Myelodysplasia and myeloproliferative disorders in childhood: an update

The myelodysplastic syndromes (MDS) and the myeloproliferative disorders (MPD) arising during childhood, even if combined, are generally thought to represent an uncommon occurrence of a heterogenous group of clonal stem cell disorders. Previous reported incidence rates, based on small series, have suggested that childhood MDS represents approximately 3% of paediatric haematological malignancies. Only two actual population-based studies have been reported for childhood MDS (62; 73). The recent study based in Denmark (62), found an annual incidence of 4.0 per million corresponding to 9% of all malignant haematological disorders in children. In contrast, 73) found a much lower incidence of childhood MDS in the range of 0.5 per million, but there were also significant differences between these studies for the reported incidences of acute myeloid leukaemia, acute lymphoid leukaemia and chronic myeloid leukaemia. A number of conditions have been identified as predisposing factors for childhood MDS or MPD (6; 52; 62; 64; 89; 98). These conditions include: Down's syndrome, Kostmann's syndrome, Noonan's syndrome, Fanconi anaemia, trisomy 8 mosaicism, neurofibromatosis (as discussed in further detail below), Schwachmann's syndrome, immunodeficiency and familial leukaemia. In addition, previous chemotherapy administered to children for other disorders can be a predisposing factor for the subsequent development of either childhood or adult MDS and MPDs. The incidence of therapy-related MDS is likely to increase in the coming decades as chemotherapy dose escalation is now being attempted for numerous malignant diseases. Therapy-related MDS will not be further addressed in this review but represents a serious problem with few effective therapies at present. In addition to the uncommon occurrence of these diseases, much of the difficulty in assigning incidence rates has arisen from a lack of consensus for a classification scheme. Since these diseases generally occur with a much higher frequency in adults, wherein classification schemes have been at least partially devised, for the most part attempts have been made to apply these adult classifications to the paediatric cases (Table I). Most MDS patients present with signs and symptoms of the cytopenias present in the peripheral blood. Hepatosplenomegaly is uncommon. Dysplastic features are common and the marrow cellularity is normal to increased. If one applies the French–American–British (FAB) group criteria (10, 11) devised for adult MDS to cases of childhood MDS, one notes that refractory anaemia with ringed sideroblasts (RARS) is only very rarely reported in childhood cases, whereas chronic myelomonocytic leukaemia (CMML) in childhood is more common, especially in children under the age of 5 (24; 60; 98; 82; 94; 84). Cases of refractory anaemia (RA), refractory anaemia with excess blasts (RAEB) and refractory anaemia with excess blasts in transformation (RAEB-t) have all been reported to present during childhood. The predominating diagnosis amongst the FAB classified diseases in childhood MDS is childhood CMML, now termed juvenile myelomonocytic leukaemia (JMML) as discussed below. This disease has also been referred to by other names in the past including: juvenile chronic myelogenous leukaemia (JCML) (51; 55), juvenile chronic granulocytic leukaemia (1; 7) and subacute and chronic myelomonocytic leukaemia (24). A similar disorder, also often occurring in early childhood, has been termed infantile monosomy 7 or monosomy 7 syndrome (110; 46; 85; 98). These disorders will be discussed in much greater detail below. A strong male predominance has been noted in several MDS subtypes including CMML. The male to female ratio has ranged in various reports from 1.7:1 in both the French and American studies (24; 84) to 4.8:1 in the British study (98). The factors underlying the male predominance and its potential biological significance are unknown. The adult diseases which 32) first termed as related myeloproliferative disorders are polycythaemia vera, myelofibrosis (agnogenic myeloid metaplasia), essential thrombocythaemia and chronic myelogenous leukaemia. However, there are numerous other disorders that have also been classified previously (118; 39) in the myeloproliferative disorder category (Table I), several of which have been reported to occur in childhood populations. Reports of MPD occurring in childhood have infrequently described polycythaemia vera, essential thrombocythaemia, agnogenic myeloid metaplasia (also termed primary myelofibrosis and idiopathic myelofibrosis) (96; 88; 104), primary familial and congenital polycythaemia (100; 37) and chronic neutrophilic leukaemia (65). Since the majority of these reports of paediatric cases have been anecdotal, traditionally the classification and diagnostic criteria for these disorders in childhood generally has followed the same criteria as developed for adults with these disorders. Unlike the rare paediatric occurrence of the MPDs discussed above, Philadelphia chromosome-positive (bcr/abl-positive) or adult-type, chronic myelogenous leukaemia (ACML) clearly occurs in children with a significant occurrence constituting 2–5% of all leukaemias. It is less common under the age of 2 as compared to other age groups, ranging up to 20 years of age, at which the incidence is < 1 per 100 000. The incidence of ACML increases after the age of 20. Besides the difference in age distribution, ACML in childhood is typically easily distinguishable from JMML and from adult-type CMML (which does occur in children) by several other characteristics as illustrated in Table II. Childhood ACML patients commonly present with symptoms attributable to the splenomegaly that is invariably present. These