Clonal myeloid disorders


The clonal myeloid disorders result from acquired mutations within a multipotential marrow cell or very early progenitor cell. The chromosomal alteration resulting in the primary mutation sometimes is evident when cytogenetic analysis is performed. Translocations, inversions, and deletions of chromosomes can result in (1) the expression of fusion genes that encode fusion proteins that are oncogenic or (2) the overexpression or underexpression of genes that encode molecules critical to the control of cell growth, programmed cell death, or other regulatory pathways. Duplication of chromosomes, such as trisomy, also results in deregulated cellular behavior. Gene and miRNA (microribonucleic acid) expression profiling has also identified potentially leukemogenic gene mutations in cases without a cytogenetic abnormality. The different mutations may result in phenotypes that range from mild impairment of the steady-state levels of blood cells, insignificant functional impairment of cells, and little consequence on longevity to severe cytopenias and death in days, if the disorder is untreated. The somatically mutated (neoplastic) multipotential cell from which the clonal expansion of hematopoietic cells derives retains the ability, with various degrees of imperfection, to differentiate and mature into each blood cell lineage. The particular syndrome may have altered blood cell concentrations, structure, and function, and minimal to severe effects on a particular blood cell lineage. The effect on any one lineage occurs in an unpredictable way, even in subjects within the same category of disease. The resulting phenotypes are, therefore, innumerable and varied. In polycythemia vera or thrombocythemia, maturation of progenitors results in cells nearly normal in appearance and function, but their level in the blood is excessive. Moreover, overlapping features are common, such as thrombocytosis as a feature of polycythemia vera, essential thrombocythemia, primary myelofibrosis, or chronic myelogenous leukemia. The clonal anemias may be accompanied by insignificant or very severe neutropenia or thrombocytopenia or sometimes thrombocytosis. These findings reflect the unpredictable expression of the mutant multipotential cell’s differentiation capabilities for which the genetic explanations are largely unknown. Tight relationships between the cytogenetic alteration and the phenotype occur in only a few circumstances, and even these are imperfect, for example, translocation (t) (9;22)(q34;q11)(BCR-ABL;p210) with chronic myelogenous leukemia and t(15;17)(q22;q21) (PML-RAR) with acute promyelocytic leukemia. However, most patients can be grouped into the classic diagnostic designations listed in Table 85–1. An important feature of the clonal myeloid diseases is the potentially reversible suppression of normal (polyclonal) stem cells by the clonally expanded cells. This coexistence and competition forms the basis for the remission-relapse pattern seen in acute myelogenous leukemia after intensive chemotherapy and for the reappearance of polyclonal, normal hematopoiesis in many patients with chronic myelogenous leukemia after tyrosine kinase inhibitor therapy.

Table 85–1. Neoplastic (Clonal) Myeloid Disorders
I. Minimal-deviation neoplasms (no leukemic blast cells are evident in marrow)
A. Underproduction of mature cells is prominent
1. Clonal (refractory) sideroblastic anemiaa (Chap. 88)
2. Clonal (refractory) nonsideroblastic anemiaa (Chap. 88)
3. Clonal bi- or tricytopeniaa (Chap. 88)
4. Paroxysmal nocturnal hemoglobinuria (Chap. 40)
B. Overproduction of mature cells is prominent
1. Polycythemia verab (Chap. 86)
2. Primary thrombocythemiab (Chap. 87)
II. Moderate-deviation neoplasms (small proportions of leukemic blast cells usually present in marrow)
A. Chronic myelogenous leukemia (Chap. 90)
1. Ph chromosome-positive, BCR rearrangement positive (~90%)
2. Ph chromosome-negative, BCR rearrangement positive (~6%)
3. Ph chromosome-negative, BCR rearrangement negative (~4%)
B. Primary myelofibrosisb (chronic megakaryocytic leukemia) (Chap. 91)
C. Chronic eosinophilic leukemia (Chaps. 62 and 90)
1. PDGFR rearrangement-positive
2. FGFR1 rearrangement-positive
D. Chronic neutrophilic leukemia (Chap. 90)
E. Chronic basophilic leukemia (Chap. 90)
F. Systemic mastocytosis (chronic mast cell leukemia) (Chap. 63)
1. KITD816V mutation-positive (~90 %)
2. KITV560G mutation-positive (rare)
III. Moderately severe deviation neoplasms (moderate concentration of leukemic blast cells present in marrow)
A. Oligoblastic myelogenous leukemia (refractory anemia with excess blasts)a (Chap. 88)
B. Subacute myelomonocytic leukemia (Chap. 90)
1. PDGFR rearrangement positive (rare)
C. Juvenile myelomonocytic leukemia (Chap. 90)
IV. Severe deviation neoplasms (leukemic blast or early progenitor cells frequent in the marrow and blood)
A. Phenotypic variants of acute myelogenous leukemia (Chap. 89)
1. Myeloblastic (granuloblastic)
2. Myelomonocytic (granulomonoblastic)
3. Promyelocytic
4. Erythroid
5. Monocytic
6. Megakaryocytic
7. Eosinophilicc
8. Basophilicd
9. Mastocytice
10. Histiocytic or Dendriticf
B. High-frequency genotypic variants of acute myelogenous leukemia [t(8;21), Inv16 or t(16;16), t(15;17), or (11q23)]g
C. Myeloid sarcoma
D. Acute biphenotypic (myeloid and lymphoid markers) leukemiah
E. Acute leukemia with lymphoid markers evolving from a prior clonal myeloid disease
aThe World Health Organization includes these four disorders under the rubric of the “Myelodysplastic Syndromes,” the classification of which is discussed in Chap. 88.bThe World Health Organization includes these three disorders under the rubric of the “Myeloproliferative Syndromes,” the classification of which is discussed in Chaps. 86, 87, and 90.

cAcute eosinophilic leukemia is rare. Most cases are subacute or chronic and formerly were included in the category of the hypereosinophilic syndrome (see Chaps. 62, 89, and 90).

dRare cases of acute basophilic leukemia are Ph-negative and are variants of acute myelogenous leukemia. Most cases have the Ph chromosome and evolve from chronic myelogenous leukemia (see Chaps. 63, 89, and 90).

eSee Chap. 63.

fSee Chap. 72.

gThe World Health Organization has designated these subtypes as separate entities even though they also have phenotypes listed under phenotypic variants.1

hApproximately 10 percent of cases of acute myeloblastic leukemia may be biphenotypic (myeloid and lymphoid markers on individual cells) when studied with antimyeloid and antilymphoid monoclonal antibodies (see Chap. 89).

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CD, cluster of differentiation; CML, chronic myelogenous leukemia; FGFR, fibroblast growth factor receptor; FLT-3, FMS-like tyrosine kinase 3; G-banding, Giemsa banding; GPI, glycosylphosphatidylinisotol; JAK2, Janus kinase 2; miRNA, microribonucleic acid; 32P, phosphorus-32; PDGFR, platelet-derived growth factor receptor; PNH, paroxysmal nocturnal hemoglobinuria; PO2, pressure of oxygen; t, translocation; WHO, World Health Organization.

Classification and Clinical Manifestations of the Clonal Myeloid Disorders: Introduction

A wide array of clonal (neoplastic) syndromes or diseases can result from a somatic mutation in a multipotential hematopoietic progenitor cell (Table 85–1). This mutated cell behaves like a stem cell, self-replicating and feeding cells into the various hematopoietic lineages. Strong circumstantial evidence has existed for a myelogenous leukemia stem cell for approximately 60 years. This concept has been buttressed by experimental verification of such cells by transplantation of human leukemia cells into immunodeficient mice1,2 and by techniques to isolate and characterize their phenotype.3 Although most attention has been given to the leukemic stem cell in acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), it is very likely that a similar cell underlies (initiates and sustains) each of the clonal myeloid diseases.

The clonal myeloid diseases can be grouped, somewhat arbitrarily, by their degree of malignancy, using the classic terminology of experimental carcinogenesis, which considers the degree of loss of differentiation and maturation potential and the rate of progression of the disease. The term deviation relates to the relationship to normal cellular differentiation and maturation potential and the regulation of cell population homeostasis (birth and death rates). This terminology has been used to array the diagnostic categories of clonal hematopoietic diseases into a framework related to their pathogenesis for the reader.

Minimal-Deviation Clonal Myeloid Disorders

The neoplasms in this category in Table 85–1 retain a higher degree of differentiation and maturation capability and permit median life spans measured in decades without treatment or with minimally toxic treatment approaches.4 Use of the term minimal deviation should not be construed as indicating these conditions do not have morbidity, shorten life, and have other consequences to the patient. The term is used relative to AML, in which differentiation and maturation and regulation of cell proliferation and cell death are profoundly disturbed, and in which expected life span is measured in days to weeks, if untreated.

