Preleukemic Syndromes and Other Syndromes Predisposing to Leukemia

The Leukemias

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Preleukemic Syndromes and Other Syndromes Predisposing to leukemia

Cindy L. Schwartz, MD, * and Harvey]. Cohen, MDt

A large number of children are referred to pediatric hematologists each year for the evaluation of various cytopenias (anemia, thrombocytopenia, or granulocytopenia), or occasionally for proliferative disorders (thrombocytosis, polycythemia, or granulocytosis). Often the foremost question in the referring physicians' or parents' minds is "Is this leukemia?" In most instances a definitive answer can be given and the patient and family can either be reassured that the disorder is not leukemia or the patient can embark on a treatment regimen offering hope of cure, or at least, prolonged survival. Occasionally, however, the answer is more elusive. Leukemia is a clonal disturbance of hematopoietic cells characterized by disturbances in both proliferation and differentiation. A diagnosis of leukemia is usually made when cells arising from this clone establish hematopoietic dominance. There are, however, a number of disorders that are preleukemic in that they virtually always progress to overt leukemia, or predispose to leukemia; that is, an excessive proportion of patients develop leukemia. These disorders include the myeloproliferative and myelodysplastic syndromes, the hallmarks of which are, respectively, excessive proliferation or abnormal differentiation of hematopoietic cells. These are the disorders that are most difficult for patients and physicians. For these disorders, reassurance cannot be given and the ability to influence the outcome is limited. These disorders, however, offer a unique opportunity to observe the evolution of leukemia and are helping to unravel the mechanisms by which abnormal clonal cells arise and establish dominance. In this article we will review our current understanding of hematopoiesis, with an emphasis on biologic mechanisms that result in proliferation and differentiation. This sets the stage for a subsequent discussion of the individual myeloproliferative and myelodysplastic syndromes.

*Assistant Professor of Pediatrics,

Department of Pediatrics (Divison of Hematology/Oncology); The Cancer Center, University of Rochester Medical Center, Rochester, New York tProfessor of Pediatrics, Department of Pediatrics, and Chief, Division of Hematology/ Oncology, The Cancer Center, University of Rochester Medical Center, Rochester, New York

Pediatric Clinics of North America-Vol. 35, No.4, August 1988

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HEMATOPOIESIS Appropriate numbers of all hematopoietic cells can be formed only when proliferation (expansion of cell populations) of progenitor cells and differentiation (progressive maturation of cells) to end stage cells are coupled processes. A stem cell pool, which is capable of carrying the genetic information of all hematopoietic progeny, must be maintained by self renewal. Some stem cells become committed to differentiation by progressive restriction of lineage potential from multipotent (myeloid or lymphoid) to tri- or bipotent lineage to unilineage and, finally, to mature blood cells 62 (Fig. 1). Although differentiation and proliferation are normally coupled processes, they may be controlled separately. Cell-cell interactions,31 growth factors,106 and stochastic (random) processeslO3 may affect the ultimate developmental pathway of a particular hematopoietic precursor. Hematopoiesis has been studied for over two decades using in vitro culture systems. l7 Bone marrow progenitor cells seeded in semisolid media (agar or methylcellulose) form colonies, with each colony representing a clone. Some colonies containing granulocytes (G), erythrocytes (E), monocytes (m), and megakaryocytes (M) are presumed to arise from an early progenitor called the colony forming unit GEMm (CFU-GEMm), while others, CFU-Gm (granulocyte/monocyte), CFU-E (erythroid), BFU-E (burst forming unit-erythroid), CFU-G (granulocyte), CFU-m (monocyte), and CFU-M (megakaryocyte) arise from cells with more restricted lineage. l7 , 54, 72, 100 Supernatants of cell suspensions (from placenta, phytohemagglutinin-stimulated mononuclear cells, tumor cell lines) have been utilized to provide colony stimulating factors (CSF) necessary for progenitor colony formation. These appear to be glycoprotein hormones, produced in vivo by activated T-cells, monocytes, stromal and endothelial cells. 19 Some, such as granulocyte CSF (G-CSF) or monocyte CSF (m-CSF) stimulate unilineage colonies, while others stimulate multilineage progenitors (e.g., Gm-CSF stimulates granulocyte-monocyte colonies and interleukin [IL]-3 stimulates multiple lineages, including all cells arising from the CFU -GEMm). 21,50.77, 98 Erythropoietin, an extramedullary hormone, affects erythropoiesis. II The recent use of pure growth factors has confirmed these lineage-specific phenomena. Another factor, hematopoietin 1 (also known as synergistic factor or IL-1a), induces stem cells to become responsive to other CSF.99 Many of the genes encoding for these proteins and their receptors have been localized to chromosome 5 (e.g., Gm-CSF, m-CSF, and the m-CSF receptor, as well as the receptor for platelet-derived growth factor, PDGF, a growth factor causing fibroblastic proliferation). 64, 81, 84, 113 The gene coding for G-CSF has been localized to chromosome 17.81 Cellular oncogenes, genes with extensive homology to viral genomes capable of malignant transformation of cells, may playa role in hematopoietic control. This is suggested by the discovery that the receptor for m-CSF is encoded by c-fms, a cellular oncogene. 92 Since hematopoiesis appears to be under genetic control, aberrant hematopoiesis may occur with chromosomal disturbances, resulting in abnormal growth factors or receptors. For example, an abnormal tyrosine kinase is produced when c-abl translocates to chromosome 9 in chronic

