CHAPTER 92 MYELODYSPLASTIC DISORDERS (INDOLENT CLONAL MYELOID DISEASES AND OLIGOBLASTIC LEUKEMIA)
CHAPTER 92 MYELODYSPLASTIC DISORDERS (INDOLENT CLONAL MYELOID DISEASES AND OLIGOBLASTIC LEUKEMIA)
MARSHALL A. LICHTMAN
JAMES K. BRENNAN
Definition and History
Etiology and Pathogenesis
Incidence by Age, Sex, and Familial Occurrence
Symptoms and Signs
Special Clinical Features
Monosomy 7 Syndrome
Specific Clonal Myeloid Syndromes
Acquired Idiopathic Sideroblastic Anemia
Acquired Idiopathic Nonsideroblastic Anemia
Multilineal Cytopenia with Hypercellular Marrow
Uncommon Preleukemic Syndromes
Aplastic Anemia, Paroxysmal Nocturnal Hemoglobinuria, and Eosinophilic Fasciitis
Definition and History
Oligoblastic Leukemia (Refractory Anemia with Excess Myeloblasts)
Treatment, Course, and Prognosis
Stem Cell Transplantation
Course and Prognosis
Prodromal Syndromes Antedating Lymphocytic Leukemia
Indolent Clonal Myeloid Disorders or Oligoblastic (Myelogenous) Leukemia Preceding or Emerging in Lymphoid Malignancies other than Acute Lymphocytic Leukemia
In contrast to florid acute myelogenous leukemia, there are a group of neoplastic (clonal) myeloid disorders that range from non-progressive to more slowly progressive than AML. The disorders may appear in childhood, but the incidence increases exponentially after age 50 years, and most cases occur between 60 and 90 years of age. These disorders range from acquired idiopathic anemias with or without ringed sideroblasts to oligoblastic myelogenous leukemia. The diseases share a propensity to cytopenias and multilineage dysmorphogenesis of blood cells. Red cells often have striking poikilocytosis, anisocytosis, anisochromia, and stippling. The marrow usually contains increased erythroid precursors with dysmorphic features and nuclear and granular anomalies in neutrophils associated with increased granulocyte precursors. Giant or microcytic platelets, often with abnormal granulation, in the blood are associated with megakaryocytic hyperplasia and atypical lobulation and size of megakaryocytes in the marrow. In the nonprogressive syndromes, anemia is accompanied by only slight variations in neutrophil and platelet levels, and blast cells are not increased in the marrow. Clonal cytogenetic abnormalities occur, however. The syndromes may follow radiation or chemotherapy for another malignancy. In the more progressive syndromes, leukemic blast cells are increased, cytopenias are more severe, and the disease has high morbidity and mortality from infection and bleeding. In each of the syndromes, there is a propensity to evolve into frank AML ranging from about 10 percent in the idiopathic anemias to about 40 percent of patients with trilineage cytopenias and increased marrow blast cells. Mortality from infection also is a high risk in those with severe leukopenia. In the most indolent forms, therapy may not be required. Therapy with cytotoxic drugs, red cell or platelet transfusion, antibiotics, and hematopoietic cytokines may palliate the disease when it is progressive (oligoblastic leukemia). In young patients allogeneic stem cell transplantation may be very useful.
Acronyms and abbreviations that appear in this chapter include: ALIP, abnormal localized immature precursors; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; ATRA, all-trans retinoic acid; CFU-BL, blast cell progenitors; CFU-GM, colony-forming units for granulocytes and monocytes; GM-CSF, granulocyte-macrophage colony-stimulating factor; IRF-1, interferon regulatory factor 1; LE, lupus erythematosus; M-CSF, monocyte colony-stimulating factor; MCV, mean cell volume; NF1, neurofibromatosis; RAEB, refractory anemia with excess blasts; RAEM, refractory anemia with excess myeloblasts; SCF, stem cell factor; WT1, Wilm’s tumor.
DEFINITION AND HISTORY
Myelodysplasia is a term used to encompass a spectrum of clonal (neoplastic) myeloid disorders marked by ineffective hematopoiesis, cytopenias, qualitative disorders of blood cells and their precursors, and a variable predilection to undergo clonal evolution to florid AML. The disorders range from relatively indolent idiopathic anemias, with a relatively lower frequency of progression to AML, to more troublesome clonal multilineage cytopenias, to oligoblastic myelogenous leukemias that often progress into overt AML. The somatic mutation that leads to these disorders arises in a multipotential hematopoietic cell. Dysplasia is a term that classically implies a polyclonal and, therefore, nonneoplastic process. The choice of the term myelodysplasia to denote clonal (neoplastic) disorders is unfortunate because it is hard for students and patients to understand its relationship to other clonal stem cell disorders such as idiopathic myelofibrosis that can have all the features of “myelodysplasia” but are ignored in its classification. Moreover, drawing diagnostic distinctions among 10, 20, and 30 percent leukemic blast cells is inconsistent with the biological behavior of cancer and medicine’s classification of cancer. The term myelodysplasia is, however, widely used.1,2 and 3
The term indolent clonal myeloid disease, or hemopathy, refers to neoplasias arising in a multipotential hematopoietic marrow cell that result in diseases with no discernible leukemic blast cells in the marrow or blood (e.g., acquired idiopathic anemias) or in oligoblastic leukemia in which an increased number of (leukemic) blast cells is present in the marrow but in which, untreated, the course is smoldering or subacute in contrast to AML.
The boundary between acquired idiopathic anemia and oligoblastic myelogenous leukemia may be indistinct because of the insensitivity of the marrow examination; however, continued observation clarifies the situation. If leukemic blast cells are evident in marrow, the diagnosis of oligoblastic leukemia can be made, maintaining the principle that the histopathologic diagnosis should depend on the presence or absence of tumor cells, not the rate of progression or severity of the manifestations of the malignancy. The proportion of marrow myeloblasts is not increased in reactive states, for example, granulocytic hyperplasia as a result of infection, noninfectious inflammation, solid tumors, and drug-induced granulocytosis (e.g., glucocorticoids, lithium). Indeed, the proportion of blasts usually falls to less than the normal value of 1.0 ± 0.4 SD percent. It is rare to have more than 2.0 percent myeloblasts in a normal marrow in older children and adults, and higher proportions, for example, over 3 percent, are virtually confined to cases of oligoblastic leukemia. The one exception to this rule is that some patients treated with granulocytic growth factors may have a slight increase in blast cells.
The clonal proliferation of multipotential hemopoietic cells is accompanied by variable effects on all blood cell lineages and is usually associated with pathologically enhanced apoptosis of marrow precursor cells such that leukopenia and thrombocytopenia of varying severity often accompany the anemia. Qualitative abnormalities of cell shape, organelle structure, biochemical pathways, and function can occur. The range of clinical expression is broad. Thus, clonal myeloid hemopathies can occur with isolated anemia and a nearly normal-appearing marrow or with severe pancytopenia, profoundly hypercellular marrow, and alterations in blood cell shape, size, and function. The more profound the disorder, the more likely oligoblastic leukemia will be discovered on marrow examination. Since leukemic blast cells may not be evident and some patients with clonal hemopathies do not develop overt leukemia (although their risk is several-thousand-fold that of unaffected individuals), the designation myelodysplasia has been applied. The choice of the term was intended to highlight the striking dysmorphic appearance of blood and marrow cells neglecting the central alteration, neoplasia. As currently used, myelodysplasia encompasses syndromes that are frankly leukemic, such as so-called refractory anemia with excess blasts.4 Indeed, many of the affected individuals have myelogenous leukemia that is more indolent (smoldering) than overt AML.
At the beginning of the twentieth century, reports of highly morbid cytopenic disorders, refractory to treatment, began to appear in the medical literature.3 Chevallier and colleagues, in 1942, discussed formally the “odo-leukemia.”5 They chose the Greek word odo, meaning threshold, to highlight disorders that are on the threshold of leukemia. Chevallier proposed leucoses as the generic term for leukemias so that marked variations in white cell counts and other presenting features would not engender inappropriate terminology. It was a sage but neglected proposal.