symptoms include: abdominal distension and discomfort, dysphagia and weight loss. Other common presenting symptoms are malaise, bone and joint pains, fever, night sweats and bleeding diathesis. Leucostasis signs and symptoms including strokes, papilloedema, cerebellar signs and priapism occur slightly more commonly in childhood ACML than in adults with ACML. A definitive diagnosis is made by the demonstration of the translocation between chromosomes 9 and 22, or by detection of the bcr/abl fusion gene. Patients with ACML, JMML or adult type CMML must all be distinguished from the occasional paediatric patient who will present with leucocytosis or a ‘leukaemoid reaction’ resulting from infectious causes, metastatic cancer or congenital heart disease. The latter cases are distinguished from the former cases by normal cytogenetics, lack of associated features as depicted in Table II, and resolution and/or lack of progression of signs and symptoms. The classification of CMML in childhood (now termed JMML) into either the MDS category or the MPD category has been particularly problematic. Likewise, the classification of CMML in adulthood has also fallen more recently under similar scrutiny. Attempts to re-categorize adult CMML into either the MDS or MPD heading, based on the total leucocyte count, have thus far not proved useful in regards to prognostic information (53; 97). Until more knowledge is elucidated regarding the pathogenetic mechanisms of these two disorders we may not be able to clearly classify adult CMML, or its paediatric counterpart JMML, into either the MDS category or the MPD category. For the present, and in order that common nomenclature is used by all to compare similar groups in future studies, the most appropriate classification of these two disorders may be to classify them (as noted by 9) as ‘bridging’ disorders and call them myeloproliferative/myelodysplastic disorders (Table I). Besides childhood ACML, of all of the remaining subtypes of childhood MPD and MDS, JMML and monosomy 7 together make up by far the largest porportion of patients. JMML has several distinguishing characteristics (51; 39; 4; 20; 27). Common clinical features include: marked hepatosplenomegaly, generalized lymphadenopathy, and skin changes including eczematous rashes, café-au-lait macules and dermal neurofibromas. Common laboratory findings include: moderate leucocytosis with monocytosis, anaemia and thrombocytopenia, elevated fetal haemoglobin, and hypergammaglobulinaemia. Pathologic findings include infiltration of various non-haemopoietic organs (skin, lungs, intestines) with leukaemic monocytic cells. Molecular findings include: lack of the bcr/abl fusion gene, and increased incidences of monosomy 7 as well as NF1 and RAS abnormalities. One of the previously most commonly accepted names for JMML was JCML. This term was coined to distinguish this myeloproliferative/myelodysplastic disorder from the adult type (bcr/abl-positive) CML. However, the disorder named JCML never really had sufficient similarities to ACML to warrant the name since a monocytic presence predominated and the disease course was generally much more aggressive than ACML. Similarities to the adult form of CMML are much broader than those to ACML (Table II), but distinct differences are also noted including: lack of incidence of neurofibromatosis in adults and rare elevations in fetal haemoglobin in adults, higher incidence of and more complex karyotypic abnormalities in adults, and differences in in vitro cell growth characteristics between the two disorders (41; 21). As a result, over the last several years discussions have taken place amongst the International JMML Working Group and the European Working Group of MDS in Childhood (EWOG-MDS) and an international consensus has been reached to rename this myeloproliferative/myelodysplastic disorder to JMML (4; 95). To the clinician, JMML can pose a diagnostic dilemma. The initial presentation and early clinical course of these patients can be quite heterogenous. Morphologically, in some cases the cells may show minimal dysplastic changes and there is no evidence of maturation arrest. The issue is further clouded by the fact that the clinical presentation can mimic that of several viral infections including Epstein-Barr virus, cytomegalovirus and human herpes virus-6 (68; 75; 83). Through the ongoing deliberations of the International JMML Working Group and the EWOG-MDS, a consensus has been reached on a set of clinical and laboratory features to be utilized as minimal diagnostic criteria (Table III, adapted from Niemeyer et al, 1998) until the molecular abnormalities defining JMML have been substantially characterized. Some young children with a monosomy 7 karyotype share many of the same clinical, laboratory and pathological features of JMML. Several groups have attempted to classify this group of young children with monosomy 7 into a separate disorder called infant monosomy 7 syndrome (110; 46; 98). This group, when first defined, appeared to initially differ from other JMML patients by a lower fetal haemoglobin level, a longer survival, but a higher rate of transformation to AML. However, many areas of overlap exist amongst these two disorders. Beyond this group of infantile patients, monosomy 7 as a cytogenetic finding is seen in children with JMML, AML and in children with all of the FAB subtypes of MDS (31; 84). Although some reports have advocated classifying these young children with monosomy 7 as a truly separate disorder (110; 19), more recent studies suggest there is no data to support the concept of monosomy 7 as a distinct syndrome, but rather it should be viewed as a ‘cytogenetic opportunist’ (84; 61). The International JMML Working Group and the EWOG-MDS have concluded that these disorders should be treated