Chapter 11: Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia

The hypoproliferative anemias are normochromic, normocytic, or macrocytic and are characterized by a low reticulocyte count. Hypoproliferative anemia is also a prominent feature of hematologic diseases that are described as bone marrow failure states; these include aplastic anemia, myelodysplastic syndrome (MDS), pure red cell aplasia (PRCA), and myelophthisis. Anemia in these disorders is often not a solitary or even the major hematologic finding. More frequent in bone marrow failure is pancytopenia: anemia, leukopenia, and thrombocytopenia. Low blood counts in the marrow failure diseases result from deficient hematopoiesis, as distinguished from blood count depression due to peripheral destruction of red cells (hemolytic anemias), platelets (idiopathic thrombocytopenic purpura [ITP] or due to splenomegaly), and granulocytes (as in the immune leukopenias). Marrow damage and dysfunction also may be secondary to infection, inflammation, or cancer.

Hematopoietic failure syndromes are classified by dominant morphologic features of the bone marrow (Table 11-1). Although practical distinction among these syndromes usually is clear, some processes are so closely related that the diagnosis may be complex. Patients may seem to suffer from two or three related diseases simultaneously, or one diagnosis may appear to evolve into another. Many of these syndromes share an immune-mediated mechanism of marrow destruction and some element of genomic instability resulting in a higher rate of malignant transformation.

It is important that the internist and general practitioner recognize the marrow failure syndromes, as their prognosis may be poor if the patient is untreated; effective therapies are often available but sufficiently complicated in their choice and delivery so as to warrant the care of a hematologist or oncologist.

DEFINITION

Aplastic anemia is pancytopenia with bone marrow hypocellularity. Acquired aplastic anemia is distinguished from iatrogenic aplasia, marrow hypocellularity after intensive cytotoxic chemotherapy for cancer. Aplastic anemia can also be constitutional: the genetic diseases Fanconi anemia and dyskeratosis congenita, although frequently associated with typical physical anomalies and the development of pancytopenia early in life, can also present as marrow failure in normal-appearing adults. Acquired aplastic anemia is often stereotypical in its manifestations, with the abrupt onset of low blood counts in a previously well young adult; seronegative hepatitis or a course of an incriminated medical drug may precede the onset. The diagnosis in these instances is uncomplicated. Sometimes blood count depression is moderate or incomplete, resulting in anemia, leukopenia, and thrombocytopenia in some combination. Aplastic anemia is related to both paroxysmal nocturnal hemoglobinuria (PNH; Chap. 33) and to MDS, and in some cases, a clear distinction among these disorders may not be possible.

EPIDEMIOLOGY

The incidence of acquired aplastic anemia in Europe and Israel is two cases per million persons annually. In Thailand and China, rates of five to seven per million have been established. In general, men and women are affected with equal frequency, but the age distribution is biphasic, with the major peak in the teens and twenties and a second rise in older adults.

ETIOLOGY

The origins of aplastic anemia have been inferred from several recurring clinical associations (Table 11-2); unfortunately, these relationships are not reliable in an individual patient and may not be etiologic. In addition, although most cases of aplastic anemia are idiopathic, little other than history separates these cases from those with a presumed etiology such as a drug exposure.

Radiation

Marrow aplasia is a major acute sequela of radiation. Radiation damages DNA; tissues dependent on active mitosis are particularly susceptible. Nuclear accidents involve not only power plant workers but also employees of hospitals, laboratories, and industry (food sterilization, metal radiography, etc.), as well as innocents exposed to stolen, misplaced, or misused sources. Whereas the radiation dose can be approximated from the rate and degree of decline in blood counts, dosimetry by reconstruction of the exposure can help to estimate the patient’s prognosis and also to protect medical personnel from contact with radioactive tissue and excreta. MDS and leukemia, but probably not aplastic anemia, are late effects of radiation.

Chemicals

Benzene is a notorious cause of bone marrow failure: epidemiologic, clinical, and laboratory data link benzene to aplastic anemia, acute leukemia, and blood and marrow abnormalities. For leukemia, incidence is correlated with cumulative exposure, but susceptibility must also be important, because only a minority of even heavily exposed workers develop myelotoxicity. The employment history is important, especially in industries where benzene is used for a secondary purpose, usually as a solvent. Benzene-related blood diseases have declined with regulation of industrial exposure. Although benzene is no longer generally available as a household solvent, exposure to its metabolites occurs in the normal diet and in the environment. The association between marrow failure and other chemicals is much less well substantiated.