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myelogenous leukemia (CML).61 Adults with a deletion of a portion of chromosome 5 (5q - syndrome) have refractory anemia, myeloid hyperplasia, and abnormal thrombopoiesis. The cluster of genes on chromosome 5 affecting hematopoiesis is missing in this disorder. Either this loss or the resulting expression of abnormal alleles on the remaining chromosome may cause the hematologic abnormalities. 64. 81 Sachs has suggested that uncoupling of pathways of gene expression controlling growth and differentiation results in leukemia. 90 In some instances, this may occur in a two-step process of sequential genetic mutation similar to that which occurs in retinoblastoma and Wilms' tumor. 58 The first step may occur when either proliferation or differentiation of a myeloid stem cell becomes aberrant as occurs in myeloproliferative and myelodysplastic syndromes, respectively. The second step, resulting in both proliferation and differentiation abnormalities may be the result of a second genetic event (e.g., amplification of the abnormal oncogene c-abl in CML)24 or may be related to the effects of aberrant growth factors on stromal or hematopoietic cells, causing selection of, or proliferation of, a particular clone. A two-step process, encoded for by two separate genomic regions of the Friend leukemia virus, has been shown to cause hemolytic anemia followed by erythroleukemia. 97 The individual myeloproliferative and myelodysplastic syndromes can be considered in terms of these biologic events and may give clues as to the process of leukemogenesis. We classify the myelodysplastic syndromes as preleukemic disorders since virtually all will develop leukemia. In contrast, the myeloproliferative syndromes are classified as disorders which predispose to leukemia, since leukemia will arise in many, but not all cases.

MYELOPROLIFERATIVE SYNDROMES (DISORDERS PREDISPOSING TO LEUKEMIA)

Definition CML, polycythemia vera (PV), essential thrombocythemia, and agnogenic myeloid metaplasia and myelofibrosis (AMMM) are disorders initially thought to be "pure" proliferations of granulocytes, red blood cells (RBC), platelets, and fibroblasts, respectively. In 1951, Dameshek grouped them together as the myeloproliferative syndrome (MPS) noting that, to variable degrees, stimulation of all hematopoietic cells occurS. 25 Thrombocytosis, fibrosis, and polycythemia can be seen in addition to granulocytosis in CML. CML is now identified by a translocation from chromosome 22 to chromosome 9, forming the so-called Philadelphia chromosome. 85 This welldefined disorder is known to terminate in acute leukemic blast crisis in all patients and is further described in a separate article. PV is defined as an increase in red cell mass, although thrombocytosis may also be seen. CML and other secondary etiologies for increased red cell mass (e.g., cardiac, pulmonary, renal) must be ruled out. AMMM is a syndrome of idiopathic myelofibrosis with extramedullary hematopoiesis (myeloid metaplasia) differentiated from CML in some patients by the absence of the Philadelphia