In 1949, Hamilton-Paterson used the term preleukemic anemia to describe patients with refractory anemia antecedent to the development of AML,6 and in 1953, Block and coworkers expanded the concept to include cytopenias of all lineages and described cases that closely fit with our current concepts of a clonal myeloid hemopathy prior to the evolution to overt AML.7 Thus, by midcentury, the relationship of acquired idiopathic cytopenias to the subsequent onset of AML had become broadly appreciated.8,9,10,11,12,13,14 and 15 Terms such as herald state of leukemia, refractory anemia, sideroachrestic anemia, idiopathic refractory sideroblastic anemia, pancytopenia with hyperplastic marrow, and others were coined to describe the various manifestations of the hematopoietic derangement that preceded the onset of AML.
In 1975, at a conference on unclassifiable leukemias held in Paris, Marcel Bessis, Jean Bernard, and others suggested the term hemopoietic dysplasia, later shortened to myelodysplasia for the group of disorders that had a more indolent course than AML.16,365
One classification scheme,2 which is now undergoing change, separates myelodysplastic syndrome arising de novo into several subsets: refractory anemia (with other cytopenias implied), refractory anemia with ringed sideroblasts (with other cytopenias implied), and refractory anemia with excess blasts (smoldering myelogenous leukemia).2 Chronic myelomonocytic leukemia, although proposed as a myelodysplastic syndrome, can also be included among the chronic myelogenous leukemias17 (see Chap. 94). The designation refractory anemia with excess blasts in transformation has been dropped, since it conveys no additional diagnostic or prognostic information. The myelodysplastic syndromes include entities that have marrow blast percentages ranging from less than 2 percent in refractory anemia to over 20 percent in refractory anemia with excess blasts.2 This approach is unfortunate, since in no other neoplasms is the designation of the cancer, in this case myelogenous leukemia, called by another name when there is more or less of the tumor cells present. Thus, myelogenous leukemia, not refractory anemia, is the name of the tumor whether the marrow has 8 percent or 80 percent blast cells. The arrest in myeloid development is a major component of pathogenesis, not just ineffective hematopoiesis and dysmorphogenesis.
ETIOLOGY AND PATHOGENESIS
There are, not unexpectedly, close similarities to AML in etiologic factors. Benzene,18,19,20 and 21 chemotherapeutic agents,363,364 particularly alkylating agents and topoisomerase inhibitors,21,22,23,24,25,26,27,28 and 29 and radiation30 are exposures that can increase the risk of these indolent clonal hemopathies. These exposures may cause DNA damage, impair DNA repair enzymes, and induce loss of chromosome integrity. Diseases such as Fanconi anemia, known to predispose to the development of AML, occasionally can evolve instead into a clonal myeloid hemopathy.31,32
Aging is an important factor in the development of clonal myeloid disorders. They increase exponentially in frequency after the age of 40 years.33,34
These disorders arise from the clonal expansion of a multipotential hematopoietic cell. The clonal origin is supported by studies of women who were heterozygotes for glucose-6-phosphate dehydrogenase isoenzymes A and B and who had such a syndrome. The hematopoietic progenitors35,36 and in some cases lymphocytes37,38 of such patients had only one isoenzyme present, supporting the concept of clonal expansion of a neoplastic marrow cell.39 Clonal studies using X-linked restriction length polymorphisms with probes for hypoxanthine phosphoribosyl transferase or phosphoglycerate kinase also supported the origin of these disorders in a single multipotential stem cell.40,41 and 42
Fluorescent in situ hybridization of interphase blood cell populations with probes for chromosomes 7 or 8 in patients with monosomy 7 or trisomy 8 indicates that chromosome abnormalities may not be present in lymphoid populations.42,43 Studies of immunoglobulin heavy-chain gene rearrangement and assay of the human androgen receptor and other genes on the X chromosome have also concluded that lymphocytes are not derived from the neoplastic clone.44,45 and 46 However, pseudodiploidy has been observed in the Epstein-Barr virus-stimulated cell populations of two patients with idiopathic refractory sideroblastic anemia,47 suggesting that B lymphocytes may be derived from the affected stem cell in some patients.
Molecular genetic studies of patients cells show identifiable gene mutations in about 60 percent. Mutated RAS is most common48,49,50,51,52 and 53; lower frequencies of FMS and p53 mutations are present. Codon 12 of RAS and codon 969 of FMS are the predominant sites of alteration in the respective genes.54,55 Methylation of p15, an inhibitor of cyclin-dependent kinases 4 and 6, was present in over one-third of patients examined.56 A variety of other mutations in protooncogenes, or genes encoding proteins involved in the cell cycle, or of transcription factors have been described sporadically.54,55 Interpretation of these molecular studies is difficult because the mutations are present in advanced disease patients and may be late changes, not seminal in the neoplastic transformation.
The major specific pathophysiologic mechanism in the clonal hemopathies with cytopenias is ineffective hemopoiesis, that is, defective maturation of marrow precursor cells.57 The specific characteristics of ineffective erythropoiesis and granulopoiesis include a decreased proportion of cells in the DNA synthesis phase of the mitotic cycle and a marked increased in the fraction of late precursor cells undergoing apoptosis.58,59 and 60 Increased levels of apoptotic mediators are present in cells including TNF-a, FAS antigen, and calcium-dependent nuclease activity. Characteristic stepwise degradation of DNA is evident in late precursors.61,62 and 63 The proliferation of progenitor and early precursor cells is usually normal or enhanced, resulting in a hypercellular marrow, but there is a failure to accumulate adequate numbers of mature cells. Mild shortening of cell life-span also contributes to the cytopenias.9 As the phenotype of the disease evolves toward myelogenous leukemia, proliferative patterns supersede ineffective hematopoeisis as a result of precursor apoptosis.64 Once the marrow blast percentage is unequivocally above normal (>3 percent) the disease process represents oligoblastic leukemia.
INCIDENCE BY AGE, SEX, AND FAMILIAL OCCURRENCE
The onset of the disease before age 50 years is uncommon except in cases preceded by irradiation or chemotherapy.33,34,65 Myelodysplasia can occur in children aged 5 months to 15 years at a rate of about 0.5 per million,66,67,68 and 69,360 and about half of such cases are oligoblastic leukemia. The incidence increases logarithmically after age 40 years to over 20 per 100,000 in septuagenarians.361 Males are affected about 1.5 to 2.0 times as often as females. Families with an unusually high frequency of clonal myeloid disorders has been described.70,71,362
SYMPTOMS AND SIGNS
Patients can be asymptomatic or, if anemia is more severe, can have pallor, weakness, loss of a sense of well-being, and exertional dyspnea.14,72,73 A small proportion of patients have infections related to granulocytopenia or hemorrhage related to thrombocytopenia at the time of diagnosis, but patients with severe depressions of neutrophil and platelet counts at diagnosis usually have oligoblastic leukemia. Rarely, patients can have fever unrelated to infection.74 Arthralgias are the initial complaint in some patients.75 Very rarely, the presentation may mimic a connective tissue disease.76,77 Hepatomegaly or splenomegaly occurs in about 5 or 10 percent of patients, respectively.