Drugs

(Table 11-3) Many chemotherapeutic drugs have marrow suppression as a major toxicity; effects are dose dependent and will occur in all recipients. In contrast, idiosyncratic reactions to a large and diverse group of drugs may lead to aplastic anemia without a clear dose-response relationship. These associations rest largely on accumulated case reports until a large international study in Europe in the 1980s quantitated drug relationships, especially for nonsteroidal analgesics, sulfonamides, thyrostatic drugs, some psychotropics, penicillamine, allopurinol, and gold. Association does not equal causation: a drug may have been used to treat the first symptoms of bone marrow failure (antibiotics for fever or the preceding viral illness) or provoked the first symptom of a preexisting disease (petechiae by nonsteroidal anti-inflammatory agents administered to the thrombocytopenic patient). In the context of total drug use, idiosyncratic reactions, although individually devastating, are rare events. Risk estimates are usually lower when determined in population-based studies. Furthermore, the low absolute risk is also made more obvious: even a 10- or 20-fold increase in risk translates, in a rare disease, to just a handful of drug-induced aplastic anemia cases among hundreds of thousands of exposed persons.

Infections

Hepatitis is the most common preceding infection, and posthepatitis marrow failure accounts for approximately 5% of etiologies in most series. Patients are usually young men who have recovered from a bout of liver inflammation 1 to 2 months earlier; the subsequent pancytopenia is very severe. The hepatitis is seronegative (non-A, non-B, non-C) and possibly due to an as yet undiscovered infectious agent. Fulminant liver failure in childhood also follows seronegative hepatitis, and marrow failure occurs at a high rate in these patients. Aplastic anemia can rarely follow infectious mononucleosis. Parvovirus B19, the cause of transient aplastic crisis in hemolytic anemias and of some PRCAs (see below), does not usually cause generalized bone marrow failure. Mild blood count depression is frequent in the course of many viral and bacterial infections but resolves with the infection.

Immunologic diseases

Aplasia is a major consequence and the inevitable cause of death in transfusion-associated graft-versus-host disease (GVHD) that can occur after infusion of nonirradiated blood products to an immunodeficient recipient. Aplastic anemia is strongly associated with the rare collagen vascular syndrome eosinophilic fasciitis that is characterized by painful induration of subcutaneous tissues. Thymoma and hypoimmunoglobulinemia are occasional associations with aplastic anemia. Pancytopenia with marrow hypoplasia can also occur in systemic lupus erythematosus (SLE).

Pregnancy

Aplastic anemia very rarely may occur and recur during pregnancy and resolve with delivery or with spontaneous or induced abortion.

Paroxysmal nocturnal hemoglobinuria

An acquired mutation in the PIG-A gene in a hematopoietic stem cell is required for the development of PNH, but PIG-A mutations probably occur commonly in normal individuals. If the PIG-A mutant stem cell proliferates, the result is a clone of progeny deficient in glycosylphosphatidylinositol-linked cell surface membrane proteins (Chap. 33). Small clones of deficient cells can be detected by sensitive flow cytometry tests in one-half or more of patients with aplastic anemia at the time of presentation. Functional studies of bone marrow from PNH patients, even those with mainly hemolytic manifestations, show evidence of defective hematopoiesis. Patients with an initial clinical diagnosis of PNH, especially younger individuals, may later develop frank marrow aplasia and pancytopenia; patients with an initial diagnosis of aplastic anemia may suffer from hemolytic PNH years after recovery of blood counts.

Constitutional disorders

Fanconi anemia, an autosomal recessive disorder, manifests as congenital developmental anomalies, progressive pancytopenia, and an increased risk of malignancy. Chromosomes in Fanconi anemia are peculiarly susceptible to DNA cross-linking agents, the basis for a diagnostic assay. Patients with Fanconi anemia typically have short stature, café au lait spots, and anomalies involving the thumb, radius, and genitourinary tract. At least 16 different genetic defects (all but one with an identified gene) have been defined; the most common, type A Fanconi anemia, is due to a mutation in FANCA. Most of the Fanconi anemia gene products form a protein complex that activates FANCD2 by monoubiquitination to play a role in the cellular response to DNA damage and especially interstrand cross-linking.