Precursor Apoptosis Prominent

The clonal (refractory) anemias and bi- and tricytopenias are characteristic of this category. Cytopenias resulting from exaggerated apoptosis of marrow late precursors (referred to as ineffective hematopoiesis) are a principal feature of this subgroup of clonal hematopoietic multipotential cell diseases. A common additional characteristic is striking dysmorphogenesis of blood cells.5 These cytologic abnormalities, characteristic of the clonal anemias, bicytopenias, or pancytopenias, include changes in the size (macrocytosis and microcytosis), shape (poikilocytosis), and nuclear or organelle structure (hypogranulation or hypergranulation, nuclear hypolobulation) of blood cells and their precursors (see Chap. 88). Abnormal maturation of blood cells leads to morphologic, biochemical, and functional alterations of the cells. Ineffective erythropoiesis, the intramedullary, apoptotic death of late erythroblasts before they reach full maturation, is a common feature. Ineffective granulopoiesis and thrombopoiesis also can occur, resulting in neutropenia and thrombocytopenia, despite a cellular marrow.

There is no clinical distinction in the presenting manifestation or the course of clonal anemia with less than 15 or greater than 15 percent pathologic sideroblasts in the marrow. Therefore, this distinction, nonsideroblastic vis-à-vis sideroblastic clonal (refractory) anemia, has no nosologic or clinical utility, yet the World Health Organization (WHO) has retained it.6 Indeed, the clonal anemias nearly invariably have pathologic sideroblasts in the marrow, and, thus, are virtually all sideroblastic, in fact. Leukemic blast cells are not evident in these syndromes. If marrow blasts are elevated above the normal upper limit of 2 percent, the disorder should be considered oligoblastic myelogenous leukemia (synonym: refractory anemia with excess blasts; see below, “Moderately Severe Deviation Disorders”). The WHO has defined “acute myelogenous leukemia” as having ≥20 percent leukemic blast cells in marrow; whereas, a marrow with fewer blasts (5 to 20 percent) is referred to as refractory anemia with excess blasts (e.g., myelodysplasia). The use of 5 percent blasts as a threshold is an anachronism that dates back approximately 50 years to a time when supportive care was inadequate (no platelets for transfusion, limited antibiotics, etc.). At that time, the risk of “overtreating” children with acute lymphocytic leukemia (ALL) was so great and the presence of atypical lymphoid cells in the marrow after treatment so common, that an arbitrary threshold of 5 percent blasts was used to avoid an unnecessarily long period of posttreatment-induced aplasia. It is too high a threshold at the time of diagnosis. In no other cancer is the diagnosis defined by the proportion of cancer cells in histologic or cytologic examinations, thus using ≥20 percent blasts as the basis for diagnosis of leukemia versus myelodysplasia represents an aberration in cancer diagnosis.7 Because the differential cell count in a marrow aspirate (or biopsy) is variable and represents a small sample of marrow, such distinctions also are made arbitrary by problems of sampling at the time of diagnosis.

The term hematopoietic dysplasia, later simplified to myelodysplasia, has become ensconced as the category into which clonal anemia, clonal multicytopenia, and refractory anemia with excess blasts (oligoblastic myelogenous leukemia) have been grouped. In strict pathologic terms, a dysplasia is a polyclonal, and thus nonmalignant, change in the cells of a tissue. These myeloid syndromes are clonal, often have aneuploid or pseudodiploid cells in the clone, and can be associated with significant morbidity and premature death; thus, they are neoplasias not dysplasias. They demonstrate clonal instability, and each has a propensity to evolve into polyblastic AML that far exceeds that of the general population. The term dysplasia was instituted in the early 1970s at a time when prominent dysmorphogenesis and cytopenias were thought to be the singular abnormalities and arguments existed as to whether these syndromes represented a preneoplastic (polyclonal) or neoplastic (clonal) condition.8 They have long been established as the latter, but the terminology has not been rectified.

Overproduction of Cells Prominent

Polycythemia vera (see Chap. 86) and essential thrombocythemia (see Chap. 87) are clonal myeloid disorders. They are so named because of the overaccumulation of red cells, and often neutrophils, and platelets in polycythemia, and of platelets, and to a lesser extent neutrophils, in thrombocythemia.9 Each cell lineage is affected in each disorder, reflecting a multipotential hematopoietic cell origin, but the magnitude of the effects on each lineage differs. The decrease in red cell production in essential thrombocythemia usually is mild. Polycythemia vera and essential thrombocythemia do not show morphologic evidence of leukemic hematopoiesis; the proportion of blast cells in the marrow is not increased above normal, and blast cells are not present in the blood. Hematopoietic differentiation and maturation are maintained. These disorders do not have a specific cytogenetic abnormality, but approximately 95 percent of cases of polycythemia and approximately 40 percent of cases of essential thrombocythemia have an acquired mutation in the Janus kinase 2 (JAK2) gene.9 The survival of cohorts of patients with these diseases is only slightly less than expected for age- and gender-matched unaffected persons.4,10,11 Two exceptions are the uncommon onset of polycythemia vera in childhood in which there is a shortened life span,12 and adults with the homozygous JAK2 V61F mutation who have a more aggressive form of the disease (Chap 86).

Moderate-Deviation Clonal Myeloid Disorders

CML (see Chap. 90) and primary myelofibrosis (see Chap. 91) classically share the features of overproduction of granulocytes and platelets and impaired production of red cells. In contrast to the minimally deviated clonal myeloid neoplasms, CML and primary myelofibrosis have a small proportion of leukemic blast cells in marrow and often blood. The most constant feature in primary myelofibrosis is the abundance of dysmorphic megakaryocytes and the resultant predisposition to marrow reticulin and collagen fibrosis, extramedullary fibrohematopoietic tumors, splenomegaly, and teardrop-shaped red cells (dacryocytes) in every oil immersion field on the blood film. The megakaryocytic abnormalities are so dominant and consistent in this disorder that it could be called chronic megakaryocytic leukemia.13 The cells in this disorder have no specific cytogenetic change, but approximately 40 to 50 percent of cases carry a mutation in the JAK2 gene (see Chaps. 87 and 91). CML, in contrast, has a rearrangement of the BCR gene on chromosome 22. The shortening of the long arm of chromosome 22 gives it the designation of the Philadelphia chromosome, now called the Ph chromosome. It can be identified by Giemsa (G)-banding cytogenetic study in approximately 90 percent of patients with CML. This mutation is caused by and reflected in translocation t(9;22)(q34;q11)(BCR-ABL). The BCR-ABL fusion in CML cells can be found in virtually all cases studied by fluorescence in situ hybridization. An unrelenting increase in the white cell (granulocyte) count, splenomegaly, and a progressive course are common features. Blast cells are very slightly increased in marrow and often blood in most patients with these two disorders. CML has a very high (nearly universal) propensity to transform to acute leukemia. Primary myelofibrosis terminates in acute leukemia in approximately 15 percent of patients. Median life span in these disorders is measured in years but is significantly decreased compared to age- and gender-matched unaffected cohorts. Therapy is required in all cases of CML and in some but not all cases of primary myelofibrosis at the time of diagnosis. Both diseases can be cured by stem cell transplantation. Median life span is projected to be increased by decades in CML with the use of tyrosine kinase inhibitors (see Chap. 90).14

Chronic eosinophilic leukemia, chronic neutrophilic leukemia, chronic basophilic leukemia, and systemic mastocytosis are included in this category. Chronic basophilic leukemia is a rare disease, thus far only reported by the Mayo Clinic.15 Chronic neutrophilic leukemia is uncommon but well described and defined (see Chap. 90). Chronic eosinophilic leukemia represents cases previously called hypereosinophilic syndrome with evidence of clonal hematopoiesis involving eosinopoiesis. Some cases are associated with a rearrangement of the platelet-derived growth factor receptor- (PDGFR-) gene and these are called out in Table 85–1 because they are specifically responsive to the tyrosine kinase inhibitor, imatinib mesylate (see Chaps. 62 and 90). Chronic clonal eosinophilia may also be associated with a PDGFR- gene rearrangement, but histopathologic examination may be consistent also with systemic mastocytosis. This rearrangement is usually the result of a FIP1L1-PDGFR- fusion gene. Identification of this fusion gene in cases of eosinophilia-mastocytosis is important because of the sensitivity of those gene products to imatinib mesylate. A clonal myeloid syndrome that includes eosinophilia and a translocation between 8p11, at the site of the tyrosine kinase domain of the fibroblast growth factor receptor-1 (FGFR1) gene, and several different partner chromosomes, is not responsive to imatinib mesylate. Systemic mastocytosis may have several types of KIT gene mutation; KITV560G is sensitive to imatinib mesylate and KITD816V is insensitive to imatinib but may be responsive to second-generation tyrosine kinase inhibitors. PDGFR- mutations also may be present in the cells of patients with systemic mastocytosis and be responsive to imatinib mesylate.16

Moderately Severe Deviation Clonal Myeloid Disorders

These disorders fall into a group that progresses less rapidly than acute leukemia and more rapidly than chronic leukemia.17,18 They have a predisposition to develop with a granulocytic and monocytic phenotype, either morphologically or cytochemically. These diseases include oligoblastic myelogenous leukemia (refractory anemia with excess blasts), subacute myelomonocytic leukemia, and juvenile myelomonocytic leukemia. Occasional patients have an atypical or unclassifiable syndrome. The latter designation is used for uncommon cases that do not fall into a classical or easily classifiable designation and usually are seen in patients older than age 70 years.