as the same disorder in treatment protocols, and subjected to subset analysis later. The clonal nature of JMML was inferred by several reports of small numbers of patients who had chromosomal abnormalities (66; 69, 70; 16; 2). Recent methodological improvements in clonality assessment, based on X-chromosome inactivation patterns, have made possible the tracing of the clonal origin of JMML cells to at least the level of the myeloid stem cell, and potentially even the pluripotent stem cell (18). Further, JMML cells appear to maintain clonality for relatively long periods in cell cultures (at least up to 42 d), in contrast to ACML cells (38). JMML mononuclear cells, obtained from either a peripheral blood or bone marrow source, have long been known for to form in with the monocytic predominating (1; Other MPD patient cells can growth but not as as in JMML This growth is not to or mechanisms of but rather is to the JMML cells a to factor factor of these cells to either or to is This of the JMML myeloid to in which in other as and factor which can the of JMML by normal This pathogenetic of is similar to that for the in primary familial and congenital polycythaemia However, primary familial and congenital polycythaemia in which are in some with the disorder no have been reported to in JMML has as a common pathogenetic in at least myeloproliferative disorders If one monosomy 7 under the classification of JMML, of patients will have normal cytogenetics, approximately will have monosomy and only will have other chromosomal this small latter several will have other 7 only a very small number of JMML patients who have more complex 98; 94; 84). is a common disorder with a incidence of 1 in JMML patients have a increased incidence of clinical signs of being in of patients 94; In addition, a recent has that an of JMML patients in the neurofibromatosis gene, clinical signs of the disease In addition to NF1 various studies reported a rate of of JMML patients RAS cells These groups of patients with NF1 or RAS abnormalities appear to be This of the of one of the significant for cells Further, the NF1 for a with a which as a which to from its The NF1 abnormalities in JMML patients represent of that NF1 as a in myeloid cells by two groups have the neurofibromatosis in to the in JMML patients who have of for NF1 The who the an at of However, when these the fetal cells (which at this the majority of from these and subjected them to growth the same growth as in JMML patient Further, if these same cells were into the developed a myeloproliferative disorder of JMML. These definitive studies clearly that a can in cells to and at least one potential pathogenetic for the development of JMML. the reported RAS in JMML, the majority of which are either or are in JMML, to be However, the NF1 and RAS in all JMML patients thus far to be in up to of JMML patients. The occurring in the other of JMML cases is an of Childhood cases of and even adult-type CMML have been noted in children. to occur only very The clinical course of childhood MDS can be quite rate to AML is similar to that in adult MDS MDS must be distinguished from AML with a count, as the latter to have a higher rate associated with As in adult cases, some childhood cases of have been with or in some cases treatment with of or growth factors have been which have been attempted include and most of these attempts with from all have in only in a subset of patients. Cases of and CMML have been treated with chemotherapy with or bone marrow 94; as to these childhood MDS cases as well or to this type of as compared to AML. of chemotherapy which not stem cell as part of the have potential It appear that stem cell early in the course of the disease and from the most the for Some a for childhood MDS to be as as whereas a lower As we further of MDS based on and molecular may that of with Down's syndrome can several haematological including: a myeloproliferative disorder in the which relatively occurrence of MDS, and higher incidence of AML with a to the Several recent all appear to on the fact that children with Down's syndrome and haematological disorders represent a distinct which are more to than children Down's syndrome who have the same haematological than in these Down's syndrome patients even be The of which are typically in most adults over the course of are also typically present in most children with ACML. Most patients in chronic on during which disease is with minimal may the or patients may into the The is by leucocytosis refractory to previous anaemia and weight loss. The can be either of the myeloid or the lymphoid either or chemotherapy had been used to the leucocytosis in ACML. However, in the of either or with chemotherapy as have the of these in children with ACML, as have in adults can to very of the leucocytosis in ACML. present the only known potentially is stem cell from either related or can have an or greater of with a related or are early in disease course should be made to children with ACML a from of disease was identified as a of in the study by be to when to the leucocytosis after a definitive diagnosis of ACML has been A for a stem cell either related or should If all potential stem cell related and and from marrow or blood to an stem cell may be as a If this does a from to with or be Patients who have to can have of or more if treated with A of patients treated with can a cytogenetic as by marked or of the Philadelphia or the bcr/abl fusion However, since these of can of to the of for after present, for childhood ACML must be viewed as a stem cell of may to primary or The primary and disorders are by an elevated cell whereas the have a normal cell but a The cell study should be one of the first in the of patients. from a of including from several with and The majority of the can be by