Dyskeratosis congenita is characterized by the triad of mucous membrane leukoplasia, dystrophic nails, reticular hyperpigmentation, and with the development of aplastic anemia in childhood. Dyskeratosis is due to mutations in genes of the telomere repair complex, which acts to maintain telomere length in replicating cells: the X-linked variety is due to mutations in the DKC1 (dyskerin) gene; the more unusual autosomal dominant type is due to mutation in TERC, which encodes an RNA template, and TERT, which encodes the catalytic reverse transcriptase, telomerase. Mutations in TNF2, a component of the shelterin complex, proteins that bind the telomere DNA, also occur.

In Shwachman-Diamond syndrome, presentation is early in life with neutropenia with pancreatic insufficiency and malabsorption; most patients have compound heterozygous mutations in SBDS that may affect both ribosomal biogenesis (as in Diamond-Blackfan anemia; see below) and marrow stroma function.

While these constitutional syndromes can on occasion present in adults, genetic mutations are also risk factors for bone marrow failure. In the recently recognized telomeropathies, mutations in TERT and TERC have subtle effects on hematopoietic function. Typical presentations include not only severe but also moderate aplastic anemia, which can be chronic and not progressive, and isolated macrocytic anemia or thrombocytopenia. Physical anomalies are usually not found in the patient, although early hair graying is a clue to the diagnosis. A careful family history may disclose pulmonary fibrosis and hepatic cirrhosis. Specific involvement of the bone marrow, liver, and lung is highly variable, as is penetrance of clinical phenotype, both within families and among kindreds. Variable penetrance means that TERT and TERC mutations represent risk factors for marrow failure, as family members with the same mutations may have normal or only slight hematologic abnormalities but more subtle evidence of (compensated) hematopoietic insufficiency.

PATHOPHYSIOLOGY

Bone marrow failure results from severe damage to the hematopoietic cell compartment. In aplastic anemia, replacement of the bone marrow by fat is apparent in the morphology of the biopsy specimen (Fig. 11-1) and magnetic resonance imaging (MRI) of the spine. Cells bearing the CD34 antigen, a marker of early hematopoietic cells, are greatly diminished, and in functional studies, committed and primitive progenitor cells are virtually absent; in vitro assays have suggested that the stem cell pool is reduced to ≤1% of normal in severe disease at the time of presentation.

An intrinsic stem cell defect exists for the constitutional aplastic anemias: cells from patients with Fanconi anemia exhibit chromosome damage and death on exposure to certain chemical agents. Telomeres are short in some patients with aplastic anemia, due to heterozygous mutations in genes of the telomere repair complex. Telomeres may also shorten physiologically in acquired marrow failure due to replicative demands on a limited stem cell pool.

Drug injury

Extrinsic damage to the marrow follows massive physical or chemical insults such as high doses of radiation and toxic chemicals. For the more common idiosyncratic reaction to modest doses of medical drugs, altered drug metabolism has been invoked as a likely mechanism. The metabolic pathways of many drugs and chemicals, especially if they are polar and have limited water solubility, involve enzymatic degradation to highly reactive electrophilic compounds; these intermediates are toxic because of their propensity to bind to cellular macromolecules. For example, derivative hydroquinones and quinolones are responsible for benzene-induced tissue injury. Excessive generation of toxic intermediates or failure to detoxify the intermediates may be genetically determined and apparent only on specific drug challenge; the complexity and specificity of the pathways imply multiple susceptibility loci and would provide an explanation for the rarity of idiosyncratic drug reactions.

Immune-mediated injury

The recovery of marrow function in some patients prepared for bone marrow transplantation with antilymphocyte globulin first suggested that aplastic anemia might be immune mediated. Consistent with this hypothesis was the frequent failure of simple bone marrow transplantation from a syngeneic twin, without conditioning cytotoxic chemotherapy, which also argued both against simple stem cell absence as the cause and for the presence of a host factor producing marrow failure. Laboratory data support an important role for the immune system in aplastic anemia. Blood and bone marrow cells of patients can suppress normal hematopoietic progenitor cell growth, and removal of T cells from aplastic anemia bone marrow improves colony formation in vitro. Increased numbers of activated cytotoxic T cell clones are observed in aplastic anemia patients and usually decline with successful immunosuppressive therapy; type 1 cytokines are implicated; and interferon γ (IFN-γ) induces Fas expression on CD34 cells, leading to apoptotic cell death. The early immune system events in aplastic anemia are not well understood, but an oligoclonal, T cell response implies antigenic stimulus. The rarity of aplastic anemia despite common exposures (medicines, seronegative hepatitis) suggests that genetically determined features of the immune response can convert a normal physiologic response into a sustained abnormal autoimmune process, including polymorphisms in histocompatibility antigens, cytokine genes, and genes that regulate T cell polarization and effector function.

CLINICAL FEATURES

History

Aplastic anemia can appear abruptly or insidiously. Bleeding is the most common early symptom; a complaint of days to weeks of easy bruising, oozing from the gums, nose bleeds, heavy menstrual flow, and sometimes petechiae will have been noticed. With thrombocytopenia, massive hemorrhage is unusual, but small amounts of bleeding in the central nervous system can result in catastrophic intracranial or retinal hemorrhage. Symptoms of anemia are also frequent, including lassitude, weakness, shortness of breath, and a pounding sensation in the ears. Infection is an unusual first symptom in aplastic anemia (unlike in agranulocytosis, where pharyngitis, anorectal infection, or frank sepsis occurs early). A striking feature of aplastic anemia is the restriction of symptoms to the hematologic system, and patients often feel and look remarkably well despite drastically reduced blood counts. Systemic complaints and weight loss should point to other etiologies of pancytopenia. Prior drug use, chemical exposure, and preceding viral illnesses must often be elicited with repeated questioning. A family history of hematologic diseases or blood abnormalities, of pulmonary or liver fibrosis, or of early hair graying points to a telomeropathy.

Physical examination

Petechiae and ecchymoses are typical, and retinal hemorrhages may be present. Pelvic and rectal examinations can often be deferred but, when performed, should be undertaken with great gentleness to avoid trauma; these will often show bleeding from the cervical os and blood in the stool. Pallor of the skin and mucous membranes is common except in the most acute cases or those already transfused. Infection on presentation is unusual but may occur if the patient has been symptomatic for a few weeks. Lymphadenopathy and splenomegaly are highly atypical of aplastic anemia. Café au lait spots and short stature suggest Fanconi anemia; peculiar nails and leukoplakia suggest dyskeratosis congenita; early graying (and use of hair dyes to mask it!) suggests a telomerase defect.

LABORATORY STUDIES

Blood

The smear shows large erythrocytes and a paucity of platelets and granulocytes. Mean corpuscular volume (MCV) is commonly increased. Reticulocytes are absent or few, and lymphocyte numbers may be normal or reduced. The presence of immature myeloid forms suggests leukemia or MDS; nucleated red blood cells (RBCs) suggest marrow fibrosis or tumor invasion; abnormal platelets suggest either peripheral destruction or MDS.

Bone marrow

The bone marrow is usually readily aspirated but dilute on smear, and the fatty biopsy specimen may be grossly pale on withdrawal; a “dry tap” instead suggests fibrosis or myelophthisis. In severe aplasia, the smear of the aspirated specimen shows only red cells, residual lymphocytes, and stromal cells; the biopsy (which should be >1 cm in length) is superior for determination of cellularity and shows mainly fat under the microscope, with hematopoietic cells occupying <25% of the marrow space; in the most serious cases, the biopsy is virtually all fat. The correlation between marrow cellularity and disease severity is imperfect, in part because marrow cellularity declines physiologically with aging. Additionally, some patients with moderate disease by blood counts will have empty iliac crest biopsies, whereas “hot spots” of hematopoiesis may be seen in severe cases. If an iliac crest specimen is inadequate, cells may also be obtained by aspiration from the sternum. Residual hematopoietic cells should have normal morphology, except for mildly megaloblastic erythropoiesis; megakaryocytes are invariably greatly reduced and usually absent. Granulomas may indicate an infectious etiology of the marrow failure.

Ancillary studies

Chromosome breakage studies of peripheral blood using diepoxybutane or mitomycin C should be performed on children and younger adults to exclude Fanconi anemia. Very short telomere length (available commercially) strongly suggests the presence of a telomerase or shelterin mutation, which can be pursued by family studies and nucleotide sequencing. Chromosome studies of bone marrow cells are often revealing in MDS and should be negative in typical aplastic anemia. Flow cytometry offers a sensitive diagnostic test for PNH. Serologic studies may show evidence of viral infection, such as Epstein-Barr virus and HIV. Posthepatitis aplastic anemia is seronegative. The spleen size should be determined by computed tomography (CT) scanning or ultrasound if the physical examination of the abdomen is unsatisfactory. Occasionally MRI may be helpful to assess the fat content of vertebrae in order to distinguish aplasia from MDS.

DIAGNOSIS

The diagnosis of aplastic anemia is usually straightforward, based on the combination of pancytopenia with a fatty bone marrow. Aplastic anemia is a disease of the young and should be a leading diagnosis in the pancytopenic adolescent or young adult. When pancytopenia is secondary, the primary diagnosis is usually obvious from either history or physical examination: the massive spleen of alcoholic cirrhosis, the history of metastatic cancer or SLE, or miliary tuberculosis on chest radiograph (Table 11-1).

Diagnostic problems can occur with atypical presentations and among related hematologic diseases. Although pancytopenia is most common, some patients with bone marrow hypocellularity have depression of only one or two of three blood lines, with later progression to pancytopenia. The bone marrow in constitutional aplastic anemia is morphologically indistinguishable from the aspirate in acquired disease. The diagnosis can be suggested by family history, abnormal blood counts since childhood, or the presence of associated physical anomalies. Aplastic anemia may be difficult to distinguish from the hypocellular variety of MDS: MDS is favored by finding morphologic abnormalities, particularly of megakaryocytes and myeloid precursor cells, and typical cytogenetic abnormalities (see below).

PROGNOSIS

The natural history of severe aplastic anemia is rapid deterioration and death. Historically, provision first of RBC and later of platelet transfusions and effective antibiotics were of some benefit, but few patients show spontaneous recovery. The major prognostic determinant is the blood count. Severe disease has been defined by the presence of two of three parameters: absolute neutrophil count <500/μL, platelet count <20,000/μL, and corrected reticulocyte count <1% (or absolute reticulocyte count <60,000/μL). In the era of effective immunosuppressive therapies, absolute numbers of reticulocytes (>25,000/μL) and lymphocytes (>1000/μL) may be better predictors of response to treatment and long-term outcome.

TREATMENT

Other, more restricted forms of marrow failure occur, in which only a single circulating cell type is affected and the marrow shows corresponding absence or decreased numbers of specific precursor cells: are generative anemia as in PRCA (see below), thrombocytopenia with amegakaryocytosis (Chap. 20), and neutropenia without marrow myeloid cells in agranulocytosis (Chap. 5). In general, and in contrast to aplastic anemia and MDS, the unaffected lineages appear quantitatively and qualitatively normal. Agranulocytosis, the most frequent of these syndromes, is usually a complication of medical drug use (with agents similar to those related to aplastic anemia), either by a mechanism of direct chemical toxicity or by immune destruction. Agranulocytosis has an incidence similar to aplastic anemia but is especially frequent among older adults and in women. The syndrome should resolve with discontinuation of exposure, but significant mortality is attached to neutropenia in the older and often previously unwell patient. Both pure white cell aplasia (agranulocytosis without incriminating drug exposure) and amegakaryocytic thrombocytopenia are exceedingly rare and, like PRCA, appear to be due to destructive antibodies or lymphocytes and can respond to immunosuppressive therapies. In all of the single-lineage failure syndromes, progression to pancytopenia or leukemia is unusual.

DEFINITION AND DIFFERENTIAL DIAGNOSIS

PRCA is characterized by anemia, reticulocytopenia, and absent or rare erythroid precursor cells in the bone marrow. The classification of PRCA is shown in Table 11-4. In adults, PRCA is acquired. An identical syndrome can occur constitutionally: Diamond-Blackfan anemia, or congenital PRCA, is diagnosed at birth or in early childhood and often responds to glucocorticoid treatment; mutations in ribosome protein genes are etiologic. Temporary red cell failure occurs in transient aplastic crisis of hemolytic anemias due to acute parvovirus infection and in transient erythroblastopenia of childhood, which occurs in normal children.

CLINICAL ASSOCIATIONS AND ETIOLOGY

PRCA has important associations with immune system diseases. A small minority of cases occur with a thymoma. More frequently, red cell aplasia can be the major manifestation of large granular lymphocytosis or complicate chronic lymphocytic leukemia. Some patients may be hypogammaglobulinemic. Infrequently (compared to agranulocytosis), PRCA can be due to an idiosyncratic drug reaction. Subcutaneous administration of erythropoietin (EPO) has provoked PRCA mediated by neutralizing antibodies.

Like aplastic anemia, PRCA results from diverse mechanisms. Antibodies to RBC precursors are frequently present in the blood, but T cell inhibition is probably the more common immune mechanism. Cytotoxic lymphocyte activity restricted by histocompatibility locus or specific for human T cell leukemia/lymphoma virus I–infected cells and natural killer cell activity inhibitory of erythropoiesis have been demonstrated in particularly well-studied individual cases.

PERSISTENT PARVOVIRUS B19 INFECTION

Chronic parvovirus infection is an important, treatable cause of PRCA. This common virus causes a benign exanthem of childhood (fifth disease) and a polyarthralgia/arthritis syndrome in adults. In patients with underlying hemolysis (or any condition that increases demand for RBC production), parvovirus infection can cause a transient aplastic crisis and an abrupt but temporary worsening of the anemia due to failed erythropoiesis. In normal individuals, acute infection is resolved by production of neutralizing antibodies to the virus, but in the setting of congenital, acquired, or iatrogenic immunodeficiency, persistent viral infection may occur. The bone marrow shows red cell aplasia and the presence of giant pronormoblasts (Fig. 11-2), which is the cytopathic sign of B19 parvovirus infection. Viral tropism for human erythroid progenitor cells is due to its use of erythrocyte P antigen as a cellular receptor for entry. Direct cytotoxicity of virus causes anemia if demands on erythrocyte production are high; in normal individuals, the temporary cessation of red cell production is not clinically apparent, and skin and joint symptoms are mediated by immune complex deposition.

TREATMENT

DEFINITION

The myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic disorders broadly characterized by both (1) cytopenias due to bone marrow failure and (2) a high risk of development of acute myeloid leukemia (AML). Anemia, often with thrombocytopenia and neutropenia, occurs with dysmorphic (abnormal appearing) and usually cellular bone marrow, which is evidence of ineffective blood cell production. In patients with “low-risk” MDS, marrow failure dominates the clinical course. In other patients, myeloblasts are present at diagnosis, chromosomes are abnormal, and the “high risk” is due to leukemic progression. MDS may be fatal due to the complications of pancytopenia or the incurability of leukemia, but a large proportion of patients will die of concurrent disease, the comorbidities typical in an elderly population. A clinically useful nosology of these often confusing entities was first developed by the French-American-British Cooperative Group in 1983. Five entities were defined: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). The World Health Organization (WHO) classification (2002) recognized that the distinction between RAEB-t and AML is arbitrary and grouped them together as acute leukemia and that CMML behaves as a myeloproliferative disease; the WHO classification also separated refractory anemias with dysmorphic change restricted to erythroid lineage from those with multilineage changes. In a 2008 revision, specific categories for unilineage dysplasias were added (Table 11-5).

The diagnosis of MDS may be a challenge, because sometimes subtle clinical and pathologic features must be distinguished and precise diagnostic categorization requires a hematopathologist knowledgeable in the latest classification scheme. Nonetheless, it is important that the internist and primary care physician be sufficiently familiar with MDS to expedite referral to a hematologist, both because many new therapies are now available to improve hematopoietic function and the judicious use of supportive care can improve the patient’s quality of life.

EPIDEMIOLOGY

Idiopathic MDS is a disease of the elderly; the mean age at onset is older than 70 years. There is a slight male preponderance. MDS is a relatively common form of bone marrow failure, with reported incidence rates of 35 to >100 per million persons in the general population and 120 to >500 per million in the older adult. MDS is rare in children, but monocytic leukemia can be seen. Secondary or therapy-related MDS is not age related. Rates of MDS have increased over time, due to better recognition of the syndrome by physicians and an aging population.

ETIOLOGY AND PATHOPHYSIOLOGY

MDS is associated with environmental exposures such as radiation and benzene; other risk factors have been reported inconsistently. Secondary MDS occurs as a late toxicity of cancer treatment, usually a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5–7 years) or the DNA topoisomerase inhibitors (2-year latency). Acquired aplastic anemia, Fanconi anemia, and other constitutional marrow failure diseases can evolve into MDS. However, the typical MDS patient does not have a suggestive environmental exposure history or a preceding hematologic disease. MDS is a disease of aging, suggesting random cumulative intrinsic and environmental damage to marrow cells.

MDS is a clonal hematopoietic stem cell disorder characterized by disordered cell proliferation and impaired differentiation, resulting in cytopenias and risk of progression to leukemia. Both chromosomal and genetic instability have been implicated, and both are likely aging-related. Cytogenetic abnormalities are found in approximately one-half of patients, and some of the same specific lesions are also seen in frank leukemia; aneuploidy (chromosome loss or gain) is more frequent than translocations. More sensitive assays, such as comparative genomic hybridization and single nucleotide polymorphism arrays, reveal chromosomal abnormalities in a large proportion of patients with normal conventional cytogenetics. Accelerated telomere attrition may destabilize the genome in marrow failure and predispose to acquisition of chromosomal lesions. Cytogenetic abnormalities are not random (loss of all or part of 5, 7, and 20, trisomy of 8) and may be related to etiology (11q23 following topoisomerase II inhibitors). The type and number of cytogenetic abnormalities strongly correlate with the probability of leukemic transformation and survival.

Genomics has illuminated the role of point mutations in the pathophysiology of MDS. Recurrent somatic mutations, acquired in the abnormal marrow cells and absent in the germline, have been identified in almost 100 genes. Many of the same genes are also mutated in AML without MDS, whereas others are distinctive in subtypes of MDS. A prominent example of the latter is the discovery of mutations in genes of the RNA splicing machinery, especially SF3B1, which strongly associate with sideroblastic anemia. Some mutations correlate with prognosis: spliceosome defects with favorable outcome, and mutations in EZH2, TP53, RUNX1, and ASXL1 with poor outcome. Mutations and cytogenetic abnormalities are not independent: TP53 mutations associate with complex cytogenetic abnormalities and TET2 mutations with normal cytogenetics. Correlation and exclusion in the pattern of mutations indicate a functional genomic architecture. Analysis of deep sequencing results in patients whose MDS evolved to AML has shown evidence of clonal succession, with founder clones acquiring further mutations that allow clonal dominance. Furthermore, the prevalence of abnormal cells by morphology underestimates bone marrow involvement by MDS clones, as cells normal in appearance are apparently derived from the abnormal clones. Both presenting and evolving hematologic manifestations result from the accumulation of multiple genetic lesions: loss of tumor-suppressor genes, activating oncogene mutations, epigenetic pathways that affect mRNA processing and methylation status, or other harmful alterations. Pathophysiology has been linked to mutations and chromosome abnormalities in some specific MDS syndromes. The 5q– deletion leads to heterozygous loss of a ribosomal protein gene that is also mutant in Diamond-Blackfan anemia, and both are characterized by deficient erythropoiesis. An immune pathophysiology may underlie trisomy 8 MDS, in which patients often experience improved blood counts after immunosuppressive therapy; there is T cell activity directed to hematopoietic progenitors, which the cytogenetically aberrant clone resists. However, in general for MDS, the role of the immune system and its cells and cytokines; the role of the hematopoietic stem cell niche, the microenvironment, and cell-cell interactions; the fate of normal cells in the Darwinian competitive environment of the dysplastic marrow; and how mutant cells produce marrow failure in MDS are not well understood.

CLINICAL FEATURES

Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least one-half the patients are asymptomatic, and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important historic fact. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. MDS in childhood is rare and, when diagnosed, increases the likelihood of an underlying genetic disease. Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia, Fanconi anemia, or a telomeropathy. Inherited GATA2 mutations, as in the MonoMAC syndrome (with increased susceptibility to viral, mycobacteria, and fungal infections, as well as deficient numbers of monocytes, natural killer cells, and B lymphocytes), also cause MDS in young patients.

The physical examination is remarkable for signs of anemia; approximately 20% of patients have splenomegaly. Some unusual skin lesions, including Sweet syndrome (febrile neutrophilic dermatosis), occur with MDS. Accompanying autoimmune syndromes are not infrequent. In the younger patient, stereotypical anomalies point to a constitutional syndrome (short stature, abnormal thumbs in Fanconi anemia; early graying in the telomeropathies; cutaneous warts in GATA2 deficiency).

LABORATORY STUDIES

Blood

Anemia is present in most cases, either alone or as part of bi- or pancytopenia; isolated neutropenia or thrombocytopenia is more unusual. Macrocytosis is common, and the smear may be dimorphic with a distinctive population of large red blood cells. Platelets are also large and lack granules. In functional studies, they may show marked abnormalities, and patients may have bleeding symptoms despite seemingly adequate numbers. Neutrophils are hypogranulated; have hyposegmented, ringed, or abnormally segmented nuclei; contain Döhle bodies; and may be functionally deficient. Circulating myeloblasts usually correlate with marrow blast numbers, and their quantity is important for classification and prognosis. The total white blood cell count (WBC) is usually normal or low, except in chronic myelomonocytic leukemia. As in aplastic anemia, MDS can be associated with a clonal population of PNH cells. Genetic testing is commercially available for constitutional syndromes.

Bone marrow

The bone marrow is usually normal or hypercellular, but in about 20% of cases, it is sufficiently hypocellular to be confused with aplasia. No single characteristic feature of marrow morphology distinguishes MDS, but the following are commonly observed: dyserythropoietic changes (especially nuclear abnormalities) and ringed sideroblasts in the erythroid lineage; hypogranulation and hyposegmentation in granulocytic precursors, with an increase in myeloblasts; and megakaryocytes showing reduced numbers of or disorganized nuclei. Megaloblastic nuclei associated with defective hemoglobinization in the erythroid lineage are common. Prognosis strongly correlates with the proportion of marrow blasts. Cytogenetic analysis and fluorescent in situ hybridization can identify chromosomal abnormalities.

DIFFERENTIAL DIAGNOSIS

Deficiencies of vitamin B₁₂ or folate should be excluded by appropriate blood tests; vitamin B₆ deficiency can be assessed by a therapeutic trial of pyridoxine if the bone marrow shows ringed sideroblasts. Marrow dysplasia can be observed in acute viral infections, drug reactions, or chemical toxicity but should be transient. More difficult are the distinctions between hypocellular MDS and aplasia or between refractory anemia with excess blasts and early acute leukemia. The WHO considers the presence of 20% blasts in the marrow as the criterion that separates AML from MDS. In young patients, underlying, predisposing genetic diseases should be considered (see above).

PROGNOSIS

The median survival varies greatly from years for patients with 5q– or sideroblastic anemia to a few months in refractory anemia with excess blasts or severe pancytopenia associated with monosomy 7; an International Prognostic Scoring System (IPSS; Table 11-6) assists in making predictions. Even “low-risk” MDS has significant morbidity and mortality. Most patients die as a result of complications of pancytopenia and not due to leukemic transformation; perhaps one-third will succumb to other diseases unrelated to their MDS. Precipitous worsening of pancytopenia, acquisition of new chromosomal abnormalities on serial cytogenetic determination, increase in the number of blasts, and marrow fibrosis are all poor prognostic indicators. The outlook in therapy-related MDS, regardless of type, is extremely poor, and most patients will progress within a few months to refractory AML.

TREATMENT

Fibrosis of the bone marrow (see Fig. 10-2), usually accompanied by a characteristic blood smear picture called leukoerythroblastosis, can occur as a primary hematologic disease, called myelofibrosis or myeloid metaplasia (Chap. 13), and as a secondary process, called myelophthisis. Myelophthisis, or secondary myelofibrosis, is reactive. Fibrosis can be a response to invading tumor cells, usually an epithelial cancer of breast, lung, or prostate origin or neuroblastoma. Marrow fibrosis may occur with infection of mycobacteria (both Mycobacterium tuberculosis and Mycobacterium avium), fungi, or HIV and in sarcoidosis. Intracellular lipid deposition in Gaucher’s disease and obliteration of the marrow space related to absence of osteoclast remodeling in congenital osteopetrosis also can produce fibrosis. Secondary myelofibrosis is a late consequence of radiation therapy or treatment with radiomimetic drugs. Usually the infectious or malignant underlying processes are obvious. Marrow fibrosis can also be a feature of a variety of hematologic syndromes, especially chronic myeloid leukemia, multiple myeloma, lymphomas, myeloma, and hairy cell leukemia.

The pathophysiology has three distinct features: proliferation of fibroblasts in the marrow space (myelofibrosis); the extension of hematopoiesis into the long bones and into extramedullary sites, usually the spleen, liver, and lymph nodes (myeloid metaplasia); and ineffective erythropoiesis. The etiology of the fibrosis is unknown but most likely involves dysregulated production of growth factors: platelet-derived growth factor and transforming growth factor β have been implicated. Abnormal regulation of other hematopoietins would lead to localization of blood-producing cells in nonhematopoietic tissues and uncoupling of the usually balanced processes of stem cell proliferation and differentiation. Myelofibrosis is remarkable for pancytopenia despite very large numbers of circulating hematopoietic progenitor cells.

Anemia is dominant in secondary myelofibrosis, usually normocytic and normochromic. The diagnosis is suggested by the characteristic leukoerythroblastic smear (see Fig. 10-1). Erythrocyte morphology is highly abnormal, with circulating nucleated RBCs, teardrops, and shape distortions. WBC numbers are often elevated, sometimes mimicking a leukemoid reaction, with circulating myelocytes, promyelocytes, and myeloblasts. Platelets may be abundant and are often of giant size. Inability to aspirate the bone marrow, the characteristic “dry tap,” can allow a presumptive diagnosis in the appropriate setting before the biopsy is decalcified.

The course of secondary myelofibrosis is determined by its etiology, usually a metastatic tumor or an advanced hematologic malignancy. Treatable causes must be excluded, especially tuberculosis and fungus. Transfusion support can relieve symptoms.