The subacute syndromes produce more morbidity than do the chronic syndromes, and patients have a shorter life expectancy. These are leukemic states that have low or moderate concentrations of leukemic blast cells in marrow and often blood, anemia, often thrombocytopenia, and usually prominent monocytic maturation of cells (see Chap. 88). The oligoblastic myelogenous leukemias compose approximately 50 percent of the cases that have been grouped under the title myelodysplastic syndromes. In all other malignancies, the presence of tumor cells determines the diagnosis, such as carcinoma of the colon or the uterine cervix, whether in situ, invasive, or metastatic. Use of the percentage of tumor (leukemic blast) cells as a threshold for the diagnosis of leukemia versus “dysplasia” is not consistent with usual practice; hence, the preference for oligoblastic myelogenous leukemia rather than myelodysplasia for patients with increased blast cells (leukemia) and dysmorphic cell maturation. Moreover, chronic myelogenous “leukemia,” chronic neutrophilic “leukemia,” subacute myelomonocytic “leukemia,” acute promyelocytic “leukemia,” and other subtypes of AML invariably have fewer than 20 percent blasts in the marrow. Thus, the criteria used in the WHO classification system for clonal myeloid diseases have internal inconsistencies that can be dealt with by experts but are confusing to the uninitiated.

Severe-Deviation Clonal Myeloid Disorders

Morphologic, histochemical, immunologic, and cytogenetic characteristics of cells in the blood and marrow provide the major basis for the diagnosis and classification of AML and its subtypes (see Chaps. 11 and 89). Correlation among observers and between the morphologic method of classification and the monoclonal antibody reactivity-dependent classification of AML is imperfect.19–21 The approach that uses morphology, immunocytochemistry, and immunophenotype is the most inclusive because virtually all cases can be placed into a morphologic subtype. Because immunophenotyping is a standard procedure in most laboratories, the results are readily available. Classification by cytogenetics is more limited because many cases have different infrequent abnormalities, making this approach complex. Approximately 900 unique cytogenetic abnormalities have been reported in cells of patients with AML, including unbalanced structural abnormalities, such as loss of part or all of chromosome 5 or 7, numerical abnormalities, such as an additional chromosome 8 (trisomy 8), or balanced structural abnormalities, such as translocation between chromosomes 8 and 21, 15 and 17, or between chromosome 11 and many other chromosome partners, or any one of numerous other abnormalities involving other chromosomes (genes).22 Despite this heterogeneity, knowing the cytogenetic alterations is useful for estimating the probability of entering a sustained remission (risk category). For example, AML patients whose cells contain t(8;21), t(16;16) or Inv16 (approximately 20 percent of cases) are more likely to enter a prolonged remission. The cytogenetic findings may influence the drugs used for remission-induction therapy. Notably, patients with t(15;17) AML (approximately 7 percent of all AML cases), uniquely require use of all-trans-retinoic acid and arsenic trioxide to result in the best long-term outcome, and in many cases, a cure. Thus, combined light microscopy of blood and marrow, immunocytochemistry, and immunophenotyping to designate the phenotypic subtype, supplemented by cytogenetics or molecular diagnostic methods, currently is the best approach to categorization of the AML subtype. The polymerase chain reaction may be particularly useful for determining subclinical (minimal) residual disease and monitoring therapy in cases in which an appropriate genetic marker is available, such as the t(8;21) or t(15;17) (see Chaps. 89 and 90).

Gene expression profiling using chips containing tens, hundreds, or thousands of relevant genes can be used to further genotype and subclassify AML into prognostic groups.23 One would predict, based on cytogenetics, a large and diverse group of gene expression profiles for cases of AML. This tool is currently most useful in analyzing cases with prior stratification by some relevant variable. For example, a study of patients with AML who have normal karyotypes by standard cytogenetic methods (e.g., G-banding) has identified two groups by hierarchical gene clustering with significantly different survival after current therapy.24 Patients with AML whose cells contain a FMS-like tyrosine kinase 3 (FLT-3) internal tandem duplication also can be stratified into more discriminating prognostic groups using hierarchical gene cluster analysis.25 Gene expression profiling also can identify groups of patients with AML who have previously covert gene abnormalities, such as a mutation in the nucleophosmin 1 gene that encodes a protein that shuttles between the nucleus and cytoplasm. Gene expression studies in AML are important because they (1) identify genes that cooperate or interact to result in a fully malignant phenotype, (2) provide potential new targets for therapy, and (3) help identify patients who might benefit from early stem cell transplantation. At this time, these methods and their interpretation are complex and not available in many clinical laboratories. Moreover, they require interpretation based on the time during the course of the disease that gene analyses are performed; gene expression profiles can differ over time as clonal evolution or selection occurs. Also, studies are best focused on the most primitive multipotential cells in the clone to avoid secondary changes in the mass of derivative leukemic cells.

Another molecular technique applied to understanding the molecular pathology of AML and to defining prognostic groups is the leukemic cell microribonucleic acid (miRNA) signature.26,27 miRNAs are small (19–25 nucleotides), noncoding RNAs that regulate translation of protein by messenger RNA. miRNA signatures can be analyzed by polymerase chain reaction technology of RNA samples from leukemic cells and compared to normal or compared among different categories of AML cases. For example, miRNA analysis can distinguish among cytogenetically normal cases of AML as to their expression of different genes that influence prognosis, such as the nucleophosmin 1 gene (NPM1) and the CCAAT/enhancer binding protein gene (CEPBA).

Specific miRNAs may regulate lineage differentiation of stem cells, indicating critical roles for these molecules in the regulation of hematopoiesis and in leukemogenesis.28

In general, at this time, these techniques are principally research tools because therapists do not have significantly different drug regimens to permit special treatment of poor prognosis groups identified prospectively.

Transitions among Clonal Myeloid Diseases

Patients with minimal, moderate, and moderately severe deviation clonal myeloid disorders have an increased likelihood of progressing to florid (polyblastic) AML, with a frequency ranging from approximately less than 1 percent of patients with paroxysmal nocturnal hemoglobinuria, to 10 percent of patients with clonal sideroblastic anemia, and to 35 percent of patients with clonal bi- or tricytopenia. Approximately 15 percent of patients with polycythemia vera evolve to a syndrome indistinguishable from primary myelofibrosis.29 AML develops as a terminal event in approximately 1 percent of patients with polycythemia vera not treated with phosphorus-32 (32P) or an alkylating agent and in a larger proportion of patients who are treated with cytotoxic agents.30 Occasional cases of apparent essential thrombocythemia or rare cases of primary myelofibrosis can evolve into polycythemia vera. Apparent essential thrombocythemia with cells containing the BCR-ABL fusion gene may progress to CML or acute blast crisis of CML.

A very small percentage of patients with essential thrombocythemia and approximately 15 percent of patients with primary myelofibrosis progress to overt AML. The rate of conversion to AML in polycythemia and thrombocythemia is increased by prior radiotherapy or chemotherapy, depending on the dose, duration, and type of drug. Virtually all patients with CML have the potential to progress to acute leukemia of any subtype, including lymphoid phenotypes, although in some cases the patient enters an accelerated phase that behaves like oligoblastic leukemia before it progresses to acute leukemia. The accelerated phase of CML is associated with inadequate response to therapy, progressive anemia, bone pain, enlarging spleen, thrombocytopenia, among other changes (see Chap. 90). The progression from chronic to accelerated phase of CML, however, has been delayed in the majority of patients by the application of tyrosine kinase inhibitor therapy during the chronic phase of the disease. Determining the frequency of evolution to AML in those patients with CML who enter a complete cytogenetic or major or complete molecular remission with tyrosine kinase inhibitors must await observations over the next several decades.