SPECIAL CLINICAL FEATURES
Patients with an indolent phase (smoldering myelogenous leukemia) prior to overt AML may develop diabetes insipidus. Hypothalamic involvement can lead to polyuria, polydipsia, and decreased libido. Hypothalamic-posterior hypophysis insufficiency in clonal myeloid states has been associated with monosomy 7 in hematopoietic cells.78,79 and 80
Acute neutrophilic dermatosis (Sweet disease) is an acute febrile illness with erythematous patches on arms, face, and legs that progress to painful brown plaques that may ulcerate and produce large necrotizing skin lesions. The histopathology of the skin is that of a dense dermal neutrophilic infiltrate.81 This syndrome, which occurs principally in middle-aged women, lasts for 6 to 10 weeks, is often associated with blood neutrophilia, and may recur.82 At least 10 percent of patients with Sweet disease develop AML or another clonal myeloid disease, and occasional cases have been associated with monocytosis or cytogenic abnormalities in marrow cells prior to onset of AML. G-CSF and all-trans retinoic acid (ATRA) administration has been followed by Sweet disease in some cases.83,84 Other dermatopathic conditions also have been associated with clonal myeloid diseases.85
A symptom complex that mimics systemic lupus erythematosus (fever, pleurisy, symmetric arthritis, plasma antinuclear antibody, and pancytopenia with a hyperplastic marrow) may precede AML.76 Several patients with signs of lupus erythematosus (LE) and the LE cell phenomenon have been reported in a review of the clonal hemopathic syndromes.86 Behcet’s disease, glomerulonephritis, seronegative arthritis, and inflammatory bowel disease also have been associated with clonal myeloid disorders.87,88,89 and 90
The incidence of other cancers may be increased in subjects with clonal myeloid disorders.96,97,98 and 99
Anemia is present in over 85 percent of patients.12,13,14 and 15,72 The mean cell volume (MCV) often is increased.13,14 Red cell shape abnormalities may include oval, elliptical, teardrop, spherical, or fragmented cells. There is a spectrum of red cell findings. Some patients have only slight anisocytosis. Elliptical red cells sometimes dominate. Basophilic stippling of red cells occurs. Nucleated red cells are seen in the blood film in about 10 percent of cases. Reticulocyte counts are usually low for the degree of anemia. Other abnormalities of red cells also occur, such as an increased proportion of hemoglobin F,95 decreased red cell enzyme activities, especially acquired pyruvate kinase deficiency.96 In some cases with pyruvate kinase deficiency, hemolysis has occurred. An enhanced sensitivity of membranes to complement,97 and modification of red cell blood group antigens may be observed.98,99 Acquired hemoglobin H disease results in red cell morphology similar to thalassemia (microcytosis, basophilic stippling, target cells, and teardrop cells). Intracellular precipitates of b-chain tetramers (identified by crystal violet stain) reflect an acquired decrease in the rate of a-chain synthesis in erythroblasts.100,101 The decrease in a-globin chain synthesis is profound, involves each of the four a-chain loci, and results from a transcription abnormality. There are no gross alterations in genes (e.g., insertions, deletions) in these cases.111
GRANULOCYTES AND MONOCYTES
Neutropenia is present in about 50 percent of patients at the time of diagnosis.65 The proportion of monocytes often is increased, and monocytosis per se can be the dominant manifestation of the hematopoietic abnormality for months or years.102,103 and 104 Morphologic abnormalities of neutrophils can occur, sometimes resulting in the acquired Pelger-Huët anomaly. In this condition, the neutrophils have very condensed chromatin and unilobed or bilobed nuclei that often have a pince-nez shape.105 Ring-shaped nuclei also occur in neutrophils.106 Neutrophil alkaline phosphatase activity is decreased in some patients.14 Expression of normal surface antigens on neutrophils and monocytes is decreased, and in some cases abnormal surface antigen expression may occur.107 Defective primary granules of abnormal size and shape with decreased myeloperoxidase content can be present,108 and specific neutrophil granules can be decreased in number, producing hypogranular cells.109 Neutrophil granule membranes frequently are deficient in glycoprotein.110 Chemotactic, phagocytic, and bactericidal capability may be impaired.111,112 and 113 Formyl-leucyl-methionyl-phenylamine receptor signaling and actin polymerization have been abnormal.114,115 Muramidase (lysozyme) activity in blood and urine may be increased, a reflection of granulocytic hyperplasia and heightened monocytopoiesis and monocyte turnover.
About 25 percent of patients may have mild to moderate thrombocytopenia at the time of diagnosis.14,65 Mild thrombocytosis also can occur.14,65 Platelets may be abnormally large, have poor granulation, or have large, fused central granules.116,117 Abnormal platelet function may contribute to a prolonged bleeding time, easy bruising, or exaggerated bleeding. Decreased platelet aggregation in response to collagen or epinephrine is a frequent functional abnormality.118
Patients with clonal hemopathies may have immunologic deficiencies, such as a decrease in natural killer cells in the blood but no decrease in large granular lymphocytes,119,120,121 and 122 a decrease in helper T lymphocytes,120 and a decrease in Epstein-Barr virus receptors on B lymphocytes.120,121,122 and 123 Antibody-dependent cellular cytotoxicity is normal.120 Thymidine incorporation after mitogenic stimulation124,125 and colony growth of T lymphocytes are decreased.138 Lymphocytes may have an increased sensitivity to irradiation.124 The defects in lymphoid cells could reflect the site of the somatic mutation in the pluripotential stem cell in some cases36,37 and 38,40,41 (see “Pathogenesis”).
Serum iron, transferrin, and ferritin levels may be elevated. Lactic dehydrogenase and uric acid concentrations can be increased as a result of ineffective hemopoiesis and a high death fraction of maturing marrow precursors. Monoclonal gammopathy, polyclonal hypergammaglobulinemia, and hypogammaglobulinemia each occur with an increased frequency.126,127 The frequency of autoantibodies was increased in one report127 but not in another.126
Marrow cellularity is usually normal or increased.128,129 and 130 Occasionally, it may be decreased and may simulate hypoplastic anemia or aplastic anemia,131 although islands of dysmorphic cells are usually present, especially atypical megakaryocytes. An increase in blast cells in this setting suggest hypoplastic myelogenous leukemia (see Chap. 93).
Erythroid hyperplasia is frequent, and very large or small erythroblasts, nuclear fragmentation, stippled erythroblasts, and poor hemoglobinization may be seen.13,14,132 Proerythroblasts may be in excess, and the marrow may lack normal clusters or islets of erythroblasts. Erythroblasts may resemble megaloblasts that have nuclear-cytoplasmic maturation asynchrony, nuclear fragmentation, or cytoplasmic nuclear remnants. This pattern is referred to as megaloblastoid erythropoiesis.
Pathologic sideroblasts may be identified when the marrow is treated with Prussian blue stain. These include erythroblasts with an increased number and size of siderosomes (cytoplasmic ferritin–containing vacuoles), referred to as intermediate sideroblasts, or erythroblasts with mitochondrial iron aggregates that take the form of a partial or complete circumnuclear ring of iron globules, referred to as ringed sideroblasts. Macrophage iron often is increased. Some observers believe that ringed sideroblasts are associated with progression to leukemia less often than are sideroblasts with increases in cytoplasmic ferritin.133,134 Others dispute this conclusion.135 Ringed sideroblasts, as compared with intermediate sideroblasts, are very uncommon or present only in very low proportions (less than 15 percent) in any clonal myeloid syndrome other than acquired refractory sideroblastic anemia.
Granulocytic hyperplasia is frequent.13,14,128,129 and 130 Marrow monocytes also may be increased in number. Abnormalities of granulocytes include hypogranulation, a monocytoid appearance of neutrophilic granulocytes, and the acquired Pelger-Huët nuclear abnormality of neutrophils. Progranulocytes and myelocytes may be increased. As stated previously, the proportion of blast cells is not increased in clonal hemopathies that are categorized as acquired sideroblastic or nonsideroblastic idiopathic anemia. The latter are syndromes with no increase in blast cells (i.e., less than 2 percent); if the blast percentage is above this level the patient can be considered to have oligoblastic leukemia. Marrow biopsy may show abnormal localized immature precursors (ALIP),135,136 which are clusters of immature myeloid (? blast) cells located centrally rather than subjacent to the endosteum. These clusters of atypical cells are present in virtually all cases of oligoblastic leukemia where blast cells comprise 3 percent or more of nucleated marrow cells (refractory anemia with excess blasts) and in nearly half the patients with refractory anemia, sideroblastic or nonsideroblastic, suggesting that about half these patients have a disorder closely approaching oligoblastic leukemia. Patients with this abnormality are more prone to develop overt AML.135 The number of plasma cells may be slightly increased.
Megakaryocytes are present in normal or increased numbers.13,14,128,129 and 130 Micromegakaryocytes (dwarf megakaryocytes) may occur.128,129 and 130,137,138 Megakaryocytes with unilobed or bilobed nuclei may be increased, and hypersegmented and hyposegmented megakaryocytes may be present. Clusters of megakaryocytes may be seen. Megakaryocytes may be distributed laterally from their usual parasinusoidal location.139
An increase in reticulin and collagen fibers of varying degree is common—especially in oligoblastic leukemias. When fibrosis is prominent, the disorder can resemble primary myelofibrosis, although, in contrast to the latter, splenomegaly is usually not marked. Since idiopathic myelofibrosis is an oligoblastic leukemia with striking dysmorphogenesis of cells, some overlap with other fibrotic clonal myeloid disorders is expected.140
The morphologic aberrations (dysmorphogenesis) of blood cells seen in indolent clonal hemopathies can be seen in oligoblastic myelogenous leukemia as well, contributing to the decision to group them together.