blood and or haemoglobin This is one of the two primary and is a clonal stem cell disorder has been with of cells to growth in conditions Patients with polycythaemia can present with However, the majority of including and night to the increased blood cell Since this is a stem cell disorder, in the blood cell and can also be of in cultures can be a useful diagnostic The criteria developed by the Group should be to children as well as adults in a diagnosis of polycythaemia As with the treatment of young adults with this disorder, most are to chemotherapy or to the cell of the with these as patients with polycythaemia can a long is often used to the but should be that the of for and/or is the The of is if or and are all used in adults to cell and may be useful in paediatric is more to and has than The of to be at least thus is useful only to lower the and is the and least of the familial and congenital polycythaemia is the other primary It is distinguished from polycythaemia by of only the in the former is in an but have been must be in the but not thus it possible to separate it from a polycythaemia disorder which rarely occurs in a familial Most who have with not In some patients appear to an from However, there have been other reported wherein some from disease. Most children with this disorder will have from which a disease course can be These disorders must in the category of diagnosis by since appear to be rare and since there are a of for paediatric only should the other myeloproliferative disorders including polycythaemia and ACML be but more common including infectious and disorders should be thrombocythaemia typically with elevated The must elevated over and other potential A recent that many patients a diagnosis of essential thrombocythaemia may in fact not have a clonal disorder This to further the that one must be very when a possible diagnosis of essential thrombocythaemia, especially in children. Patients with myelofibrosis will have more signs and symptoms to including other cell blood cell on peripheral malaise, night sweats and weight loss. Other potential to be include and bone diseases, diseases and metastatic If either essential thrombocythaemia or myelofibrosis is in fact and if there is a for the most therapies are those being attempted in adults with these disorders. and are all potential It must be in that these disorders can have a quite the common of the being to the clinical course of JMML is truly quite heterogenous. all of JMML patients are under the age of with The majority all present with hepatosplenomegaly, lymphadenopathy, anaemia, and Only a small of JMML patients or to an acute patients will a of disease followed by progression whereas will show progression (24; Several have also noted that a very small of patients long with relatively disease. It that this small can be treated with or with chemotherapy as the this small of patients from the in of is of have in myeloid marrow For the remaining majority of JMML patients, the that a disease course followed by a (24; and often occur to or non-haemopoietic to monocytic One that has been by several is that JMML patients can be into two prognostic with the most significant features being based on count, fetal haemoglobin level and age (24; 98; The group is those patients over the age of with a count, and a fetal haemoglobin have been attempted in to or at least to the aggressive progression of JMML. chemotherapy has been attempted to similar to its in AML or in MDS patients with or In contrast to the AML and the other MDS patients, JMML patients rarely a with chemotherapy and if a it is of the associated and the of this type of at the International on MDS in Childhood that should not be further it was in the of a chemotherapy has also been attempted various as or have been but on is and no have been has been noted to have some on the growth in JMML However, when to patients in a of effective in ACML, no were It is possible that other of show some in JMML. was also to JMML growth to an rate in a The also that the appeared to the in JMML cells. This rate has now been in a clinical which has recently been reported The is well at as as and numerous patients have now been on for years as with appear to be cell is the only that has thus far cell have ranged from related bone to bone to related or blood stem cells the source, it that a factor to the of stem cell to be an in most reported The at 5 years to be of the order of or the of JMML and monosomy most of the reported have been relatively the In more effective is for these disorders. the last few JMML and clinical have been on an international an that is for rare disorders as JMML it is to sufficient numbers of patients at one The European Working Group on in Childhood together with other European has a clinical early with stem cell for JMML and/or monosomy Likewise, the paediatric clinical groups in have and will a for all JMML and/or monosomy 7 children in Patients will with stem cell and further In addition to these which both stem cell the knowledge of resulting in several are now being in vitro and in for potential future in JMML. These potential future include: fusion and the of diagnostic it is that analysis of as those will more information as to incidence and to Until more is known and/or subset to the International JMML Working Group and the EWOG-MDS have to include JMML and monosomy 7 monosomy 7) under the same treatment these clinical it is that all JMML and monosomy 7 patients, at least in and be one of these two treatment and at the same into the now being developed or in It is likely that only pathogenetic and that we will the treatment of these patients. The of an with diagnostic international and has taken over the last 5 years in several of the The now with to the and the for childhood MPD and