Pathogenesis of Clonal Myeloid Diseases

In AML, a sequence of mutations in a single multipotential cell results in a clone that is severely defective and contains precursor cells that are unable to mature.31,32 Proliferation of primitive progenitors is excessive when considered in absolute terms, that is, the total number of blast cells proliferating. AML is a clinical disease with many forms of morphologic expression. This variation of phenotype is consistent with the large number of genetic lesions identified and the behavior of the leukemic multipotential cell, which is capable of differentiation into all the blood cell lineages (Fig. 85–1). Hence, the asymmetrical and uncoordinated maturation of leukemic progenitor cells may allow one or another cell type to predominate.33 These different morphologic or cytogenetic variants of AML are each rapidly progressive, however, if not treated successfully

progressive, however, if not treated successfully (see Chap. 89).

Figure 85–1.
Hematopoiesis in acute myelogenous leukemia. The malignant process evolves from a single mutant multipotential cell. This cell is represented at either level 1 or level 2 in Figure 85–2. This cell is capable of multivariate commitment to leukemic erythroid, granulocytic, and megakaryocytic progenitors. In most cases, granulocytic commitment predominates, and myeloblasts and monoblasts or their immediate derivatives are the dominant cell types. Leukemic blast cells accumulate in the marrow. The leukemic blast cells may become amitotic (sterile) and undergo programmed cell death, may stop dividing for prolonged periods (blasts in G0) but have the potential to reenter the mitotic cycle, or may divide and undergo varying degrees of maturation. Maturation may lead to mature cells, such as red cells, segmented neutrophils, monocytes, or platelets. A severe block in maturation is characteristic of AML, whereas a high proportion of leukemic blast cells mature into terminally differentiated cells in patients with CML. The disturbance in commitment and maturation in myelogenous leukemia is quantitative, thus many patterns are possible. At least five major steps in hematopoiesis are regulated: (1) stem cell self-renewal, (2) differentiation into hematopoietic cell lineages (e.g., red cells, granulocytes, platelets), (3) proliferation (cell multiplication) and maturation of progenitor and precursor cells, (4) maturation of progenitor and precursor cells, and (5) release of mature cells into the blood. These control points are defective in myelogenous leukemia. Premature or delayed apoptosis of cells may be another key abnormality contributing to premature death or cell accumulation.
Figure 85–2.
Differentiation and maturation of hematopoietic stem cells. The functioning stem cell pool is thought to be at level 1, the pluripotential cells. In healthy humans, two multipotential progenitor cell pools may be operative (level 2). The multipotential progenitors differentiate further to unipotential progenitors, which are sensitive to specific cytokines (level 3). The committed progenitor cells are referred to as colony-forming units or colony-forming cells because they form colonies of cells in semisolid medium in the presence of the appropriate growth factors. These growth factors are capable of inducing proliferation and maturation of the committed progenitor cells so that they achieve level 4, at which the first morphologically identifiable precursors have developed, such as myeloblasts and proerythroblasts, and, ultimately, level 5, the mature, functional blood cells.

Important epiphenomena are related to certain morphologic types of AML, such as tissue infiltration, including into the central nervous system (monocytic leukemia), disseminated intravascular coagulation, fibrinolysis, and hemorrhage (promyelocytic leukemia), hepatosplenomegaly (eosinophilic leukemia), mediator-release syndromes (basophilic or mast cell leukemia), and intense marrow fibrosis (megakaryocytic leukemia) (see Chap. 89).

In CML, injury to a single cell results in a clone in which there is an enormous expansion of progenitors for granulocytic and, often, megakaryocytic cells. Erythropoiesis is effective but decreased. Unlike AML, maturation of progenitor cells in CML is nearly normal; hence, the predominant leukemic cells in the blood are amitotic, mature, or partially matured cells, such as myelocytes and segmented neutrophils, erythrocytes, and platelets. This process of multilineage differentiation and maturation to cells with virtually normal function accounts for the relative infrequency of severe hemorrhage or recurrent infection in the chronic phase of CML.

Because hematopoiesis is generated by a leukemic stem cell, erythropoiesis, thrombopoiesis, and granulopoiesis are leukemic in most patients with AML, CML, and other clonal myeloid diseases. Thus, qualitative abnormalities of structure and function and clonal cytogenetic abnormalities are present in erythroblasts, megakaryocytes, and granulocyte precursors in most cases of AML (see Chap. 89) and in all cases of CML (see Chap. 90).

Phenotype of Myeloid Clonal Diseases as a Result of the Matrix of Differentiation and MaturationThe phenotype of clonal myeloid diseases is a reflection of a neoplastic stem cell’s capability to differentiate into abnormal committed progenitor cells and the ability of progenitor cells to mature into identifiable cells of the erythroid, granulocytic (neutrophilic, basophilic, mastocytic, eosinophilic), monocytic, dendritic, and megakaryocytic lineages (Fig. 85–3).31,34,35

Figure 85–3.
Phenotypic subtypes of acute myelogenous leukemia. Acute myelogenous leukemia has variable morphologic expression and a variable degree of maturation of leukemic cells into recognizable precursors of each blood cell type. This phenotypic variation results because the leukemic lesion resides in a multipotential cell normally capable of all the commitment decisions. A. Morphologic variants of AML can be considered differentiation variants in which the cells derived from one of the options of commitment accumulate prominently (e.g., leukemic erythroblasts, leukemic monocytes, leukemic megakaryocytes). In promyelocytic leukemia and in some cases of acute leukemia in younger individuals, the somatic mutation may arise in a more differentiated progenitor. B. Acute myeloblastic leukemia, promyelocytic leukemia, subacute myelogenous leukemia, and chronic myelogenous leukemia can be considered maturation variants in which blocks at different levels of maturation are present or do not exist.

Under normal circumstances, differentiation represents the changes from a multipotential cell to multiple unipotential lineage progenitors. Maturation represents the physical and chemical changes from a unipotential progenitor through a sequence of precursors to the fully mature and functional blood cell, including progression from a burst-forming unit–erythroid to proerythroblast to erythrocyte; from a colony-forming unit–granulocyte to myeloblast to segmented neutrophil; from a colony-forming unit–eosinophil to a segmented eosinophil; from a colony-forming unit–basophil to a mature basophil; from a colony-forming unit–mast cell to a mature mast cell; from a colony-forming unit–monocyte-macrophage to promonocyte to monocyte to macrophage or dendritic cell; and from a colony-forming unit–megakaryocyte to a diploid megakaryoblast to the polyploid megakaryocyte. A matrix, which is composed of the options of commitment to different lineages and the progressive stages of maturation at which partial or complete arrest can occur, results in the potential for a wide array of morphologic syndromes by which a leukemic stem cell can dominate hematopoiesis (see Fig. 85–2).

In the clonal myeloid diseases in which differentiation and maturation capability are retained, one of the cell lines, for example, erythrocytes, granulocytes, or platelets, tends to accumulate in the blood more prominently and results in a phenotypic expression of the disease that determines the nosology (e.g., platelets and essential thrombocythemia). In AML, the phenotypic expression may be predominantly myeloblastic (granuloblastic), erythroid, monocytic, megakaryocytic, or combinations thereof. Certain patterns are favored. In AML, myelocytic leukemia, monocytic leukemia, or a mosaic of the two cell types (myelomonocytic leukemia) are more common than erythroid, megakaryocytic, or eosinophilic leukemia. However, AML usually has a disturbance in all cell lines. In myeloblastic or myelomonocytic leukemia, overt, qualitative abnormalities of erythroblasts and megakaryocytes may occur. The prevalence of the abnormalities in the latter two lineages may not be great enough or evident enough for the observer to designate a case as erythroid or megakaryocytic leukemia. In the latter two cases, identification of markers unique for erythroid (e.g., cluster of differentiation [CD] 71) or megakaryocytic cells (e.g., CD41, CD42, or CD61), rather than reliance solely on light microscopy, has increased the frequency of identification of these variants.

The continuum of maturation can be completely or partially blocked at various levels, leading to morphologic variants such as acute myeloblastic, acute promyelocytic, acute myelogenous leukemia with maturation, and CML.

Pluripotential Stem Cell Pool as Site of the Lesion

Evidence points to a lesion in the multipotential hematopoietic cell pool in most of the clonal myeloid diseases, explaining the involvement of erythropoiesis, granulopoiesis, and thrombopoiesis. In CML patients, the mutation is in the pluripotential stem cell; in other syndromes, evidence for involvement of B and T lymphocytes is variable. B lymphocytes are derived from the clone in most cases. The evidence for T lymphocyte involvement is less compelling. Evidence that affected T lymphocytes undergo apoptosis before entering the blood in patients with CML may explain the absence of clonal markers in T lymphocytes in some cases of CML and other clonal myeloid disorders.36

Thus, the mutation of the cell may be at level 1, between levels 1 and 2, or at level 2 in Figure 85–2 in different clonal myeloid diseases and in different patients.

