is mean platelet count is lower and the proportion of B-lineage ALL is higher ( et al, ; et al, 1990 ; Levitt et al, 1990 ; et al, 1991 ; Robison, 1992; et al, ; et al, 1998 ; Heerema et al, 1999 ). T-cell ALL and FAB ALL are those with DS. There have been no cases of disease at diagnosis patients with DS and ALL ( Table It appears that about half the cases of ALL in DS have a normal ( Berger, and are common an is an acquired abnormality almost unique to ALL in DS ( et al, ). The and are rare ( et al, 1985 ; et al, 1986 ; et al, 1990 ; et al, ; et al, 1993; et al, 1998 ; Heerema et al, 1999 ). occurs but is usually ranging from to The favourable is ( et al, ; Heerema et al, 1999 ). cases of ALL in DS, the favourable not be by reverse chain ( et al, 1997 ). By contrast, trisomy 21 is the most common acquired numerical in ALL with ( et al, 1999 ). Table shows the of trials of ALL in children with and without DS. in the and significantly for the DS patients ( et al, 1981 ; et al, 1984; et al, 1990 ; Levitt et al, 1990 ; et al, 1998 ). failure and death in DS are die of or and have increased of and ( et al, et al, 1990 ). without leukaemia, children with DS from congenital anomalies and ( DS patients to be that their blasts are less or that there are host factors that determine Belkov et al have that the gene number of the reduced folate which to chromosome the of methotrexate in leukaemic They that the mechanism may for the increased of methotrexate in DS children with ALL ( Belkov et al, 1999 ). Table shows that DS patients with current standard ALL therapy have to patients. et al (1998) compared those with those not full to to treat ( et al, ; Levitt et al, 1990 ; et al, 1991 ; et al, ; et al, 1998 ). are DS patients of and ( et al, 1986 ; Lejeune et al, 1986 ; et al, 1990 ; Levitt et al, 1990 ; et al, 1991; et al, 1998 ). This is to from folate caused by ( Lejeune et al, 1986 ; et al, 1987 ; et al, 1990 ). in therapy are and care and is and ALL in DS children is have a of the leukaemia in children with DS and have to their disease and their for therapy. that the of TMD and its to AML are in by may genes are and on during regression of TMD and of molecular have not a for the predisposition for leukaemia in DS the of DS and leukaemia to our about and of leukaemia in all to for and for this