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chromosome. Excessive proliferation of platelets of clonal origin without criteria for CML, AMMM, or PV is described as essential thrombocythemia (ET). Biology The MrS are clonal disorders which are similar in that regulatory control of a hematopoietic precursor has become aberrant. 2, 36, 53 The abnormal tyrosine kinase produced when the c-abl oncogene of chromosome 22 translocates to the ber oncogene region of chromosome 9 in CML may cause the proliferative stage,42 perhaps by functioning as an abnormal growth factor or receptor. Marrow colony forming assays have shown that CFU-GEMm and BFU-E of patients with PV respond to erythropoietin with a greater proliferative response than do normal controls. 35, 39, 40, 115 In both CML and PV the increased proliferative potential may allow the abnormal clone to establish dominance. The proportion of normal progenitors has been shown to decrease with time in a given patient with PV (as it does in CML).1 AMMM, initially thought to be a manifestation of marrow proliferation involving primarily fibroblasts, now appears to be a secondary phenomenon. Clonally abnormal megakaryocytes and platelets may secrete PDG F, stimulating the proliferation of normal fibroblasts, 44 In both PV and ET a percentage of patients are reported to have detectable chromosomal abnormalities. 8, 10, 74, 102, 114 The abnormal clones play a role in the fact that these disorders have a variable tendency to evolve into acute nonlymphocytic leukemia (ANLL). Complex cytogenetic abnormalities are almost universal if PV undergoes leukemic transformation lO ,102 and are seen in many patients with ET at the time of leukemic transformation. 8 Treatment with radiation and chemotherapy may exaggerate the tendency, Clinical Features/Therapy: Polycythemia Vera PV is characterized by erythrocytosis with varying degrees of thrombocytosis, leukocytosis, and splenomegaly, Erythrocytosis due to increased erythropoietin production and relative polycythemia (normal red cell mass with decreased plasma volume) must be ruled out before a diagnosis of polycythemia vera is made. The differential diagnosis of polycythemia is reviewed in Table 1. (A mnemonic for each differential diagnosis is included in Tables 1, 2, and 4.) PV is rarely seen in children, with only 0.1 per cent of patients being less than 20 years of age, 12 Fewer than 20 pediatric cases have been reported and not all are clearly primary polycythemia, 4, 26, 33, 45, 46, 71, 76, 100

Manifestations of PV can be attributed to the abnormal proliferation and function of RBC, granulocytes, and platelets. Erythrocytosis with hypervolemia causes plethora, cardiac symptoms (dyspnea, hypertension), and symptoms related to disturbed cerebral circulation (dizziness, paresthesia). Thrombocytosis with abnormal platelet function results in thrombosis and hemorrhage, Myelofibrosis with associated extramedullary hematopoiesis and hypersplenism may be related to elaboration of PDGF or a PDGF-like substance. Gastrointestinal symptoms and pruritus occur with granulocytic proliferation and increased histamine turnover. Hyperuricemia

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Table 1. Differential Diagnosis of Polycythemia R-relative polycythemia-normal red cell mass, decreased plasma volume -dehydration E-elevated erythropoietin-secondary polycythemia -appropriate (decreased tissue oxygenation) -altitude ---cardiac (right to left shunt) -pulmonary -hypoventilation (Pickwickian syndrome) -hematologic-decreased O 2 affinity hemoglobin or -inapproprIate (normal tissue oxygenation) -tumors -renal abnormalities