The clonal growth of marrow progenitors in soft agar or other viscous culture systems is usually abnormal in patients with clonal hemopathies.141 Most reports indicate that growth of multipotential (CFU-GEMM) and erythroid progenitors (BFU-E, CFU-E) in the blood or marrow is markedly decreased in subjects with clonal myeloid disorders.141,142,143 and 144 Biochemical abnormalities of erythroid precursors have been found also. Colony-forming units for granulocytes and monocytes (CFU-GM) are decreased.140,142 Very small colonies or clusters with impaired maturation often dominate the cultures. Abnormally small and infrequent CFU-GM may be found when blood neutrophil and monocyte counts are nearly normal. Occasionally, overabundant growth is present. Usually, cell culture results become more abnormal as the blood cell abnormalities in the patient worsen.
In overt AML, CFU-GM growth is usually absent. Some studies indicate that very abnormal growth of progenitors in culture (decreased colonies or predominance of small clusters) is a poor prognostic sign and may be a harbinger of overt leukemia.145,146 Growth that does occur in clonal myeloid hemopathies (and AML) usually remains dependent on growth factors such as erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF).147,148 Colony growth in children with the monosomy 7 syndrome may occur without added growth factors supporting the view that there is autocrine and paracrine stimulation of progenitor cells.149,150,151 and 152 Blast cell progenitors (CFU-BL) may be increased in patients with oligoblastic leukemia.150 The long-term marrow initiating cell is decreased in some patients,151,152 and the ability of marrow stromal layers to support in vitro hematopoiesis can be impaired.152
Circulating M-CSF (CSF-1) has been increased in some patients, as well as in AML and other hematologic malignancies, for no clear reason.154 Interleukin-1a (IL-1a) and GM-CSF levels have been undetectable in most patients; IL-6, G-CSF, and erythropoietin concentrations have been variable; and tumor necrosis factor has been inversely related to hematocrit.155 Stem cell factor (SCF), a multilineage hematopoietin, has been decreased in some patients.156 FLT-3 ligand, another multilineage growth factor, is increased in patients with indolent clonal hemopathies but not oligoblastic leukemia.157 The inverse relationship between platelet count and thrombopoietin levels is maintained in acquired idiopathic anemia but not oligoblastic leukemia.158
An altered number or form of chromosomes may occur in up to 80 percent of patients with clonal hemopathies, depending on the severity of the syndrome.159,160,161,162 and 163 The chromosome abnormalities are nonrandom and often involve chromosomes that are abnormal in patients with AML, although certain chromosomal rearrangements seen in AML such as t(15;17), t(8;21), and inv16 are usually not observed except in oligoblastic leukemias161,162,163 and 164 (see Chap. 10).
Chromosomal abnormalities involving virtually every chromosome have been noted in marrow cells.170,171,172,173,174,175,176,177 and 178,366,367 Common abnormalities include an extra chromosome 8; loss of the long arm of the chromosome 5, 7, 9, 20, or 21; and monosomy for chromosomes 7 and 9. Losses of part or all of chromosomes 5 and 7 and complex chromosome abberations are particularly common in the oligoblastic myelogenous leukemias (and the overt leukemias) associated with prior treatment with cytotoxic drugs, radiation, or exposure to benzene.161,162,163,164,165,166 and 167 The Ph chromosome t(9q+;22q) and numerous other occasional chromosome abnormalities have been described in patients with indolent clonal hemopathies.193,194
The proportion of cases with chromosome abnormalities is different depending on the severity of the clinical manifestations. Chromosome abnormalities are more frequent in patients with refractory anemia with excess blasts (oligoblastic leukemia) than in those with acquired idiopathic anemia. In general, prevalence of chromosome abnormalities and the likelihood of progression to overt AML are both a function of the number of cell lines involved, the severity of the cytopenias, and the proportion of blast cells present.
Patients with the 5q-syndrome have refractory anemia and dysmorphic cells in the marrow containing a deletion in the long arm of chromosome 5 (5q-).168,169,170 and 171 The refractory anemia, observed most frequently in older women, is associated with marked dyserythropoiesis, erythroid multinuclearity, and hypolobulated and frequently small (“dwarf”) megakaryocytes. The syndrome can occur in children.171
The critical regions have been mapped to bands 5q31 to 5q33 with the proximal deletion associated with the spontaneous mutation and the distal region with the posttherapy-related event.169,170 and 171 The genes that encode for the multipotential growth factor IL-3168; for the bipotential growth factor for granulocytes and monocytes, GM-CSF172; and IL-4, -5, and -9 are located on the portion of chromosome 5 that is deleted in the 5q-syndrome. Gene mapping studies indicate that the IL-3/GM-CSF and IL-4/IL-5 gene clusters are proximal to and excluded from the rearranged region (5q31) associated with myeloid leukemias.173 The monocyte colony-stimulating factor, M-CSF (CSF-1) gene, previously thought to be on chromosome 5, has been relocated to chromosome 1174 but the FMS gene, encoding the receptor for M-CSF (CSF-1), is on the long arm of chromosome 5 in the region deleted in the 5q-syndrome.175,176 The genes for three additional growth factors, IL-1, platelet-derived growth factor, and endothelial cell growth factor, are also on chromosome 5168 but not on the segment deleted in the 5q-syndrome. The pathogenetic role of the genes deleted in this syndrome is not known, since only a single allele is involved, and unaffected cells (e.g., T lymphocytes, fibroblasts, endothelial cells) also may produce identical growth factors.
A number of other growth-related genes such as the EGR, CDC25C, and interferon regulatory genes also are located on 5q.168,177,178,179 and 180 A tumor suppressor gene might be located at 5q31, the smallest commonly deleted segment in 5q-syndrome. The interferon regulatory factor-1 (IRF-1) gene, encoding a DNA-binding protein that binds to a promoter element for IFN-a, IFN-b, and other IFN-inducible genes, also has been localized to 5q31. Rearrangements of this gene have been found in some patients with oligoblastic and overt myelogenous leukemia and 5q-.177,178,179,180 and 181 The action of IRF-1 is antagonized by IRF-2, and imbalanced expression of IRF-1 relative to that of IRF-2 activity could predispose to neoplastic transformation. The associated proximal break points at 5q12 to 15, sometimes seen in the relatively benign 5q-syndrome, may be associated with preservation of granulocyte and platelet counts and reduced infection and bleeding complications. Patients with this disorder have a risk of developing AML that is similar (about 15 percent) to that of patients with refractory anemia and marrow cells without 5q-.
MONOSOMY 7 SYNDROME
Monosomy 7 is the second most frequent cytogenetic abnormality in the marrow cells of patients with myelodysplasia. It often occurs in marrow cells of subjects exposed to chemicals or radiation and is associated with a poor prognosis and rapid transformation to AML.184,185 A critical region may reside in bands 7q35–36.186 Monosomy 7 syndromes, aside from being difficult to classify, usually are not associated with special clinical features in adults, although in children they are characterized by an atypical myeloproliferative disorder or myelomonocytic leukemia with abnormal expression of the neurofibromatosis (NF1) and Wilm’s tumor (WT1) genes, unusual susceptibility to infection, and a rapid termination in acute leukemia66,184,185,186 and 187 (see Chap. 93). Monosomy 7 also occurs in a familial form and during leukemic evolution of Down syndrome and Fanconi anemia.188,189 A variant of the monosomy 7 syndrome, translocation 1;7, also is seen in adults and children and may be preceded by exposure to cytotoxic treatment.190,191 The ERB-B gene, which encodes a shortened form of the epidermal growth factor receptor, is amplified in this syndrome.192
SPECIFIC CLONAL MYELOID SYNDROMES
These syndromes highlight the variability in expression of the clonal hemopathies (Table 92-1). Most patients have one of the syndromes described below.