Progenitor Cell Leukemia

Analysis of cases of AML in girls and women who were heterozygous for isotypes A and B of the enzyme glucose-6-phosphate dehydrogenase indicated that the AML clone in the girls was restricted to the granulocyte–monocyte pathway, whereas monoclonality was expressed in all cell lines in the women. These findings are in keeping with all prior CML and AML studies using enzymes or chromosome markers.37,38 These findings support the possibility that a leukemic transformation in some (young) patients can occur in progenitor cells (e.g., colony-forming unit—granulocyte-monocyte; level 3 in Fig. 85–2) and result in a true acute “granulocytic” leukemia. If progenitor cell myelogenous leukemia is common in younger patients, this pattern could explain their better response to treatment. In a subset of patients with acute monocytic leukemia,39 t(8;21) AML,40 and t(15;17) AML,41 the leukemia derives from the neoplastic transformation of a progenitor cell. The acute transformation of CML also appears to occur in a granulocyte-monocyte progenitor (see Chap. 90).

Quantitativeness of Clonal Myeloid Diseases

The lesions of the primitive hematopoietic multipotential cell compartment are qualitative in the sense that a distinct alteration from normal is seen in the function of that cell pool. The alteration reflects a change in the genome of one primitive hematopoietic cell.11 This qualitative change, however, is such that the mutant multipotential cell can express all or some of the normal differentiation and maturation options. This expression can mimic the differentiation (commitment) and maturation expected of normal hematopoietic cells, as occurs in CML, essential thrombocythemia, and polycythemia vera. Most cases tend to conform to readily recognized patterns, but the opportunity for a large number of variations on the most common themes is possible. Thus, some mixed and “in-between” syndromes occur in which features of ineffective hematopoiesis and myeloproliferation of different cell lineages are present. For example, extreme thrombocytosis, usually confined to primary thrombocythemia, may accompany CML, primary myelofibrosis, or clonal bicytopenia. Erythrocytosis may rarely accompany CML. Atypical myeloproliferative syndromes or other clonal myeloid diseases may have mixtures of anemia, granulocytopenia, and thrombocytosis or of anemia, granulocytosis, and thrombocytopenia rather than pancytopenia. Qualitative abnormalities of red cell, granulocyte, or platelet structure or function may be more or less prominent in a given patient. For example, qualitative abnormalities of erythroblast development may result in acquired -thalassemia (acquired hemoglobin H disease), especially in patients with primary myelofibrosis or occasionally other clonal myeloid diseases. In AML, unusual patterns of phenotypic expression occur frequently. For example, prominent leukemic erythroblasts and monocytes or eosinophils and monocytes may be seen in patients. So much opportunity for variation in disease expression exists among patients with AML that observation of patients in whom the phenotype of their leukemic cells is identical to the phenotype of other patients is unusual. Choice of treatment is little affected by these variations. Decisions about whether to treat and which drugs to use are greatly influenced by whether a patient has a chronic, subacute, or acute clonal myeloid disease; by the rate of progression of the disease; by the extent of the leukemic blast cell infiltrate; by the cytogenetic findings; and by the severity of the cytopenias. The diagnostician and therapist usually can identify variants as a clonal myeloid disorder and can manage the disorder as dictated by their manifestations regardless of their precise subclassification.

Interplay of Clonal and Polyclonal Hematopoiesis

Although potentially curative chemotherapy of myelogenous leukemia was introduced in the mid-20th century to kill “the last leukemic cell,” two important factors were not explicitly appreciated. The first was whether residual normal stem cells coexisted in marrow to restore polyclonal (normal) hematopoiesis if ablation of the leukemia was accomplished. The second was whether, given the estimates of 1 trillion leukemic cells in a patient, the therapist had to eliminate all the leukemic cells to achieve a cure. A corollary of the latter was whether the disease was the result of a leukemic stem cell and, if it was, were the replicates of the leukemic cell the only cells that mattered, ultimately, in the eradication process. We know that remissions result from sufficient suppression of the leukemic population by intensive chemotherapy to permit restitution of polyclonal hematopoiesis by normal stem cells (Fig. 85–4).42 Why monoclonal leukemic hematopoiesis is so difficult to subdue, even temporarily, with intensive chemotherapy (pretyrosine kinase therapy) in the chronic myeloid neoplasms (e.g., CML) compared to the acute myeloid neoplasms (AML) is unclear. Prolonged remission (>3 years) may occur in some cases of AML with late relapse occurring from the same clone, suggesting a new symbiotic relationship occurs after intensive therapy that suppresses the growth potential of leukemic cells. However, this phenomenon is more evident in lymphoid than myeloid neoplasms.

Figure 85–4.
Remission–relapse pattern of acute myelogenous leukemia. A. Acute myelogenous leukemia at diagnosis or in relapse. Monoclonal leukemic hematopoiesis predominates. Normal polyclonal stem cell function is suppressed. B. Following effective cytotoxic treatment leukemic cells are unapparent in marrow and blood. Severe pancytopenia exists as a result of cytotoxic therapy. The reduction in leukemic cells can release inhibition of normal polyclonal stem cell function. C. If reconstitution of normal hematopoiesis ensues, a remission is established and blood cells return to near normal as a result of the recovery of polyclonal hematopoiesis. This relapse–remission pattern has not been seen in the subacute and chronic myeloid leukemias because it has not been possible to minimize the leukemic cell population with cytotoxic therapy to a point at which polyclonal hematopoiesis is restored. The only exception is the effect of BCR-ABL inhibitor therapy in which suppression of BCR-ABL–positive cells in CML can be achieved with return of polyclonal hematopoiesis. Uncommon examples of tyrosine kinase inhibitor responses in myeloid neoplasms with PDGFR or certain KIT mutations may also show this pattern. In a proportion of cases, BCR-ABL transcripts (minimal residual disease) can be detectable along with normal, polyclonal hematopoiesis.(Reproduced from MA Lichtman,42 with permission of Alpha Med Press.)

Clinical Manifestations

Deficiency, Excess, or Dysfunction of Blood Cells

Alterations in blood cell concentration are the primary manifestations of clonal hematopoietic disorders. The clinical manifestations of deficiencies or excesses of individual blood cell types are described in the chapters on clinical manifestations of disorders of erythrocytes (Chap. 33), granulocytes (Chap. 64), monocytes (Chap. 70), and platelets (Chap. 118).

Several clonal hematopoietic diseases frequently manifest as qualitative abnormalities of blood cells. Abnormal red cell shapes, red cell or granulocyte enzyme deficiencies, abnormal neutrophil granules, bizarre nuclear configurations, disorders of neutrophil chemotaxis, phagocytosis or microbial killing, giant platelets, abnormal platelet granules, and disturbed platelet function can occur in some patients with oligoblastic myelogenous leukemia and primary myelofibrosis. In oligoblastic myelogenous leukemia, the effects of severe cytopenia usually dominate. In primary myelofibrosis and essential thrombocythemia, functional platelet abnormalities may contribute to the hemorrhagic diathesis, especially if surgery or injury occurs. Paroxysmal nocturnal hemoglobinuria is a hematopoietic multipotential cell disease resulting from a somatic mutation of the PIG-A gene on the active X chromosome. The mutation causes a highly specific alteration in blood cell membranes, a deficiency in the glycosylphosphatidylinisotol (GPI) anchor, with decreased cell surface CD59, rendering the blood cells exquisitely sensitive to complement lysis. In its classic form, chronic hemolytic anemia is coupled with mild decreases in neutrophil and platelet counts but depressions in hematopoiesis often occur (hypoplastic marrow; see Chap. 40). Patients with CML or polycythemia vera usually do not have clinically significant functional abnormalities of cells, although in polycythemia vera, neutrophils often are activated with heightened metabolic rates and enhanced phagocytosis.

Secondary clinical manifestations occur as a result of the proliferation and accumulation of the malignant (leukemic) cells.

Effects of Leukemic Blast Cells

Extramedullary Tumors

Myeloid (granulocytic) sarcomas (also called chloromas or myeloblastomas) are discrete tumors of leukemic cells that form in skin and soft tissues, breast, periosteum and bone, lymph nodes, mediastinum, lung, pleura, gastrointestinal tract, gonads, urinary tract, uterus, central nervous system, and virtually any other site (see Chap. 89).43–45 They can develop in patients with AML or the accelerated phase of CML and, occasionally, may be the first manifestation of AML, preceding the onset in marrow and blood by months or years. Myeloid sarcomas can be mistaken for large cell lymphomas because of the similarity of the histopathology in biopsy specimens from soft tissues. In the past, approximately 50 percent of cases that occur in the absence of blood and marrow involvement initially were misdiagnosed, usually as lymphoma.43 The presence of eosinophils or other granulocytes may arouse suspicion of a myeloid sarcoma; however, immunohistochemistry should be used on such lesions to identify myeloperoxidase, lysozyme, CD117, CD61, CD68/KP1, and other relevant CD markers of myeloid cells. One of four histopathologic patterns usually is evident by immunocytochemistry: myeloblastic, monoblastic, myelomonoblastic, or megakaryoblastic.