i

2,3 DPG

D-decreased or normal erythropoietin-primary polycythemia -polycythemia vera

-CML

and hypermetabolic symptoms (weakness and weight loss) are related to hyperproliferative state. 12 Most patients are diagnosed in the proliferative phase in which erythrocytosis, with varying degrees of thrombocytosis and granulocytosis, occurs. The marrow shows hyperplasia of all marrow elements. During this phase, thrombohemorrhagic events are of greatest concern. Serious complications noted in children include: hypersplenism, splenic infarction, hypertension, strokes, hemorrhage, and coagulation abnormalities. 26 Therapeutic modalities used to decrease the incidence of thrombohemorrhagic phenomena have included phlebotomy, radioactive phosphorus (32P), and chemotherapy (chlorambucil or hydroxyurea). 11. 55 Phlebotomy alone is recommended in children since chlorambucil and 32p increase the incidence of leukemia and other malignancies. 11 If the phlebotomy requirement is high or there is a history of prior thrombotic events, hydroxyurea, a nonalkylating myelosuppressive agent which may not be as mutagenic as chlorambucil, is recommended. 11. 55 A significant minority progresses into the "stable phase" during which blood counts normalize without therapy, probably due to some degree of marrow fibrosis. Many ultimately enter the spent phase of post-polycythemic myeloid metaplasia (PPMM), characterized by extensive marrow fibrosis with hepatosplenomegaly. Peripheral cytopenias then become the major clinical problems. 95 Leukemia may develop at any time in the patient's course but is most common in patients developing PPM M. 96 Clinical Features/Therapy: Essential Thrombocythemia ET is characterized by persistent thrombocytosis for which no etiology can be determined. CML, PV and AMMM must be ruled out, as must causes of reactive thrombocytosis (Table 2).3 This disorder is rarely described in children, 68. 91 although a recent study found that 13 of 94 (14 per cent) individuals with ET were less than 20 years old. Many patients are asymptomatic, and the diagnosis is suspected only when blood tests are obtained for an unrelated problem. Approximately one-third of patients present with thrombohemorrhagic events including transient cerebral isch-

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Table 2. Differential Diagnosis of Childhood Thrombocytosis I-

inflammatory/immune: infection - acute (recovery phase) - chronic (osteomyelitis, tuberculosis) inflammatory bowel disease collagen vascular disorders nephrotic syndrome Graft-vs-host disease

S-

splenectomy/splenic hypofunction, surgery

T-

thrombosis, trauma

o-

oncologic: lymphoma, neuroblastoma, carcinoma, acute megakaryoblastic leukemia

P-

pharmacologic: epinephrine corticosteroid (exogenous and endogenous hyperadrenalism) vinka alkaloids citrovorum factor

U-

unclear etiology: Histiocytosis, sarcoid, Caffey's disease

P-

proliferative: myeloproliferative syndromes (ET, PV, CML)

A

anemia: iron deficiency, vitamin E deficiency, megaloblastic anemia, hemolytic anemia

=

BLEED -

hemorrhage

emia, peripheral vascular ischemia, deep vein thrombosis, and priapism. 8 Pruritus, splenomegaly, and hepatomegaly are less severe and less frequent in ET than in PV. Laboratory abnormalities related to excessive hematopoiesis and the accompanying hypermetabolic state are apparent in some patients. These include elevations in the white blood count, leukocyte alkaline phosphatase, vitamin B12, urate, and cholesterol. 8, 74 Abnormal tests of platelet function, particularly of aggregation, have been noted. 8 , 15, 56,68 Clumps of platelets are seen on the blood smear, with megakaryocytic hyperplasia in the marrow. The course of the disorder is more benign than CML or PV. Of the 10 children described in the literature, only one (who had been treated with 32P) had died of leukemia80, 91 and one developed idiopathic myelofibrosis. 5 Adults have an 80 per cent chance of surviving more than 100 months, with 5 of 95 treated patients (2 hydroxyurea, 3 melphalan or 32P) experiencing a leukemic conversion. 8 Children appear to have a more benign course than adults,48 perhaps because they tolerate thrombocytosis of any etiology better. Asymptomatic children need not be treated, Hydroxyurea should be considered for children who have had thrombohemorrhagic episoides. Clinical Features/Therapy: Agnogenic Myeloid Metaplasia and Myelofibrosis Patients with AMMM present with myelofibrosis, myeloid metaplasia (splenomegaly) and a leukoerythroblastic blood picture (poikilocytosis, teardrops, nucleated RBC and blasts). The onset is insidious and survival is prolonged in many patients (median 10.6 years from onset).107 This is a disease of adults, with only one published case in which the child clearly fits the criteria for AMMM.16 In addition, two siblings with normal