TABLE 92-1 PRODROMAL AND OLIGOBLASTIC (LOW-INFILTRATE) MYELOGENOUS LEUKEMIA
ACQUIRED IDIOPATHIC SIDEROBLASTIC ANEMIA
The term refractory anemia has been used to define erythropoietic insufficiencies that cannot be assigned to a specific vitamin or mineral deficiency and thus are unresponsive to the known hematinics. In 1956, Bjorkman defined a subset of refractory anemias by the presence of ringed sideroblasts in the marrow.195 The intramitochondrial location of the iron in the ringed sideroblasts was described a year later.196
The disorder is a multipotential stem cell defect in which ineffective erythropoiesis with normal or slightly shortened red cell survival and only slight impairment of the maturation of other cell lineages occurs.197,198,199 and 200 The plasma iron turnover is increased, but incorporation of radioactive iron into heme and its delivery to blood as newly synthesized hemoglobin are depressed.197 Impairment of heme biosynthesis results in mitochondrial iron overload, which may inhibit mitochondrial function and contribute to the premature destruction of marrow erythroid precursors.200 Missense mutations in the gene encoding delta-aminolevulinate synthetase,201 or in a mitochondrial transfer RNA,202 and in red cell 5-aminolevulinic acid synthetase (205C) have been described, but a common gene alteration has not been correlated with this disease.
The disease is very uncommon under age 5033,203,204 and 205 except in patients in whom it occurs as a result of radiotherapy or chemotherapy of a malignant tumor.206 Males and females are affected almost equally. A rare concurrence of familial sideroblastic anemia has been reported.207 The signs and symptoms are those of anemia: pallor, easy fatigue, weakness, and dyspnea and palpitations on exertion.199,204 Most patients have the anemia detected as a result of blood cell analysis for other medical reasons. The liver may be slightly enlarged. The spleen is slightly increased in size in about 5 percent of patients. Splenic and hepatic enlargement do not necessarily occur together, and more than slight enlargement is unusual.
Most patients have mild to severe macrocytic anemia.199,204 The blood film often contains a population of hypochromic cells (dimorphic red cell changes).198,199,204,205 Red cell anisocytosis, basophilic stippling, and slight poikilocytosis may be present. The total white cell count and platelet count are usually normal, but mild abnormalities may be seen, including a decreased white cell count and an increased or decreased platelet count. Occasionally, the white cell count or platelet count may be increased markedly, or nucleated red cells may be present in the blood film. The reticulocyte percentage is usually between 0.5 and 2.0. Hemoglobin F concentration may be increased slightly.
Marrow cellularity usually is increased as a result of erythroid hyperplasia. Evidence of dyserythropoiesis in the form of vacuolated, small, large, or binucleate erythroblasts may be present. Prussian blue stain of the marrow invariably shows pathological sideroblasts. The latter may have Prussian blue–positive cytoplasmic granules in a partial or complete circumnuclear pattern (ringed sideroblasts) in 15 percent or more of cells or an increased number (more than 5) of Prussian blue–positive granules in their cytoplasm. If the disease progresses to oligoblastic leukemia, sideroblasts may become less prominent.208 Granulopoiesis and thrombopoiesis are not altered significantly in two-thirds of patients.205 In the other third, dysgranulopoiesis (hypogranulation, acquired Pelger-Huët anomaly, hypersegmented nuclei, or granule abnormalities) or dysmegakaryocytopoiesis (micromegakaryocytes, large lobulated cells) may be present. Marrow iron stores are increased often.
Cytogenetic abnormalities in marrow cells of patients with acquired refractory sideroblastic anemia provide evidence for the clonal character of the disease. About half of the reported cases with sideroblastic anemia in which cytogenetic studies have been performed have a chromosomal abnormality.204 Involvement of chromosomes 8, 11, and 20 has been notable159,160,161 and 162,209,210 and 211; the Philadelphia chromosome has been reported212; involvement of chromosome 3 has been associated with thrombocytosis.213 The absence of the Y chromosome, only in the pathological sideroblasts in one report (45;X/46;XY mosaic), substantiates the dimorphic nature of the erythroid lineage involvement and parallels the hypochromic and normochromic red cell populations.214 Involvement of the X chromosome (a breakpoint at Xq13) of female patients with sideroblastic anemia215,216 is of note because a type of hereditary sideroblastic anemia is X chromosome–linked (see Chap. 63).
Serum iron levels and saturation of transferrin are increased. Serum ferritin concentration is increased, reflecting an increase in body iron stores. Bilirubin-proteinate levels (indirect-reacting fraction) may be increased as a result of ineffective erythropoiesis and intramedullary hemolysis.
The principal considerations are those anemias with an inadequate reticulocyte response in which erythrocytes are hypochromic. Iron deficiency anemia in contradistinction to sideroblastic anemia is associated with low serum iron levels, saturation of transferrin of less than 16 percent, low serum ferritin concentration, elevated serum transferrin receptors, and absent marrow sideroblasts and macrophage iron. Beta thalassemia minor is characterized by normal to elevated serum iron and ferritin, a low mean red cell volume, elevated hemoglobin A2 concentration, and evidence of the disease in a parent, siblings, or offsprings. Detection of secondary forms of sideroblastic anemia requires evaluation for exposure to lead or other agents or diseases listed in Chap. 63, as do the hereditary sideroblastic anemias.
Some patients do not require treatment, since the moderate decrease in hemoglobin concentration is tolerated without limitation of usual activities. Occasional patients who have low serum and red cell folate concentrations may have partial improvement in blood hemoglobin concentration after the administration of folic acid (1 mg/day, orally). Rare patients may benefit temporarily from pharmacological doses of pyridoxine (200 mg/day, orally for at least 3 months) or danazol.217 A therapeutic trial with folic acid and pyridoxine is worthwhile if the anemia is symptomatic, even though only a small percentage of patients are responsive. If anemia is severe or symptoms of heart failure or coronary insufficiency are present, periodic transfusion of red cells is required. Recombinant human erythropoietin generally is not useful unless the pretreatment serum erythropoietin level is below 200 milliunits per ml, an infrequent finding in these patients.218 The combination of G-CSF with erythropoietin may increase the response rate to over 40 percent.219 Erythropoietin, 20,000 to 40,000 units subcutaneously, once a week coupled with G-CSF, 300 µg subcutaneously, two or three times per week, is one regimen that can be used if the cytopenias are not tolerated.
COURSE AND PROGNOSIS
In many patients the disorder lasts for years without progression of the anemia or symptoms. A small proportion of patients may have progressive marrow failure, severe cytopenia, and morbidity from infections or hemorrhage. Iron overload is common, and some patients may develop hemochromatosis.220 The frequency of HLA-A3 is significantly higher in patients who develop iron overload than in the general population. The frequency is comparable to that found in hereditary hemochromatosis,221 suggesting that the combination of a genetic predisposition plus sideroblastic anemia facilitates the expression of iron overload in these patients. Evidence in support of this linkage has not been found after search for mutations associated with hemochromatosis.222 The appearance of hemochromatosis may be accelerated if frequent transfusions have been required for a period of years.220 Improvement of the anemia and the adverse effects of iron overload in parenchymal tissues can occur following cautious phlebotomy or chelation therapy.223,224 and 225
Over a 10- to 15-year period about 10 percent of patients with acquired refractory sideroblastic anemia will develop AML.220,226,227,228 and 229 The progression to leukemia is correlated with the degree of dyshematopoiesis and trilineage abnormalities.208 Transformation to acute lymphocytic leukemia also has occurred.230 In one series of 37 patients, 25 had abnormalities confined to the erythroid series, transfusion dependence occurred in 26, and iron overload was common. Five patients progressed to marrow failure and five to AML. Median survival was 72 months.231 Survival in other series has ranged from 21 to over 60 months.72 Survival is better in patients without abnormalities in lineages other than erythroid cells and with favorable cytogenetic findings.232 This also applies to acquired refractory nonsideroblastic anemias and oligoblastic leukemia233 (see below).