More diffuse collections of leukemic promonocytes or monoblasts can invade the skin, gingiva, anal canal, lymph nodes, central nervous system, or other tissues of patients with AML of the monocytic subtype and may form tumors in those locations. Leukemic monocytes tend to mature to the point at which they develop many of the cytoplasmic and membrane features required for motility and tissue entry.46–48 Moreover, leukemic monocytes proliferate and survive in tissues for long periods. Consequently, this AML phenotype has a higher frequency of overt infiltrative tissue lesions than do other forms of AML.

Extramedullary tumors may usher in the accelerated phase of CML. These tumors may be composed of myeloblasts or lymphoblasts, although in each case the Ph chromosome or the BCR-ABL fusion is present in the cells, indicating the extramedullary Ph-positive lymphoblastomas are the tissue variant of the predisposition of CML to transform into a terminal deoxynucleotidyl transferase-positive lymphoblastic leukemia in approximately 30 percent of patients who enter blast crisis (see Chap. 90).

Release of Procoagulants and Fibrinolytic Activators

Microvascular thrombosis is a feature of AML of promyelocytic type, although thrombosis can occur in other forms of acute leukemia, especially in cases with elevated white cell counts or monocytic phenotypes.49,50 The leukemic promyelocytes liberate tissue factor and other procoagulants, giving rise to disseminated intravascular coagulation, and annexin II, which augments conversion of plasminogen to plasmin and contributes to the activation of fibrinolysis (see Chaps. 89, 130, and 136). Each mechanism contributes to hypofibrinogenemia and hemorrhage. Thrombin generation may mediate the microvascular thrombotic aspect of this process, which can occur in acute promyelocytic, acute monocytic, or acute myelomonocytic leukemia, either before or after cytotoxic treatment.51,52 The increased fibrinolytic activity further complicates coagulopathy in patients with promyelocytic leukemia.

Large-vessel arterial thrombosis is very rare as a presenting feature or complication of leukemia but has occurred in the setting of hyperleukocytosis and as a presenting feature of acute promyelocytic leukemia.53,54

The plasma levels of protein C antigen, functional protein C, free protein S, and antithrombin are decreased in some patients with AML. Although these changes are particularly notable in acute promyelocytic leukemia, they occur occasionally in other morphologic variants of AML. The changes are not related to liver disease or white cell count.55,56

Hyperleukocytic Syndromes

A proportion of patients with AML (5 to 15 percent) and CML (10 to 20 percent) manifest extraordinarily high blood leukocyte counts.57–61 These patients present special problems because of the effects of blast cells in the microcirculation of the lung, brain, eye, ear, and penis, and the metabolic effects that result when massive numbers of leukemic cells in blood, marrow, and tissues are simultaneously killed by cytotoxic drugs. Cell concentrations greater than 100,000/L (100 x 109/L) in AML and greater than 300,000/L (300 x 109/L) in CML usually are required to produce such problems. In CML, the manifestations of hyperleukocytosis are usually reversed by cytoreduction and may not portend a poor outcome with antityrosine kinase therapy. In AML, intracerebral hemorrhage and the impairment of pulmonary function are the most serious manifestations in predicting early death.60,61 A respiratory distress syndrome attributed to pulmonary leukostasis occurs in some patients with acute promyelocytic leukemia after all-trans-retinoic acid therapy.62 The syndrome is usually, but not always, associated with prominent neutrophilia.

The viscosity of blood is related to the total cytocrit and usually is not increased in hyperleukocytic leukemias because the reduced hematocrit compensates for increased leukocrit. This compensatory change is invariably present in AML. In CML there is a very close negative correlation of hematocrit with leukocrit, preventing an increase in bulk viscosity.57 Occasional patients with hyperleukocytic CML who are transfused initially with red cells may have a blood viscosity increased above normal.

Pathologic studies of patients who have died with hyperleukocytosis have identified leuko-occlusion, and vascular invasion in small vessels of the lung, brain, or other sites. Because viscosity in the microcirculation is a function of the plasma viscosity and the deformability of individual cells in capillaries, leukocytes should transiently raise the viscosity in such small channels. Flow in microvascular channels decreases if poorly deformable blast cells enter capillary channels.63 With high leukocyte counts, chronically reduced flow may reduce oxygen transport to tissues because the probability of leukocytes being in microchannels should increase as a function of white cell count. Moreover, trapped leukemic cells have an oxygen consumption rate that contributes to deleterious effects in the microcirculation. Leukocyte aggregation, leukocyte microthrombi, release of toxic products from leukocytes, endothelial cell damage, and microvascular invasion can contribute to vascular injury and flow impedance. Adhesive interactions between leukemic blast cells and endothelium may also be involved but have not been defined.

High leukemic blast cell counts in AML and CML may be associated with pulmonary, central nervous system, special sensory, or penile circulatory impairment (Table 85–2). Sudden death can occur in patients with hyperleukocytic acute leukemia as a result of intracranial hemorrhage.60,61 Hyperleukocytosis can be treated initially with hydration, leukapheresis, and/or cytotoxic therapy, usually hydroxyurea (see Chaps. 89 and 90). In patients with CML, leukapheresis reverses the hyperleukocytic syndrome and can reduce the extent of cytolysis-induced hyperuricemia, hyperkalemia, and hyperphosphatemia by reducing tumor cell mass before cytotoxic therapy. Hydroxyurea may follow as, or soon after, the tumor cell burden is decreased. Unfortunately, the specific effect of leukapheresis, hydroxyurea therapy, or cranial irradiation in patients with hyperleukocytic AML on duration of survival appears to be negligible.59–61

Table 85–2. Clinical Features of the Hyperleukocytic Syndrome
I. Pulmonary circulation
A. Tachypnea, dyspnea, cyanosis
B. Alveolar–capillary block
C. Pulmonary infiltrates
D. Postchemotherapy respiratory dysfunction
II. Predisposition to tumor lysis syndrome
III. Central nervous system circulation
A. Dizziness, slurred speech, delirium, stupor
B. Intracranial (cerebral) hemorrhage
IV. Special sensory organ circulation
A. Visual blurring
B. Papilledema
C. Diplopia
D. Tinnitus, impaired hearing
E. Retinal vein distention, retinal hemorrhages
V. Penile circulation
A. Priapism
VI. Spurious laboratory results
A. Decreased blood partial pressure of oxygen (PO2); increased serum potassium
B. Decreased plasma glucose; increased mean corpuscular volume, red cell count, hemoglobin, and hematocrit

Thrombocythemic Syndromes: Hemorrhage and Thrombophilia

Hemorrhagic or thrombotic episodes can develop during the course of essential thrombocythemia or thrombocythemia associated with other clonal myeloid diseases.62–64 Arterial vascular insufficiency and venous thrombosis are the major vascular manifestations of thrombocythemia. Peripheral vascular insufficiency with gangrene and cerebral vascular thrombi can occur. Thrombosis of superficial or deep veins of the extremities occurs frequently.65 Mesenteric, hepatic, portal, splenic, or penile venous thrombosis can develop. Hemorrhage is an occasional manifestation of thrombocythemia and can occur concomitantly with thrombotic episodes. Gastrointestinal hemorrhage and cutaneous hemorrhage, the latter especially after trauma, happen most frequently, but bleeding from other sites also can occur (see Chap. 87).

Procoagulant factors, such as the content of platelet tissue factor and blood platelet neutrophil aggregates, are higher in patients with essential thrombocythemia than normal subjects and are higher among patients with the V617F JAK2 mutation than patients with wild-type gene structure.65,66

Thrombotic complications occur in approximately 40 percent of patients with polycythemia vera.65,67 Erythrocytosis and thrombocytosis may interact and cause hypercoagulability, especially in the abdominal venous circulation. A syndrome of splanchnic venous thrombosis associated with endogenous erythroid colony growth, the latter characteristic of polycythemia vera, but without blood cell count changes indicative of a myeloproliferative disease, has accounted for a high proportion of patients with apparent idiopathic hepatic or portal vein thrombosis.68,69 These cases may have blood cells with the Janus kinase 2 (JAK2) gene mutation without a clinically apparent myeloproliferative phenotype.70

Nearly half of patients with paroxysmal nocturnal hemoglobinuria have thrombosis, especially in the venous system. Thrombosis of the veins of the abdomen, liver, and other organs, characteristic complications of paroxysmal nocturnal hemoglobinuria, may result from a complex thrombophilic state related to nitric oxide depletion, formation of prothrombotic platelet microvesicles, the dysfunction of tissue factor pathway inhibitor, and other factors.71,72 Thrombosis is more common in paroxysmal nocturnal hemoglobinuria (PNH) patients with the classical hemolytic syndrome than in those with the PNH-aplastic anemia hybrid (see Chap. 40).