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chromosomes were found by Sieff to have myelofibrosis and myeloid metaplasia at the ages of7 and 8 weeks. 94 This may represent a constitutional abnormality causing abnormal regulation of fibroblasts or metakaryocyte proliferation, rather than the classic clonal disorder of AMMM. Another form of idiopathic myelofibrosis in adults, known as acute myelofibrosis (AM F), presents as a rapidly fatal disorder characterized by nonspecific symptoms (fatigue, weight loss) and absence of splenomegaly. The peripheral blood smear shows pancytopenia but morphologically normal cells. The marrow is fibrotic with bizarre megakaryocytes and frequently unclassifiable blast cells. 66 Careful examination of these blasts by light microscopy, electron microscopy, and assays for platelet peroxidase suggests that AMF is actually acute megakaryoblastic leukemia (AMgL).6. 13. 18. 30 Classic AMF in childhood is rare,20 but a number of children with splenomegaly, leukoerythroblastosis, myelofibrosis with unclassifiable blast cells, and a clinical course similar to AMF have been reported. 34, 47. 79, 83. 104. m Eight of the nine who had this childhood form of AMF (C-AMF) were babies «3 yrs old) with trisomy 21. Trisomy 21 is known to be associated with AMgL, which in young children presents with splenomegaly, marrow fibrosis, bizarre megakaryocytes, and unclassified blasts. 22. 65 C-AMF thus overlaps with childhood AMgL in clinical symptomatology, marrow findings, and population at risk, suggesting that C-AMF may also be AMgL. In some instances, other myeloid cells may be involved in the leukemic proliferation, Children with C-AMF treated with new chemotherapeutic regimens for ANLL have had prolonged remissions,22 as has a child treated with allogeneic transplantation. 20 Thus, the correlation of myelofibrosis with ANLL (AMgL in this case) is not only helpful for better understanding of leukemogenesis, but also enables us to utilize appropriate therapies. The pathogenesis of myelofibrosis in all of these (AMMM, AMF, CAMF, AMgL) appears to be related to abnormal megakaryocytes in the marrow which elaborate excess alpha-granular proteins (including PDGF). 44 In AMMM this may be a first step, setting the stage for leukemic transformation. The myelofibrotic environment may allow an abnormal clone with excessive proliferative ability to become predominant. A man with a 17-year history of AMMM whose disease transformed into AMgL, had blasts with increased c-sis m-RNA,1° which codes for a polypeptide of PDGF, Activation of c-sis may have played a central role in the malignant evolution of myelofibrosis. Thus, AMMM may have been a first step in a two-step process of leukemogenesis. Myeloproliferative Syndrome Associated with Trisomy 21 Newborns with trisomy 21 may have an MPS which appears identical to ANLL, with peripheral myeloblasts (up to 95 per cent of the white cells) and an elevated white blood count (up to 400,000 per mm 3). Hyperplasia of erythroid and myeloid elements are seen in the marrow with up to 60 per cent of cells being myeloblasts (Fig, 2).109 Hepatosplenomegaly, skin infiltrates, anemia, and thrombocytopenia may occur. 38 Spontaneous remission occurs within 1 to 2 months in some, but others have a persistent leukemia. It is unclear whether the transient cases are truly clonal leukemic disorders or are non clonal, regulatory abnormalities of hematopoiesis in infants with a constitutive chromosomal abnormality,

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Figure 2. Transient myeloproliferative syndrome followed by C-AMF in trisomy 21. A, Peripheral blood: A neonate with trisomy 21 showing a picture compatible with ANLL. This myeloproliferative syndrome resolved spontaneously. Four blasts are seen showing a high nuclear:cytoplasmic ratio and nucleoli. One (arrow) shows cytoplasmic blebs, sometimes seen in the micromegakaryoblasts of AMgL. B, Marrow biopsy: Same patient presenting with pancytopenia at 15 months of age. A proliferation of bizarre megakaryocytes is seen (arrows). C, Marrow aspirate. Same patient at 15 months of age with bizarre megakaryocytes. D, Marrow aspirate: Same patient at 15 months of age with micromegakaryoblast not unlike that of Figure 2A.