ACQUIRED IDIOPATHIC NONSIDEROBLASTIC ANEMIA
This clonal disorder closely mimics sideroblastic anemia and can occur without prominent sideroblasts in the marrow. The anemia is mild to moderate, with a tendency to macrocytosis. Leukopenia and thrombocytopenia, if present, are usually mild.205,234 Hyposegmented and hypersegmented neutrophils, giant platelets, and red cell shape, size, and hemoglobinization abnormalities may be present. The marrow is usually cellular, and the precursors may show morphologic evidence of dyshemopoiesis, especially in the erythroid series, but ringed sideroblasts are absent or, in one classification scheme, less than 15 percent of erythroid cells. Since anemia predominates and other cytopenias are slight, the course and management are similar to that of acquired idiopathic sideroblastic anemia with dysmorphogenesis, principally. Patients with low erythropoietin levels may have a significant increase in hemoglobin concentration with weekly injections of the hormone. The proportion of patients transforming into AML and the median survival of patients are similar to patients with acquired idiopathic sideroblastic anemia, particularly cases with accompanying disturbances in granulopoiesis or megakaryopoiesis.232,235,236 Cytopenias and blood and marrow dysmorphic changes can become more severe, and the course and management in that instance are similar to multilineal cytopenia with hypercellular marrow, discussed below.
MULTILINEAL CYTOPENIA WITH HYPERCELLULAR MARROW
Approximately two-thirds of patients with clonal myeloid hemopathy present with neutropenia and/or thrombocytopenia in addition to anemia.
These patients present with anemia, neutropenia, and thrombocytopenia; anemia and neutropenia; or anemia and thrombocytopenia. The blood and marrow features are as described above in “Laboratory Features” and lead to a diagnosis, especially in the patient over 50 years of age.9,10,11,12,13,14,15 and 16,237,238 The patient usually seeks medical attention for symptoms of anemia: fatigue, dyspnea, and palpitations on exertion, headache, or dizziness. Exaggerated bleeding associated with thrombocytopenia also may be present. Mild hepatomegaly and/or splenomegaly may be present occasionally.
Dysmorphic blood and marrow cell changes are common. Myeloblasts are not increased in the marrow (less than 2 percent) and are absent from the blood. Cytogenetic abnormalities may be present as described under “Cytogenetics.” If monocytosis is greater than 1000/µl (1000% 106/liter), the disorder merges with chronic myelomonocytic leukemia149(see Chap. 94).
Mild to moderate bicytopenia (anemia and neutropenia) and sometimes tricytopenia with dysmorphic blood and marrow findings and hypercellular marrow occur in patients with the acquired immune deficiency syndrome239,240 but have not been associated with progression to acute leukemia. Pancytopenia with hyperplastic marrow has been associated with nonhemopoietic cancers (paraneoplastic syndrome).241 Megaloblastic anemia can be simulated and can be distinguished by the normal concentration of serum or red cell folate and of serum vitamin B12.
In patients with pancytopenia and hyperplastic marrow, cytopenias that are not troublesome should not be treated. Transfusion of blood components when necessary is the mainstay of treatment. Regular transfusion of red cells may be used for those who do not adapt to moderate anemia or in whom medical conditions, such as angina pectoris, require a higher packed red cell volume. Erythropoietin with or without G-CSF administration may increase hemoglobin concentration and decrease transfusion frequency. Thrombocytopenia is often not so severe as to require treatment. If thrombocytopenic bleeding occurs, platelet transfusions should be used. Amincaproic acid (Amicar) may be a useful adjunct to platelet transfusion for thrombocytopenic bleeding. Interleukin 11 may increase platelet counts in some patients. Stem cell factor, interleukin 3, or thrombopoietin are not approved for clinical use at this time. Amifostin, an aminothiol agent used for radioprotection, given in doses of 100 to 200 mg/m2 three times a week may increase blood counts in some patients.242 Asymptomatic neutropenia should not be treated, but fever should be evaluated promptly and suspected infection treated with broad-spectrum bactericidal antibiotics until the results of cultures are known. In appropriate situations oral antibiotics can be used in patients treated at home.243,244
Androgens have not been generally useful. Rare cases may show minor improvement, but the likelihood of substantial or sustained improvement is low. Occasional cases have shown improvement in blood cell counts and, where present, resolution of myelofibrosis following use of glucocorticoids (prednisone, 40 mg/m2 per day, orally245 or prednisone, 60 mg qd).246 Protracted use of glucocorticoids may increase the risk of infection, especially with opportunistic organisms, and has not been shown to increase survival.
For those patients with symptomatic anemia and high transfusion requirements or severe, symptomatic neutropenia, therapeutic trials of erythropoietin247,248,249 and 250 and/or GM-CSF, G-CSF,251,252,253,254 and 255 or IL-3256 have sometimes been beneficial in increasing counts and improving neutrophil function. Cytokines have not been shown to increase survival and can produce troubling side effects such as local skin reactions, fever, bone pain, and a capillary leak syndrome.247,257 They also can lead to an increase of immature granulocytes including blasts to increase in marrow and blood.258
In uncommon cases with hypoplastic marrows, cyclosporin A and antithymocyte globulin have been used,259,260 analogous to the responsiveness of some cases of aplastic anemia to such approaches. A variety of chemotherapeutic agents have been used, especially when the disease evolves to oligoblastic or frank AML (see oligoblastic leukemia, “Treatment”).
COURSE AND PROGNOSIS
In patients with multicytopenias, morbidity is great; severe infections, exaggerated bleeding, and severe anemia and lassitude may occur. Mortality from infection or hemorrhage occurs in about 25 percent of patients. AML develops in about 50 percent of patients. There is a greater likelihood of transformation to overt AML if the patient has severe cytopenias, more overt qualitative disorders of cells, abnormal localized immature myeloid precursors in marrow, complex chromosome abnormalities, and abnormalities of marrow cell colony growth in culture (excessive growth or decreased growth).233,261,262 Median survival of patients with clonal hemopathy and multicytopenias is about 20 months.
UNCOMMON PRELEUKEMIC SYNDROMES
Amegakaryocytic thrombocytopenia is a very uncommon preleukemic syndrome (less than 1 percent), although bonafide cases have transformed into AML months or years later.263,264 Among 1220 cases of myelodysplastic syndrome, 11 cases of isolated thrombocytopenia associated with clonal chromosome abnormalities, usually involving chromosomes 3, 5, 8, or 20, were identified. Antiplatelet antibodies were not present, and glucocorticoids were ineffective. Five of the 11 patients progressed to acute myelogenous leukemia.263 (See Table 92-2.)
TABLE 92-2 HYPOCELLULAR MARROW SYNDROMES THAT OCCASSIONALLY PRECEDE ONSET OF ACUTE MYELOGENOUS LEUKEMIA
Chronic neutropenic states are rare antecedents of AML.265 Congenital neutropenia (Kostmann syndrome) has evolved into AML.265,266 The evolution of Shwachman syndrome (neutropenia and exocrine pancreatic insufficiency) into oligoblastic or overt acute leukemia has been documented.267 A related disorder, Pearson syndrome (sideroblastic anemia, neutropenia, and exocrine pancreatic insufficiency), is a putative preleukemia disorder in children268 (see Chap. 31).