Systemic Symptoms

Fever, weight loss, and malaise occur as early manifestations of AML. At the time of diagnosis, low-grade fever is present in nearly 50 percent of patients.73 Although minor infections may be present, severe systemic infections are relatively uncommon at the time of AML diagnosis.74 However, fever during cytotoxic therapy, when neutrophil counts are extremely low, nearly always is a sign of infection. Fever also may be a manifestation of the acute leukemic transformation of CML and can occur in patients with oligoblastic myelogenous leukemia (refractory anemia with excess blasts).

Weight loss occurs in nearly 20 percent of patients with AML.74 Loss of well-being and intolerance to exertion may be disproportionate to the extent of anemia and may not be corrected by red cell transfusions. The pathogenesis of these effects is unknown.

Metabolic Signs

Hyperuricemia and hyperuricosuria are common manifestations of AML and CML. Acute gouty arthritis and hyperuricosuric nephropathy are less common. If therapy is instituted without a reduction in plasma uric acid and without adequate hydration, saturation of the urine with uric acid can lead to precipitation of urate (gravel) and obstructive uropathy. If the uropathy is severe, urine flow can be obliterated, and renal failure ensues. Hyponatremia can occur in AML, and in some cases results from inappropriate antidiuretic hormone secretion. Hyponatremia also can result from an osmotic diuresis of urea, creatinine, urate, and other substances released from blast cells and wasting muscles. Hypernatremia is rare but may be seen in cases with central diabetes insipidus. Hypokalemia is commonly seen in AML74–76 and is thought to be caused by injury to the kidney by increased plasma and urine lysozyme and subsequent kaliuresis. Hypokalemia is related to excessive urinary potassium loss, but the correlation with lysozymuria is imperfect. Other mechanisms probably are responsible in most cases, including osmotic diuresis and tubular dysfunction. Kaliuretic antibiotics, often administered to patients with AML, may accentuate the hypokalemia. Hyperkalemia is very unusual, but may be seen with tumor lysis syndrome. Hypercalcemia occurs in occasional patients with AML. Several causes have been proposed, including bone resorption as a result of leukemic infiltration. This explanation is in keeping with the normal serum inorganic phosphate in most patients. Occasional patients with hypercalcemia, and hypophosphatemia can have ectopic parathyroid hormone secretion by leukemic blast cells. Hypophosphatemia also can occur because of rapid utilization of plasma inorganic phosphate in some cases of myelogenous leukemia with a high blood blast cell count and a high fraction of proliferative cells. Hyperphosphatemia is uncommon, except as a reflection of the tumor lysis syndrome. Approximately 10 percent of persons with AML show varying degrees of tumor lysis syndrome in the week after onset of therapy, reflected in at least (>1.6 mmol/L [>5 doubling of baseline creatinine, and increases in serum phosphate mg/dL]), uric acid (>416 mmol/L [>7mg/dL]), or potassium (>5 mmol/L [>5 mEq/L]).77 Hypomagnesemia is common as a result of low intake coupled with gastrointestinal loss and a shift of magnesium to the intracellular compartment.

Acid–base disturbances occur in approximately 25 percent of patients, the majority having respiratory or metabolic alkalosis.76 The latter may be secondary to volume depletion, upper gastrointestinal fluid loss, and hypokalemia. Lactic acidosis also has been observed in association with AML, although the mechanism is obscure. True hypoxia can result from the hyperleukocytic syndrome as a consequence of pulmonary vascular leukostasis (see also “Factitious Laboratory Results” below)

Increased serum concentrations of lipoprotein (a) and decreased concentrations of both low-density and high-density lipoproteins have been observed in a high proportion of patients with AML.78 The increased level of lipoprotein (a), which returns to normal after successful treatment, correlates with the presence of leukemic blast cells. Serum prolactin also is increased in some patients with AML.79 Leukemic blast cells may be an ectopic source of this hormone.79

Colony-stimulating factor-1 is elevated in a variety of lymphoid and hemopoietic malignancies, including AML and CML.80 The malignant cells have been proposed as the source of excess cytokine.

Factitious Laboratory Results

Elevations of serum potassium levels have resulted from the release of potassium from platelets or, less often, leukocytes in patients with myeloproliferative diseases and extreme elevations in those blood cell concentrations. If blood is collected in a tube that contains an anticoagulant and the plasma is removed after high-speed centrifugation, the potassium concentration is normal. Glucose can be falsely decreased, especially because autoanalyzer techniques call for omission of glycolytic inhibitors such as sodium fluoride in collection tubes. Blood with high leukocyte counts, if it stands prior to separation of the plasma, may have a significant amount of glucose metabolism by leukocytes. Factitious hypoglycemia also can occur as a result of red cell utilization of glucose, especially in polycythemic patients. True hypoglycemia has been observed rarely in patients with leukemia. Arterial blood oxygen content also can be lowered spuriously as a result of in vitro utilization by large numbers of leukocytes, while the anticoagulated blood awaits measurement.

Specific Organ Involvement

Clonal myeloid diseases lead to disturbances principally in marrow, blood, and spleen. Although clusters of cells may be found in all organs, major infiltrates and organ dysfunction are unusual. In AML and the acute blastic phase of CML, clinically significant infiltration of the larynx, central nervous system, heart, lungs, bone, joints, gastrointestinal tract, genitourinary tract, skin, or virtually any other organ can occur.


In AML, palpable splenomegaly is present in approximately one-third of cases but usually is slight in extent. In the chronic myeloproliferative diseases, palpable splenomegaly is present in a high proportion of cases (polycythemia vera ~80 percent, CML ~90 percent, primary myelofibrosis ~100 percent). In essential thrombocythemia, splenic enlargement is present in approximately 60 percent of patients. A predisposition to silent splenic vascular thrombi, infarction, and subsequent splenic atrophy, analogous to that occurring in sickle cell anemia, is postulated as the cause of the lower frequency of splenic enlargement in essential thrombocythemia. Early satiety, left-upper-quadrant discomfort, splenic infarctions with painful perisplenitis, diaphragmatic pleuritis, and shoulder pain may occur in patients with splenomegaly, especially in the acute phase of CML and in primary myelofibrosis. In primary myelofibrosis, the spleen can become enormous, occupying the left hemiabdomen. Blood flow through the splenic vein can be so great as to lead to portal hypertension and gastroesophageal varices. Usually, reduced hepatic venous compliance also is present (see Chap. 91). Bleeding and, occasionally, encephalopathy can result from portal–systemic venous shunts.

Marrow Necrosis

Extensive marrow necrosis, an uncommon event, can occur in any clonal myeloid disease, especially AML, and less often, primary myelofibrosis, CML, essential thrombocythemia, and polycythemia vera. Bone pain and fever are the most common initial findings. Anemia and thrombocytopenia are very common, as are nucleated red cells and myelocytes in the blood (leukoerythroblastic reaction).81,82 Marrow aspiration does not result in a useful sample but biopsy early in the process usually shows hypocellularity with loss of marrow cell structural definition (blurred staining of residual cells), evidence of cell necrosis, gelatinous transformation of marrow, and, often, an amorphous eosinophilic material throughout. The mechanism is thought to be microvascular dysfunction. Restitution of marrow and repopulation of hematopoietic tissue often may follow. The prognosis is a function of the underlying disease.


1. Dick JE, Lapidot T: Biology of normal and acute myeloid leukemia stem cells. Int J Hematol 82:389, 2005. [PMID: 16533740]
2. Jordan CT: Searching for leukemia stem cells—Not yet the end of the road. Cancer Cell 10:253, 2006. [PMID: 17045202]
3. Jordan CT, Guzman ML, Noble M: Cancer stem cells. N Engl J Med 355:1253, 2006. [PMID: 16990388]
4. Rozman CGM, Feliu E, Rubio D, et al: Life expectancy of patients with chronic nonleukemic myeloproliferative disorders. Cancer 67:2658, 1991. [PMID: 2015567]
5. Germing U, Gattermann N, Aivado M, et al: Two types of acquired idiopathic sideroblastic anaemia (AISA): A time-tested distinction. Br J Haematol 108:724, 2000. [PMID: 10792275]
6. Jaffe ES, Harris NL, Stein H, Vardiman JW: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, 2001.
7. Lichtman MA: Myelodysplasia or myeloneoplasia: Thoughts on the nosology of clonal myeloid diseases. Blood Cells Mol Dis 26:572, 2000. [PMID: 11112390]
8. Bessis M, Bernard J: Hematopoietic dysplasias (preleukemic states) Blood Cells 2:5, 1976.
9. Spivak JL, Silver RT: The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: An alternative proposal. Blood 112:231, 2008. [PMID: 18401028]
10. Kiladjian JJ, Gardin C, Renoux M, et al: Long-term outcomes of polycythemia vera patients treated with pipobroman as initial therapy. Hematol J 4:198, 2003. [PMID: 12764352]
11. Tefferi A, Fonesca R, Pereira DL, Hoagland HC: A long-term retrospective study of young women with essential thrombocythemia. Mayo Clin Proc 76:22, 2001. [PMID: 11155408]
12. Passamonti F, Malabarba L, Orlandi E, et al: Polycythemia in young patients: A study on the long-term risk of thrombosis, myelofibrosis and leukemia. Haematologica 88:13, 2003. [PMID: 12551821]
13. Lichtman MA: Is it chronic idiopathic myelofibrosis, myelofibrosis with myeloid metaplasia, chronic megakaryocytic-granulocytic myelosis, or chronic megakaryocytic leukemia? Further thoughts on the nosology of the clonal myeloid disorders. Leukemia 19:1139, 2005. [PMID: 15902283]
14. Simon W, Segel GB, Lichtman MA: Early allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era: A preliminary assessment. Blood Cells Mol Dis 37:116, 2006. [PMID: 16904348]
15. Tefferi A, Elliott MA, Pardanani A: Atypical myeloproliferative disorders: Diagnosis and management. Mayo Clin Proc 81:553, 2006. [PMID: 16610578]
16. Tefferi A, Vardiman JW: Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 22:14, 2008. [PMID: 17882280]
17. Breccia M, Cannella L, Frustaci A, et al: Chronic myelomonocytic leukemia with antecedent refractory anemia with excess blasts: further evidence for the arbitrary nature of current classification systems. Leuk Lymphoma 49:1292, 2008. [PMID: 18604717]
18. Breccia M, Latagliata R, Cannella L, et al: Analysis of prognostic factors in patients with refractory anemia with excess of blasts (RAEB) reclassified according to WHO proposal. Leuk Res 33:391, 2009. [PMID: 18676015]
19. Barnard DR, Kalousek DK, Wiersma SR, et al: Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood. Leukemia 10:5,1996. [PMID: 8558938]
20. Bene MC, Castoldi G, Knapp W, et al: Proposals for the immunological classification of acute leukemias. Leukemia 9:1783, 1995. [PMID: 7564526]
21. Jennings CD, Foon KA: Recent advances in flow cytometry: Application to the diagnosis of hematologic malignancy. Blood 90:2863, 1997. [PMID: 9376567]
22. (accessed August 2008).
23. Oyan AM, Bø TH, Jonassen I, et al: Global gene expression in classification, pathogenetic understanding and identification of therapeutic targets in acute myeloid leukemia. Curr Pharm Biotechnol 8:344, 2007. [PMID: 18289043]
24. Valk PJM, Verhaak RGW, Beijen A, et al: Prognostically useful gene expression profiles in acute myeloid leukemia. N Engl J Med 350:1617, 2004. [PMID: 15084694]
25. Bullinger L, Döhner K, Kranz R, et al: An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML. Blood 111:4490, 2008. [PMID: 18309032]
26. Jongen-Lavrencic M, Sun SM, Dijkstra MK, et al: MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood 111:5078, 2008. [PMID: 18337557]
27. Garzon R, Croce CM: MicroRNAs in normal and malignant hematopoiesis. Curr Opin Hematol 15:352 2008.
28. Mills K I. Gene expression profiling for the diagnosis and prognosis of acute myeloid leukemia. Front Biosci 13:4605, 2008. [PMID: 18508532]
29. Andrieux J, Demory JL, Caulier MT, et al: Karyotype abnormalities in myelofibrosis following polycythemia vera. Cancer Genet Cytogenet 140:118, 2003. [PMID: 12645649]
30. Finazzi G, Caruso V, Marchioli R, et al: Acute leukemia in polycythemia vera: An analysis of 1638 patients enrolled in a prospective observational study. Blood 105:2664, 2005. [PMID: 15585653]
31. Lichtman MA: The stem cell in the pathogenesis and treatment of myelogenous leukemia: A perspective. Leukemia 15:1489, 2001. [PMID: 11587204]
32. Gilliland DG: Molecular genetics of human leukemias: New insights into therapy. Semin Hematol 39:6, 2002. [PMID: 12447846]
33. Lichtman MA, Segel GB: Uncommon phenotypes of acute myelogenous leukemia: Basophilic, mast cell, eosinophilic, and myeloid dendritic cell subtypes: A review. Blood Cells Mol Dis 35:370, 2005. [PMID: 16203163]
34. Ploemacher RE: Characterization and biology of normal human haematopoietic stem cells. Haematologica 84:4(EHA-4), 1999.
35. Bonnet D, Dick J: Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730, 1997. [PMID: 9212098]
36. Takahashi N, Maura I, Saitoh K, Miura AB: Lineage involvement of stem cells bearing the Philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood 92:4758, 1998. [PMID: 9845542]
37. Fialkow PJ, Singer JW, Adamson JW, et al: Acute nonlymphocytic leukemia: Expression in cells restricted to granulocytic and monocytic differentiation. N Engl J Med 301:1, 1979. [PMID: 286882]
38. Fialkow PJ, Singer JW, Adamson JW, et al: Acute nonlymphocytic leukemia: Heterogeneity of stem cell origin. Blood 57:1068, 1981. [PMID: 6939452]
39. Ferraris AM, Broccia G, Meloni T, et al: Clonal origin of cells restricted to monocytic differentiation in acute nonlymphocytic leukemia. Blood 64:817, 1984. [PMID: 6592008]
40. Van Lom K, Hagenmaijer A, Vandekerckhove F, et al: Clonality analysis of hematopoietic cell lineages in acute myeloid leukemia and trans-location (8;21): Only myeloid cells are part of the malignant clone. Leukemia 11:202, 1997.
41. Grimwade D, Enver T: Acute promyelocytic leukemia: Where does it stem from? Leukemia 18:375, 2004. [PMID: 14737069]
42. Lichtman MA: Interrupting the inhibition of normal hematopoiesis in myelogenous leukemia: A hypothetical approach to therapy. Stem Cells 18(5):304, 2000. [PMID: 11007914]
43. Menasce LP, Banerjee SS, Becket E, Harris M: Extramedullary myeloid tumor (granulocytic sarcoma) is often misdiagnosed. A study of 26 cases. Histopathology 34:391, 1999. [PMID: 10231412]
44. Pileri SA, Ascani S, Cox MC, et al: Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients. Leukemia 21:340, 2007. [PMID: 17170724]
45. Tsimberidou AM, Kantarjian HM, Wen S, et al: Myeloid sarcoma is associated with superior event-free survival and overall survival compared with acute myeloid leukemia. Cancer 113:1370, 2008 .
46. Lichtman MA, Weed RI: Peripheral cytoplasmic characteristics of leukemia cells in monocytic leukemia: Relationship to clinical manifestations. Blood 40:52, 1972. [PMID: 4504250]
47. Peterson L, Dekner LP, Brunning RD: Extramedullary masses as presenting features of acute monoblastic leukemia. Am J Clin Pathol 75:140, 1981. [PMID: 6937136]
48. Tobelem G, Jacquillat C, Chastang C, et al: Acute monoblastic leukemia: A clinical and biologic study of 74 cases. Blood 55:71, 1980. [PMID: 6927957]
49. Weltermann A, Pabinger I, Geissler K, et al: Hypofibrinogenemia in non-M3 acute myeloid leukemia. Incidence, clinical and laboratory characteristics and prognosis. Leukemia 12:1182, 1998. [PMID: 9697871]
50. Uchiumi H, Matsushima T, Yamane A, et al: Prevalence and clinical characteristics of acute myeloid leukemia associated with disseminated intravascular coagulation. Int J Hematol 86:137, 2007. [PMID: 17875527]
51. Falanga A, Rickles FR: Pathogenesis and management of the bleeding diathesis in acute promyelocytic leukaemia. Best Pract Res Clin Haematol 16:463, 2003. [PMID: 12935963]
52. Tallman MS, Abutalib SA, Altman JK: The double hazard of thrombophilia and bleeding in acute promyelocytic leukemia. Semin Thromb Hemost 33:330, 2007. [PMID: 17525890]
53. Kalk E, Goede A, Rose P: Acute arterial thrombosis in acute promyelocytic