Chromosomal studies of marrow cells have, in some patients, revealed abnormalities other than trisomy 21, which disappeared as the MPS resolved. 63. 73 This is suggestive of a cl6nalleukemic or preleukemic disorder which remits, possibly as regulatory influences allow the normal trisomic hematopoietic cells to gain dominance over the abnormal clone. A newborn reported by Honda had an extra C chromosome in 6 per cent of his trisomic cells during a neonatal MPS which resolved. 49 However, the abnormal clone persisted as a minor cell line until the age of 26 months. Leukemia then arose, with the extra chromosome in 93 per cent of the cells. This cell line may have been genetically unstable, predisposing it to leukemic transformation. Alternatively, it may have been a truly leukemic line which became suppressed initially, but then proliferated. CFU-Gm grew normally in several children with a transient MPS, but did not grow in one patient with persistent leukemia. 7. 27, 29. 51 Further studies are necessary to see if colony assays are predictive of outcome.

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Patients with chromosomal abnormalities in addition to trisomy 21 need to be studied by colony assays to determine whether the normal CFU-Gm are normal trisomic cells which are becoming the dominant cell line or if cells which form these normal appearing colonies include those of the aberrant line. The latter would suggest that the abnormal clone is not leukemic and that the MPS is due to ineffective regulation of hematopoiesis. Until better predictors of outcome are available, children with this disorder should be supported as long as possible without the use of chemotherapy to see if the disorder will be transient.

MYELODYSPLASTIC SYNDROMES (PRELEUKEMIC SYNDROMES) Definition The myelodysplastic syndromes (MDS) are syndromes of ineffective hematopoiesis (peripheral cytopenias with hypercellular bone marrow) which precede the development of ANLL. Preleukemia is the commonly used term. Morphologic abnormalities suggestive of an abnormal differentiation process occur in at least one, and often multiple cell lines, particularly erythrocytes. A classification system based on the number of blasts in the periphery and marrow, peripheral blood monocytes and ringed sideroblasts was devised in 1982 by the French-American-British (FAB) group.9 Although five types of MDS are described (see Table 3), children appear to have either refractory anemia with an excess of blasts (RAE B), or RAEB in transition (RAEB t ). Both progress inexorably to ANLL. As the names suggest, the main feature is anemia and a hypercellular marrow with an excessive number of myeloblasts and promyelocytes. They are differentiated from each other and from ANLL by the numbers of peripheral and marrow blasts. Based on the observation of MDS in 6 of 37 children with ANLL, it has been suggested that an MDS precedes ANLL in children as often as in adults. 14 Biology The MDS are clonal disorders affecting cells of multiple hematopoietic lineage. Fifty to sixty percent of patients with MDS are reported to have detectable chromosomal abnormalities. 78 Deletions of chromosome 5 or 7 are most common in adults treated with cytotoxic chemotherapy or radiation as well as those with chemical, petroleum solvent, pesticide or industrial exposure. 41. 86 Trisomy 8 occurs relatively frequently. In children however, monosomy 7 is particularly frequent, occurring in 25 of 51 children in the literature. 108 Of the other 26, 16 had chromosome studies performed, 7 of whom had abnormalities. Colony forming assays have been utilized to evaluate patterns of cell growth, maturation and regulation. In RAEB and RAEB" CFU-Gm are usually decreased, with increased numbers of abortive clusters of myeloid cells exhibiting defective maturation similar to that found in leukemia. 88 BFU-E are often unable to proliferate 23 ,88 in these patients, 90 per cent of whom have anemia.

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Table 3. FAB Classification of the MDS BLASTS

Blood RA

RARS

CMML

RAEB

RAEB t

< 1%

Marrow

<5%

MORPHOLOGY

Blood

RBC-oval macrocytes reticulocytopenia PLT/PMN-rarely, decreased or dysplastic <1% <5% As in RA plus: RBC-basophilic stippling hypoand normochromic <5% Up to As in RA plus: 20% Monocytosis PMN -granulocytosis -Pelger-Huet -Hypogranular PLT-thrombocytopenia <5% 5-20% As in RA plus: Dysplasia/cytopenia of at least 2 cell lines PMN-Pelger Huet Hypogranular PLT-Abnormal size Hypogranular As per RAEB plus 1 of the following: >5% 20-30% Auer rods

Marrow

Erythroid hyperplasia Dyserythropoiesis

Erythroid hyperplasia Dyserythropoiesis 15% ringed sideroblasts Monocytic hyperplasia Erythroid hyperplasia

Granulocytic hyperplasia Erythroid hyperplasia Dyserythropoiesis Dysgranulocytopoiesis Dysmegakaryopoiesis

Auer rods

Abbreviations: RBC-red blood cells, PLT-platelets; PMN-polymorphonuclear leukocytes; RA-refractory anemia; RARS-refractory anemia with ringed sideroblasts; RAEB-refractory anemia with excess blasts; RAEBt-RAEB in transition; CMML-chronic myelomonocytic leukemia.