In a small proportion of patients with preleukemia, monocytosis may be the most striking blood cell abnormality for months or years before the development of acute leukemia.102,103 and 104
APLASTIC ANEMIA, PAROXYSMAL NOCTURNAL HEMOGLOBINURIA, AND EOSINOPHILIC FASCIITIS
AML occurs in a small fraction of patients (approximately 5 percent) with acquired aplastic anemia.269,270 Since aplasia itself is a disease with a high early mortality rate, the propensity to leukemia may be greater than is apparent. Patients initially responding to glucocorticoids or antithymocyte globulin have later developed myelodysplastic syndromes.270
Paroxysmal nocturnal hemoglobinuria is a hemopoietic stem cell disease that often is associated with marrow hypoplasia (see Chap. 36). AML may ensue in some patients.97 It is a preleukemic syndrome with a very low incidence of leukemic transformation. There is a propensity for all chronic hemopoietic stem cell disorders (e.g., polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, chronic myelogenous leukemia) to undergo transformation to AML (see Chap 91). Patients with indolent myeloid clonal disorders may have a PNH-like defect of their blood cell membranes.27
Eosinophilic fasciitis mimics the cutaneous manifestations of scleroderma. Symmetrical swelling and induration of arms and legs, sparing the hands and feet, are common.272,273 Eosinophilia and hypergammaglobulinemia are frequent, and immune cytopenias, aplastic anemia, myelodysplasia, AML, and lymphoma has been associated with the disease.274 An immune mechanism has been postulated for all the manifestations of the disease. The risk of developing AML is greatly increased compared with healthy individuals.272,273 and 274 Marrow transplantation has been used to treat the aplastic anemia.275
DEFINITION AND HISTORY
In 1963, the term smoldering acute leukemia was introduced to highlight a subset of patients, usually those over 50 years of age, who had a low proportion of leukemic blast cells in marrow (5 to 30 percent) and blood (0 to 10 percent) and who survived for months or years without specific therapy for leukemia.276,277 and 278 Oligoblastic leukemia has been called refractory anemia with excess myeloblasts, and when the blast count increases further the phrase in transformation had been added.2 The latter distinction has proved of little value and has been abandoned. Chronic myelomonocytic leukemia, previously included under the rubric myelodysplasia, is better linked to the subacute and chronic myelogenous leukemias discussed in Chap. 94. Happily this change further minimizes the oxymoronic classification that considers leukemia a dysplasia.
OLIGOBLASTIC LEUKEMIA (REFRACTORY ANEMIA WITH EXCESS MYELOBLASTS)
This disorder is referred to by the acronym RAEM (or RAEB, refractory anemia with excess blasts).2,279,280 Most patients are over 50 years of age. Males and females are affected about equally. Reticulocytopenic anemia, granulocytopenia, and/or thrombocytopenia are present. Qualitative abnormalities of blood cells may develop as described above under “Laboratory Features.” Myeloblasts and progranulocytes constitute from 3 to 30 percent of nucleated marrow cells. Some subclassify this group into RAEB (20 percent or fewer marrow blasts). (RAEB in transformation had been used in those cases with 20 to 30 percent marrow blasts but has been dropped.) Auer rods may be present in blast cells. Dysmorphic changes that may occur in marrow precursor cells are described above in “Laboratory Features.” This syndrome evolves into overt AML in about 30 to 50 percent of cases.281 Median survival in RAEB is about 9 months, although there are occasional long-term survivors.
TREATMENT, COURSE, AND PROGNOSIS
The treatment of oligoblastic leukemia should be highly individualized. In some cases no active treatment is required. Periodic evaluation is essential to detect deterioration in well-being or blood cell counts. Most patients will require treatment in weeks to months. The response to cytotoxic therapy is poor, and symptomatic therapy with component transfusion and antibiotics, as required, is the preferable management if that approach can sustain a reasonable functional status. If the disease progresses to frank AML and if the patient is fit, standard therapy as for AML is warranted (see Chap. 93). If the patient is over 70 years, attenuation of doses should be considered. Cytarabine combined with anthracycline antibiotics, etoposide, or topotecan have produced remissions in about half of a group of selected patients.282,283,284,285,286,287,288 and 289,370 Recovery may be slow, and remissions tend to be short, however. Patients with a poor performance status, in advanced age, or choosing not to be treated with combined-agent chemotherapy have been treated with low-dose cytarabine, 5-azacytidine or decitabine, etoposide, hydroxyurea, retinoids, butyrates, or interferon coupled with transfusion therapy for palliation of the disease (see below). Although occasional patients have improvement, these approaches have been of limited benefit. Patients under 50 years of age with a histocompatible donor should be considered for stem cell transplantation.290,291 and 292 Other patients including older individuals who achieve a remission may be considered for intensive therapy and autologous stem cell rescue.293
Chemotherapeutic regimens containing standard doses of cytarabine and daunomycin (see Chap. 93) result in remission in fewer than 20 percent of patients with oligoblastic leukemia. Moreover, a proportion of patients are made worse with intensive chemotherapy. The advanced age and the high frequency of cardiac, renal, immunologic, and other organ system impairment in most patients with oligoblastic leukemia are largely responsible for the poor outcome. Patients who are less than 50 years of age have higher remission rates and should undergo intensive therapy. However, such cases represent only about 10 percent of all patients.
Low-dose cytarabine, 5 to 20 mg/m2 per day by subcutaneous injection every 12 h for up to 8 to 16 weeks or by continuous intravenous infusion, has been used in lieu of intensive chemotherapy.294,295 Although this approach has led to remission in about 20 percent of patients with oligoblastic leukemia, the median duration of remission is only about 10 months, and survival has not been prolonged when compared with supportive care alone. Also, in contrast to AML, survival has not been influenced greatly by induction of a remission. Moreover, low-dose cytosine arabinoside is usually cytotoxic, inducing marrow hypoplasia and worsening cytopenias. Often the patient requires hospitalization and blood cell component transfusion and antibiotic treatment analogous to that used for intensive treatment of AML. In some cases, outpatient therapy is possible with self-administration of subcutaneous cytarabine. Although occasional reports of remission following low-dose cytarabine have been consistent with an effect on leukemia cell maturation, most patients experience suppression of the malignant stem cell clone leading to marrow repopulation with polyclonal hemopoiesis.289,294,295 Combinations of low-dose cytarabine with growth factors have not shown a clear advantage over chemotherapy alone.295
This agent is a pyrimidine analogue that inhibits DNA methyltransferase, reduces cytosine methylation, and induces maturation of some leukemic cell lines. It also is an antiproliferative drug. Administration of the drug and its congener, decitabine, has resulted in improvement of some pateients with oligoblastic leukemia.287,288 5-azacytidine in a dose of 75 mg/m2 once per day given subcutaneously for 7 consecutive days each month provided significantly more frequent benefit to two-thirds of the patients than did supportive care. Quality of life was enhanced, and disease progression was delayed.288 The drug is available from the National Cancer Institute on the basis of “compassionate use.”
OTHER CYTOTOXIC DRUGS
Agents such as hydroxyurea and low-dose etoposide are useful in controlling leukemic cell proliferation but usually produce only partial responses and do not influence survival duration.296 Occasional patients have achieved remissions with etoposide (50 mg as a 2-h infusion, two to seven times weekly for 4 weeks; or 100 mg per day, orally, for 3 days and then 50 mg twice weekly).297 Thalidomide has shown effectiveness in early pilot studies. Further trials alone and in combination with other agents are in progress.369
RETINOIDS, VITAMIN D DERIVATIVES, OTHER POTENTIALLY MATURATION-ENHANCING AGENTS
Glucocorticoids, vitamin A analogues (retinoids), vitamin D analogues (dihydroxyvitamin D3), pyrimidine analogues (cytarabine), hexamethylene bisacetamide, and interferons among other agents can induce in vitro maturation of mouse and human leukemic cells.298,299,300 and 301 The use of 20 to 100 mg/m2 of cis-retinoic acid, 25 mg/m2 of isotretinoin, or 45 mg/m2 of all-trans retinoic acid, orally, daily for up to 3 months has produced only slight, transient (few weeks) improvement in a very small proportion of patients with oligoblastic leukemia.302,303 Adverse effects of these vitamin A derivatives include dry skin, cheilitis, pruritus, lethargy, and arthralgia, which usually disappear after discontinuation of the agent.