It is unclear whether the abnormal hematopoiesis reflects the growth pattern of the abnormal clone itself, or the effect of the abnormal clone on normal progenitor cells, perhaps mediated by inhibitors of hematopoiesis. A mixture of normal and abnormal cells may coexist for a prolonged period. 101 A proliferative abnormality which, in leukemia, results in the expansion of an abnormal clone at the expense of normal cells, may occur after a variable time period in the MOS. It is conjecture as to whether the cells apparent at the time of leukemic proliferation result from an acute karyotypic change of the dysplastic cells or from abnormal cells which slowly gain predominance over the normal ones.

Clinical Features Although adults may be asymptomatic, most children with pre-ANLL are symptomatic. Fever, pallor, hemorrhage, and infection are commonly seen. 14,89 Hepatosplenomegaly occurs frequently, particularly in monosomy 7.108 Monosomy 7, as it occurs in children, is characterized by onset at a young age (median 10 months), lymphadenopathy, and recurrent bacterial infections even when non-neutropenic, probably due to granulocyte dysfunction. 93 The classic laboratory features of the MOS in adults include anemia (90 per cent) and pancytopenia (50 per cent). Children with MOS in one study were found to present with a normocytic normochromic anemia.

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Macrocytosis and ovalocytosis appear later, followed by poikilocytosis and anisocytosis.1 4 The reticulocyte count is low, although nucleated RBC are seen. White cell abnormalities including Pelger-Huet abnormalities, hypersegmentation and hypogranularity occur, but are more subtle than RBC abnormalities. Platelets are occasionally hypogranular. Peripheral blasts may be seen at the time of nonleukemic marrow examinations. The bone marrow is hypercellular, reflecting ineffective erythropoiesis. Megaloblastoid changes are seen in erythroid precursors that may be multinucleated, as well as in myeloid cells. Megakaryocytes are increased in adult studies,60 although decreased numbers of megakaryocytes are reported in children. 14. 69 In five of six children, blasts were monocytoid or myelomonocytic, with Auer rods seen in two. These peripheral blood and marrow findings are indicative of aberrant differentiation (Fig. 3). Vitamin B12 levels were increased in six children tested. 14 Neutrophil abnormalities noted in adults include decreased leukocyte alkaline phosphatase, myeloperoxidase, chemotaxis, phagocytosis, and bactericidal activity.87 Decreased RBC enzyme activity (pyruvate kinase, 2,3-diphosphoglyceromutase), abnormal iron metabolism, increased fetal hemoglobin, and abnormal expression of RBC antigens occur. 32, 69, 105 Differential Diagnosis The unequivocal diagnosis of preleukemia must be retrospective. However, clues such as anemia and other cytopenias, peripheral blasts in the presence of a hypercellular marrow with dyserythropoiesis and abnormal cluster formation in in vitro colony assays are indicative of an MDS. Since children most often present with pancytopenia, the differential diagnosis of this must be considered (Table 4). In children, the diagnosis is complicated by the occurrence of two types of preleukemia, pre-ANLL or pre-acute lymphoblastic leukemia (ALL). Presenting symptoms are not specific. Marrow hypoplasia is more common in pre-ALL. Ineffective erythropoiesis and myelopoiesis may be seen in either, but ineffective megakaryopoiesis is limited to pre-ANLL. Morphologic abnormalities of all cell lines occur primarily in pre-ANLL. As is the situation with the overt leukemias, pre-ALL is seen throughout the childhood age range, whereas pre-ALL occurs most often in children aged 1 to 6. Males predominate in pre-ANLL while females predominate in pre-ALL. Karyotypic abnormalities are common in pre-ANLL but rare in pre-ALL. 89 Seven children with hematopoietic dysplasia were found upon review of 760 pediatric marrow samples performed during a lO-year period. 59 Six had constitutional abnormalities, including skin abnormalities (5), short stature (4), unusual facies (4), mental retardation (3), and endocrine abnormalities (2). An otherwise normal patient had a hydrocele. Four developed ANLL, two of whom had family histories of childhood leukemia. One died of hemorrhage. Another appeared to have Schwachman syndrome, which has been associated with hematopoietic dysplasia and progression to ANLL. 112 A kindred with hematopoietic dysplasia, monosomy 7, and cerebellar atrophy has also been described. 67 Other constitutional disorders with hematologic manifestations, including Kostmann's agranulocytosis,

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Figure 3. Myelodysplastic syndrome. A, Peripheral blood. A nucleated RBC (N), ovalocytosis and poikilocytosis reflect dyserythropoiesis. A Pelger-Huet (P) granulocyte is seen, as well as a myeloblast (B). B, Marrow aspirate. Same patient, dysgranulopoiesis is shown by abnormal sedimentation (s). A mitotic figure and increased numbers of myeloblasts are seen (B). Erythroid abnormalities include dyssynchronous maturation (d) and irregular nuclear budding (n). C, Marrow aspirate. Same patient. Two large cells with multilobulated nuclei are seen that appear to be abnormal megakaryocytes.

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Table 4. Differential Diagnosis of Pancytopenia A L L M I S S I N'

- aplastic anemia -leukemia - lupus and other collagen vascular disorders - myelodysplastic syndromes and pre leukemias - infiltrations (non-neoplastic): osteopetrosis, myelofibrosis - splenic enlargement - suppression by infection: virus, bacteria, TB - iatrogenic: chemotherapy, radiation, anticonvulsants - neoplasms (other): lymphoma. neuroblastoma, Ewings, rhabdomyosarcoma

Down's syndrome, Bloom's syndrome, Diamond-Blackfan syndrome, and Fanconi's anemia also have an increased incidence of leukemia. 57, 69 They do not have evidence of a clonal abnormality initially and therefore are not categorized as preleuk~mias. Patients with certain constitutional hematopoietic dysplasias may thus present similarly to children with the MOS. Prognosis Although MDS in adults can be indolent, with patients dying of unrelated causes, this is not true of children. Nineteen of 25 children with monosomy 7 progressed to ANLL, with 5 dying during a preleukemic phase. Twenty-three of 25 children with other MDS developed overt leukemia, with 3 dying in a preleukemic stage. lOS The median preleukemic phase in children is short, lasting 12 to 18 months. 89 The rapidity of disease progression in children necessitates consideration of treatment options beyond supportive care. Attempts to treat with aggressive chemotherapy has, in adults and children, been disappointing since periods of aplasia are prolonged, and responses limited. 75 Allogeneic bone marrow transplantation after conditioning with cyclophosphamide and total body irradiation has resulted in long-term survival in seven of nine patients. This should be considered the preferred therapy if an allogeneic donor is available. 28 Therapies which intend to cause differentiation of these abnormal cells, the so-called maturational therapies, include low-dose cytosine arabinoside (ara-C) (which may actually exert its effect via cytotoxic clonal suppression) and retinoic acid, and vitamin 0 3 , Review of studies of low-dose ara-C suggests that hematopoiesis may improve in some (-50 per cent) for 3 to 27 months, but hospital admission increased and overall survival did not improve significantly.43, 60 Retinoic acid has been shown to enhance CFUGm differentiation and increase BFU-E growth. Although the granulocyte count improved, transfusion requirements did not change. 82 In vitro data suggest that a combination of maturational (differentiation) therapies with agents that slow proliferation by inhibiting DNA synthesis may be synergistic. 37 The phase during which maturation agents are effective may be lengthened by slowing DNA synthesis. The two processes of hematopoiesis, proliferation and differentiation, must remain coupled in order to ensure production of normal blood cells. If leukemia is due to the abnormality in both of these processes, then the MPS and MDS may represent first steps in the two-step process of leukemogenesis. Study of these disorders, as models of leukemogenesis,

SYNDROMES PREDISPOSING TO LEUKEMIA

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may increase our understanding of leukemogenic processes and will perhaps enable us to affect the course of disease before leukemic transformation.

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