A regimen including 2.5 µg per day, orally, of dihydroxyvitamin D3 for at least 8 weeks has not been beneficial in patients with oligoblastic leukemia.304,305 Hypercalcemia has been a dose-limiting factor. Analogues with less hypercalcemia-inducing capacity such as alphacalcidol have shown some effect on reducing blasts and promoting monocytoid differentiation, while others have been inactive.306,307
A combination of low-dose cytarabine, retinoic acid, and 1,25-dihydroxyvitamin D3 in 44 patients with oligoblastic leukemias produced 50 percent response rates, with longer survival in responders than in nonresponders.308 Hexamethylene bisacetamide given in a dosage of 20 to 24 g/m2 per day intravenously for 10 days followed by an 18- to 75-day observation period produced increased neutrophil counts and reduced marrow blasts in only 4 of 16 patients with oligoblastic leukemia.301 In another study no responses were observed.299 Sodium phenylbutarate is an agent that has shown some activity against oligoblastic leukemia and is in early clinical trials.300
Amifostine, pentoxifylline, and dexamethasone has shown effectiveness in prolonging survival of patients. The combination is thought to reverse the exaggerated apoptosis of maturing precursor cells.368
Interferons also have been used to treat oligoblastic leukemia.309,310,311 and 312 Doses of IFN-a ranged from 3 × 106 units per day to 1 × 106 units/m2 three times a week. Occasional reductions in blast percentages or transfusion requirements have occurred at the price of substantial toxicity. AML occurred in some patients. IFN-g at 0.01 mg to 0.1 mg/m2 three times weekly improved counts and reduced blast percentages in about 40 percent of 30 patients with oligoblastic leukemia in one series. Median survivals were no longer than in untreated historical controls, although they were longer than in untreated concurrent patients. Other reports show little effect from interferon treatment.313,314
In one case of therapy-related oligoblastic leukemia developing during a third complete remission of ALL, IL-2 given subcutaneously at 2.5 to 8 × 105 IU twice daily for 30 days enhanced natural killer cell activity and eliminated blasts in the marrow.315 A phase II clinical trial, however, failed to show improvement in blood counts or decrease in transfusion requirement in patients so treated.316
ERYTHROPOIETIN, GM-CSF, G-CSF, IL-3, AND IL-11
Randomized, double-blind studies have not shown that any cytokine prolongs survival or reduces morbidity in oligoblastic leukemia, although the results of early studies suggest that (1) erythropoietin occasionally can reduce transfusion requirement, (2) GM-CSF and G-CSF can increase neutrophil counts and functions, and (3) IL-3 can result in increased white cell count and, less frequently, increased red cell and platelet counts.248,249 and 250,317,318,371 Responses have been seen in oligoblastic leukemias as well as in severe refractory anemias. There is no evidence that cytokines can delay emergence of acute leukemia; rather, they increase blast percentages in a proportion of patients, an event that is not always reversible with cessation of the cytokine.317,318 In one review, 22 of 83 reported cases of myelodysplasia treated with G-CSF or GM-CSF had an increase in marrow blast percentage, and AML developed in 12 of 69 patients. An increased percentage of abnormal macrophages has also been reported.319 Use of these agents without chemotherapeutics in oligoblastic leukemias carries a risk of accelerating the leukemia.320 Combinations of growth factors alone or coupled with maturing agents have not significantly improved response or survival rates.321,322 IL-11 is being studied as a means of increasing the platelet count in patients with myelodysplasia and symptomatic thrombocytopenia.373
STEM CELL TRANSPLANTATION
ALLOGENEIC STEM TRANSPLANTATION
This approach has been used to treat various myelodysplastic syndromes in patients from 1 month to 60 years of age.323,324,325,326,327,328 and 329,372 Conditioning regimens have been cyclophosphamide plus irradiation or busulfan plus cyclophosphamide. Most patients have received transplants from histocompatible sibling donors, although there is some experience with partially mismatched, related, and unrelated donors. A good representation of the results of this approach using marrow stem cells is the study of 93 patients ranging in age from 1 month to over 60 years (median of 30 years), conditioned with cyclophosphamide and total body irradiation or busulfan and cyclophosphamide, and transplanted with an identical twin donor (3 patients), genotypically HLA-identical sibling (62 patients), HLA-matched family member (2 patients), one to three antigen HLA-mismatched family member (20 patients), or unrelated donor marrow (6 patients). Twenty-nine patients were in the refractory anemia category. Forty-seven recipients were in the oligoblastic leukemia category, and the remainder comprised miscellaneous disorders. Most patients received graft-versus-host disease prophylaxis with methotrexate and cyclosporine, with or without prednisone. The most favorable results were in patients less than age 40 years with shorter duration of disease and without blasts. These patients may have a disease-free survival of 60 percent at 4 years and an overall disease-free survival estimated at 40 percent. Older patients had more peritransplant mortality and higher relapse rates. Actuarial relapse probability at 4 years was 30 percent for the entire group and 50 percent for patients with greater than 5 percent marrow blasts. Cytogenetic abnormalities did not predict outcome in this study, but adverse cytogenetics were an important prognostic factor in other studies. Results with unrelated marrow donors are inferior to those for other donor categories.
AUTOLOGOUS STEM CELL INFUSION
Patients with oligoblastic leukemia have been treated with their own stem cells following intensive chemotherapy therapy.330 The approach is limited by the contamination of the stem cell product with leukemic cells and the absence of a graft-versus-leukemia effect. The absence of a graft-versus-host reaction makes it more applicable to the age group usuially affected. In selected patients, peritransplant mortality with intensive therapy and stem cell rescue has been about 10 percent, and about 50 percent of selected patients have had extended survivals.331 The more advanced the disease at the time of treatment the worse the outcome.
COURSE AND PROGNOSIS
The median survival in published series of patients with oligoblastic leukemia has varied from 6 to 36 months, with a range of survival of individual patients from 1 to 160 months.332,333,334,335 and 336 In a very large single series that included refractory anemia as well, the median survival was 15 months.278 About half the patients died of infection associated with severe neutropenia or with dysfunctional neutrophils and monocytes, and about 25 percent died of bleeding complications of thrombocytopenia. About 30 percent of cases evolved into AML. The length of survival after diagnosis of patients with oligoblastic leukemia is inversely correlated with the severity of the cytogenetic abnormality, the proportion of blast cells in the marrow, the presence of N-RAS mutations, the presence of adverse cytogenetic patterns, and the severity of the neutropenia and thrombocytopenia.332,333,334,335 and 336,374,375
A rare case of spontaneous disappearance of oligoblastic leukemia has been documented.337
PRODROMAL SYNDROMES ANTEDATING LYMPHOCYTIC LEUKEMIA
The indolent clonal disorder usually implies a condition that is an antecedent of myelogenous leukemia. AML often begins with a protracted period (weeks to months) of symptoms or signs preceding clinical diagnosis, and a significant proportion of cases are preceded by a myelodysplastic syndrome. Acute lymphocytic leukemia (ALL) usually begins explosively, and it is rare for symptoms to be present for more than a few weeks prior to diagnosis (see Chap. 97). Intermediate syndromes, for example, smoldering or oligoblastic lymphocytic leukemia or prodromal clonal anemias, are rare, but the latter have been reported, especially in adults.338,339,340,341 and 342,376
Apparent aplastic anemia343,344,345,346 and 347 or erythroid hypoplasia348 has been described as an antecedent to ALL in a few children and a rare adult.348 The aplasia is promptly improved by glucocorticoids, and ALL ensues quickly, usually within 1 to 8 months. The brief interval between remission of aplastic anemia and the onset of leukemia suggests that the leukemia, although inapparent on marrow biopsy, may in some way initiate the aplasia.347 Remission of aplasia followed shortly by ALL has occurred in the absence of glucocorticoid or other specific therapy in several cases. The aplastic marrow prodrome of ALL may be distinguishable by its very high prevalence in females (about 90 percent), high prevalence of fibrosis on marrow biopsy (about 90 percent), frequent marrow lymphocytosis (about 60 percent), and spontaneous, temporary recovery (greater than 90 percent).349
INDOLENT CLONAL MYELOID DISORDERS OR OLIGOBLASTIC (MYELOGENOUS) LEUKEMIA PRECEDING OR EMERGING IN LYMPHOID MALIGNANCIES OTHER THAN ACUTE LYMPHOCYTIC LEUKEMIA
Sideroblastic anemia sometimes associated with qualitative disorders of other blood cell lines (such as thrombopathy) has developed in patients who have had, or later developed, a lymphoproliferative disease such as hairy-cell leukemia, lymphocytic lymphoma, myeloma, chronic lymphocytic leukemia, or Hodgkin’s disease.350,351,352,353,354,355,356,357,358 and 359 The sideroblastic anemia in these cases was not preceded by cytotoxic therapy. Similar associations have been reported in patients who have received chemotherapy or radiotherapy for a lymphoproliferative disease or a solid tumor, and who later developed a preleukemic syndrome presumed to be the result of the prior treatment. Other types of myelodysplasia also can occur concurrent with B- or T-lymphocyte–derived tumors.350,351,352,353,354,355,356,357,358 and 359
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn