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MD Consult: Books: Goldman: Cecil Medicine: Chapter 171 – APLASTIC ANEMIA AND RELATED DISORDERS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 171 – APLASTIC ANEMIA AND RELATED DISORDERS

Hugo Castro-Malaspina   Richard J. O’Reilly

   APLASTIC ANEMIA

Definition

Aplastic anemia is a disorder of hematopoiesis characterized by pancytopenia and a marked reduction or depletion of erythroid, granulocytic, and megakaryocytic cells in bone marrow. Hematopoiesis ( Chapter 160 ) is markedly decreased as shown by the near absence of myeloid elements and by the absence or low numbers of CD34 and colony-forming cells in bone marrow. In aplastic anemia, hematopoietic stem cells are unable to proliferate, differentiate, or give rise to mature blood cells and their precursors. In most cases, this failure of stem cells seems to result from an immune mechanism.

Epidemiology

The incidence of aplastic anemia in Western countries is about two new cases per 1 million persons per year. The incidence is higher in Asia, with almost four new cases per 1 million persons per year in Bangkok and rural Thailand. The disease occurs at all ages but is more common in young adults aged 15 to 30 years and in persons older than 60. The incidence is similar in males and females.

Etiology

Aplastic anemia may occur as the result of inherited abnormalities, such as Fanconi’s anemia, but most cases are acquired. Causative factors include drugs, viruses, organic compounds, and radiation ( Table 171-1 ). For more than 50% of patients, however, no cause can be determined. Even when a well-defined association exists between an exposure and the subsequent development of aplastic anemia (e.g., chloramphenicol), it remains unclear why the disease develops in only a small proportion of exposed individuals. Furthermore, the mechanisms by which certain agents or classes of agents (e.g., viruses, drugs) contribute to the pathogenesis of aplastic anemia are still poorly understood.


TABLE 171-1   — 
CAUSES OF APLASTIC ANEMIA

ACQUIRED
Drugs: antimetabolites, antimitotic agents, chloramphenicol, phenylbutazone, sulfonamides
Radiation
Chemicals: benzene, solvents, insecticides
Viruses: non-A, non-B, non-C hepatitis, Epstein-Barr virus
Paroxysmal nocturnal hemoglobinuria
Miscellaneous: pregnancy, connective tissue disorders
HEREDITARY
Fanconi anemia
Dyskeratosis congenita
Schwachman syndrome
IDIOPATHIC: 50–65% OF CASES
Drugs

Population-based studies have demonstrated an association between certain drugs and aplastic anemia. Drug-induced aplastic anemia is most commonly caused by anticonvulsants, antibacterial agents, antidiabetic drugs, diuretics, sulfonamides, antimetabolites, antimitotic agents, and synthetic antithyroid drugs ( Table 171-2 ). Many other drugs have been linked to aplastic anemia, but the current data are less convincing. For antineoplastic drugs, antimetabolites, and sulfonamides, the myelotoxicity is dose dependent. For the other agents, however, particularly chloramphenicol, phenylbutazone, oxyphenbutazone, indomethacin, and gold salts, aplasias are idiosyncratic and not dose related. The mechanisms contributing to aplasia are unclear. For example, chloramphenicol can induce a dose-related reversible suppression of erythropoiesis during treatment or an idiosyncratic dose-independent marrow aplasia that develops many weeks or months after cessation of therapy.


TABLE 171-2   — 
DRUGS ASSOCIATED WITH APLASTIC ANEMIA

   Antineoplastic drugs

   Antimetabolites: fluorouracil, mercaptopurine, methotrexate
   Alkylating agents: busulfan, cyclophosphamide, nitrogen mustard melphalan
   Cytotoxic antibiotics: daunorubicin, doxorubicin, mitoxantrone
   Sulfonamides and derivatives

   Antibacterials: sulfonamides
   Diuretics: acetazolamide, chlorothiazide, furosemide
   Hypoglycemics: chlorpropamide, tolbutamide
   Other antimicrobial drugs

   Antibacterials: chloramphenicol, dapsone, β -lactam antibiotics
   Antifungals: amphotericin, flucytosine
   Antiprotozoals: quinacrine, chloroquine, pyrimethamine, mepacrine
   Anti-inflamatory drugs: phenylbutazone, oxyphenbutazone, indomethacin, ibuprofen, naproxen, sulindac
   Antiarthritic drugs: gold salts, colchicine
   Anticonvulsant drugs: carbamazepine, hydantoins, ethosuximide, primidone
   Analgesic drugs: phenacetin, salicylamide, aspirin
   Antiarrhythmic drugs: quinidine, tocainide
   Antithyroid drugs: carbimazole, methimazole, methylthiouracil, potassium perchlorate, propylthiouracil, sodium thiocyanate
   Antihypertensive drugs: captopril, enalapril, methyldopa
   Antihistamine drugs: chlorpheniramine, pyrilamine, tripelennamine
   Sedatives: chlordiazepoxide, chlorpromazine, lithium, meprobamate
   Antiplatelet drugs: ticlopidine
Radiation

Acute exposure to total body irradiation causes a dose-related transient marrow suppression that is reversible at low doses but permanent and life-threatening at high doses ( Chapter 18 ). Total body irradiation exceeding 700 to 1000 cGy can induce persistent aplasia by eradicating hematopoietic cells, depending on the radiation energy and dose rate. At a dose exceeding 4000 cGy, the marrow microenvironment in sites of irradiation does not support hematopoiesis. Chronic exposure to low-dose and extensive localized radiation may cause late permanent marrow failure; for example, patients irradiated for ankylosing spondylitis ( Chapter 286 ) have a higher incidence of aplastic anemia. However, the incidence of aplastic anemia has not been increased in long-term survivors of the atomic bombings in Hiroshima and Nagasaki.

Benzene and Insecticides

Benzene, which was the first organic solvent linked to aplastic anemia, has a dose-dependent marrow-suppressive effect. Chronic exposure has been associated with the development of aplastic anemia and leukemias. Benzene and related aryl hydrocarbons may generate catabolites that are directly toxic to stem cells, and they may also induce the formation of haptens that may stimulate immune responses.

Viruses

The most common viral infection associated with aplastic anemia is viral hepatitis ( Chapters 151 and 152 ), with approximately 1 to 5% of cases of aplastic anemia following overt hepatitis. Even though hepatitis A, B, C, and G viruses have been implicated in aplastic anemia in a small number of cases, most cases are not related to these viruses. Although hepatitis viruses may induce lytic infection of primitive hematopoietic stem cells, the remission of aplasia induced by immunosuppressive therapy in a proportion of cases of posthepatitic aplasia has suggested that the immune responses induced by infection may play a central role.

Parvovirus B19, the etiologic agent of exanthema subitum, can cause transient erythroid aplasia in patients with underlying spherocytic anemia and hemoglobinopathy. This virus infects and lyses erythroid progenitor cells. Persistent infection results from an inability to mount an adequate antibody response. Epstein-Barr virus–induced infectious mononucleosis ( Chapter 400 ) is rarely associated with aplastic anemia, and blood counts usually recover spontaneously in most patients. Cytomegalovirus (CMV) infections in newborns and immunocompromised individuals commonly cause neutropenia or thrombocytopenia, or both ( Chapter 399 ). CMV has also been associated with marrow failure, particularly in recipients of marrow transplants. Evidence suggests that certain strains of CMV may infect the bone marrow’s stromal cells, which support hematopoietic cell growth, thereby inducing secondary aplasia. Human immunodeficiency virus ( Chapter 416 ) can also suppress erythropoiesis.

Pregnancy

Case reports have documented that aplastic anemia develops during pregnancy in some women. The aplasia has resolved with natural or premature termination of pregnancy in some cases but has recurred with a subsequent pregnancy. The pathogenesis and causal relationship between pregnancy and aplastic anemia remain unknown.

Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) ( Chapter 164 ) is a clonal disease caused by acquired mutations in the PIGA gene, which results in partial or complete inability to construct a glycosyl phosphatidylinositol (GPI) anchor for the attachment of membrane proteins such as CD55, CD59, and others. Aplastic anemia can be the initial hematologic manifestation of PNH. Conversely, PNH can develop in patients with aplastic anemia months to years after immunosuppressive therapy. This clinical observation and laboratory studies have shown that a PNH clone can expand in a marrow that is depleted of normal stem cells. A history of thrombosis plus evidence of hemolysis in a patient with an aplastic anemia picture suggests PNH. However, the diagnosis may be difficult to make because the proportion of PNH cells in blood may be too small to be detected by the Ham test; flow cytometric studies using antibodies against cell surface proteins such as CD55 and CD59, which are lacking in PNH, are helpful in establishing the diagnosis.

Other Acquired Causes

Eosinophilic fasciitis ( Chapter 447 ), a rare connective tissue disease characterized by painful swelling and induration of the skin and subcutaneous tissue, has been associated with aplastic anemia. Suppression of marrow function in this condition is thought to be antibody mediated. A similar mechanism has been implicated in the rare case reports of patients with systemic lupus erythematosus (SLE) ( Chapter 287 ) in whom spontaneous aplastic anemia develops. However, patients with SLE and other autoimmune diseases are often treated with anti-inflammatory drugs and gold salts, both of which have been linked to aplastic anemia; as a consequence, the independent role of SLE in the pathogenesis of secondary aplasia is uncertain. In recipients of allogeneic stem cell transplants ( Chapter 184 ), graft-versus-host disease (GvHD) may cause severe marrow suppression. Aplasia has also been documented in rare patients with congenital or acquired immunodeficiency ( Chapter 271 ) and in recipients of organ allografts who have been engrafted with HLA-mismatched T cells derived from nonirradiated blood products or allografts. Certain disorders of the immune system, including thymoma, X-linked lymphoproliferative disorder, and T gamma lymphocyte proliferation, have also been associated with marrow failure. In addition, aplastic anemia may, in rare instances, precede acute leukemia. The hypocellular variant of myelodysplastic syndrome ( Chapter 193 ) may be manifested by clinical and pathologic features that are difficult to distinguish from aplastic anemia.

Pathobiology

The observation that 40 to 50% of syngeneic transplants for aplastic anemia can achieve hematologic reconstitution without pretransplant immunosuppression is consistent with an isolated stem cell defect. Conversely, the fact that the other 50 to 60% of recipients of syngeneic grafts fail to engraft but can achieve hematologic reconstitution if adequate immunosuppression is given before a second transplant strongly suggests that an immune mechanism contributes to the disease. This suggestion is further supported by documentation of autologous recovery in patients who receive allogeneic marrow transplants after immunosuppressive conditioning or antithymocyte globulin (ATG) or cyclosporine (or both). Moreover, the observation that approximately 25% of patients with aplastic anemia are cured by immunosuppressive therapy suggests that in some patients, the disease is due to an isolated reversible immune defect that induces a quantitative deficiency of healthy hematopoietic stem cells. Conversely, the observation that 20 to 30% of patients with aplastic anemia who achieve partial or, less commonly, complete reconstitution of hematopoiesis after treatment with ATG or cyclosporine (or both) contract a clonal disease, either PNH (10 to 13%) or a myelodysplastic syndrome (10 to 15%), months to years after completion of immunosuppressive therapy suggests that aplastic anemia develops in these patients as a manifestation of an immune response directed against preexisting abnormal hematopoietic stem cells or that these abnormal hematopoietic stem cells preferentially recover after immunosuppressive therapy.

In vitro studies have confirmed that the pancytopenia in acquired aplastic anemia results from a quantitative deficiency of hematopoietic stem cells, as documented by colony-forming cell assays, long-term marrow cultures, and quantification of marrow cells expressing CD34 antigen. This stem cell deficiency is due to the cytotoxic or suppressive effect of the patient’s own T cells, but the nature of the antigen or antigens causing this pathologic immune response and the intimate mechanisms triggering this abnormal response are not known. In vitro studies have also demonstrated that oligoclonal populations of activated cytotoxic T cells derived from the blood and marrow of a significant proportion of patients with aplastic anemia cause a Fas-mediated death of stem cells and that they overproduce T helper type 1 (TH1)-associated cytokines, specifically interferon-γ and tumor necrosis factor-β, that suppress hematopoietic progenitors. In patients who respond to immunosuppressive therapy, these colony-inhibiting and interferon γ–producing T cells are no longer detected in the marrow. T cells from patients with aplastic anemia kill hematopoietic stem cells in an HLA-DR–restricted manner, via Fas ligand. The most primitive hematopoietic stem cells express little or no HLA-DR or Fas and can therefore escape the cytolytic effect of T cells and then repopulate the marrow after immunosuppressive therapy. As in other autoimmune diseases, certain histocompatibility genotypes, especially within the HLA-DR2 locus, are associated with a predisposition to acquired aplastic anemia. Moreover, polymorphisms of the interferon-γ and transforming growth factor-β1 genes are associated with an increased risk for acquired aplastic anemia.

Clinical Manifestations

The most common initial symptoms of aplastic anemia are caused by anemia and thrombocytopenia: progressive weakness, fatigue, headaches, dyspnea on exertion, petechia, ecchymoses, epistaxis, metrorrhagia, and gum bleeding. Even when the neutropenia is very severe, infection is rarely an initial symptom. The most frequent physical findings are cutaneous and conjunctival pallor and hemorrhages (petechiae, ecchymoses, and gum bleeding). If the anemia is severe, the patient may be tachy-cardic and have cardiac murmurs associated with high-flow states. Hepatosplenomegaly and lymphadenopathy are notably absent.

Diagnosis

Diagnostic Evaluation

The diagnosis of aplastic anemia should be considered if a pancytopenic patient has a normochromic, normocytic (or slightly macrocytic), and aregenerative anemia; thrombocytopenia with normal-sized platelets; neutropenia; and no abnormal cells in the leukocyte differential. The absolute reticulocyte count is low because the anemia is secondary to reduced or absent red cell production. Confirmation of the diagnosis requires morphologic and cytogenetic evaluation of the bone marrow.

Bone marrow typically shows numerous spicules with empty fatty spaces and a few hematopoietic cells ( Fig. 171-1 ). The hypocellularity is due to a marked decrease in megakaryocytes and granulocytic and erythroid cells. Lymphocytes, plasma cells, and mast cells are relatively increased and, in severe cases, constitute more than 65% of the cells. Although erythroid cells may exhibit megaloblastic changes, the morphology of marrow elements is generally normal. The presence of overt dysplasia favors the diagnosis of hypocellular myelodysplasia ( Chapter 193 ). Sometimes the cellularity may appear normal because of isolated foci (hot spots) of hematopoiesis. The marrow biopsy allows better assessment of cellularity and permits evaluation for the presence of tumor cells, hairy cells, and fibrosis. Cytogenetic studies are important to distinguish aplastic anemia from myelodysplasia: the presence of clonal chromosomal abnormalities favors myelodysplasia, but a normal karyotype does not exclude it.

FIGURE 171-1  Aplastic anemia. A bone marrow biopsy specimen shows a virtually empty marrow.  (Courtesy of Andrew Schafer, MD.)

Lactate dehydrogenase levels, serum haptoglobin levels, and flow cytometric analysis of peripheral blood cells with antibodies against GPI-linked proteins are useful to establish or exclude the diagnosis of PNH ( Chapter 164 ). In younger patients, cytogenetic studies of marrow cells in the presence or absence of diepoxybutane should be performed because patients with Fanconi’s anemia may not have a family history or other clinical findings of the disease.

Differential Diagnosis

Patients with hypocellular myelodysplastic syndrome ( Chapter 193 ) also have pancytopenia and hypocellular bone marrow. However, review of blood smears may show the presence of immature granulocytes or nucleated red cells. The few myeloid elements in the marrow have dysplastic changes, and the marrow karyotype may show a clonal abnormality. The differential diagnosis may be difficult when the dysplastic changes are subtle and there are no chromosomal abnormalities. Hypocellular acute leukemia ( Chapter 194 ) can be misdiagnosed as aplastic anemia when the few mononuclear cells present in bone marrow are not identified as blasts. Although hairy cell leukemia ( Chapter 195 ) is usually manifested as splenomegaly and hypercellular marrow, it occasionally occurs without these features; the diagnosis is established by recognizing the few hairy cells by their typical morphology, as well as by their cytochemical and phenotypic characteristics.

Determination of Severity

Aplastic anemia can be categorized as moderate, severe, or very severe based on the degree of pancytopenia. Severe aplastic anemia is defined by two or more of the following criteria: neutrophils less than 500/mL, platelets less than 20,000/mL, and reticulocytes less than 20,000/mL; these patients have an 80% risk for death by 2 years after diagnosis if treated with supportive care alone. The very severe form meets the aforementioned criteria and in addition has a neutrophil count of less than 200/mL; this very severe form has the worst prognosis, with a lower response rate and poorer survival rate after immunosuppressive therapy. Patients with less profound cytopenia (neutrophils >500/mL, platelets >20,000/mL, and reticulocytes >20,000/mL) are classified as having a moderate form of aplastic anemia.

Treatment

Prompt and aggressive treatment is indicated for most patients ( Fig. 171-2 ). If a specific cause is suspected, withdrawal of the etiologic agent is the most direct approach to treatment. Discontinuation of the suspected drug, thymectomy in patients with thymoma ( Chapter 448 ), and delivery or therapeutic abortion in pregnancy-associated aplastic anemia may result in recovery of blood counts. Aplastic anemia that develops after hepatitis B may resolve if the virus is cleared with antiviral therapy ( Chapter 152 ). Unfortunately, however, remissions are observed in only a small proportion of patients.

Once the diagnosis of aplastic anemia is established, family HLA typing should be performed as soon as possible, particularly in younger patients (<50 years) because these individuals are most likely to benefit from stem cell transplantation from a histocompatible sibling ( Chapter 184 ). Transplantation is a curative treatment, but it is associated with an early mortality risk ranging from 10% in children and young adults to more than 20% in older patients. Transplantation is the preferred therapy in children who have a histocompatible sibling. Transfusions of blood products from family members should be avoided in transplant candidates to prevent sensitization to minor antigens because sensitization increases the risk for graft rejection after transplantation. Whenever possible, only CMV-negative blood products should be given to CMV-seronegative potential transplant candidates to reduce the incidence of CMV infection in the post-transplant period. At diagnosis and during the interval between diagnosis and response to immunosuppressive therapy and allogeneic transplantation, supportive care, including the judicious use of red cell and platelet transfusions and aggressive treatment of infections with parenteral antimicrobial agents, is essential in the treatment of patients with aplastic anemia.

Immunosuppression is the most common therapy used for aplastic anemia because only 25 to 30% of patients have a histocompatible sibling. In older adult patients, the choice between immunosuppression and allogeneic stem cell transplantation is sometimes difficult because of differences in short- and long-term complications. Immunosuppression has a low early mortality rate (<10%), but it is not curative and carries a 30 to 50% risk for relapse and a 20 to 30% probability of development of a myelodysplastic syndrome or PNH.

FIGURE 171-2  Management of aplastic anemia. HLA = human leukocyte antigen; KPS = Karnofsky performance status score. *Alternative therapy includes a second course of immunosuppressive therapy and allogeneic stem cell transplantation from an HLA-matched sibling for older patients and stem cell transplantation from an unrelated donor or a partially matched related donor for younger and older patients who are refractory to immunosuppressive therapies and are also severely thrombocytopenic and refractory to platelet transfusions.

Immunosuppressive Therapy

ATG (40 mg/kg/day for 4 days) alone or in combination with cyclosporine (10 mg/kg/day divided into two doses, with dose adjustments as needed to maintain levels of 200 to 400 μg/mL for 3 to 6 months and then tapered over a period of 3 months) is the treatment of choice for aplastic patients who lack a histocompatible sibling or are older than 40 years. Prospective trials have demonstrated that ATG in combination with cyclosporine induces a higher response rate (60 to 80% vs. 40 to 60%) and a more rapid response (median of 60 days vs. 80 days) than ATG alone does, but rates of relapse, development of secondary clonal disease, and survival are similar.[1] Combined ATG plus cyclosporine is recommended for patients with the severe and very severe forms of aplastic anemia, whereas ATG alone is often used for patients with moderate aplastic anemia.

The exact mechanism for the response to immunosuppressive therapy in patients with aplastic anemia is unclear. The licensed ATG preparations contain purified and concentrated IgG from hyperimmune sera derived from horses or rabbits immunized with human thymocytes or thoracic duct lymphocytes. These antibodies may delete an abnormal clone of T cells. Cyclosporine induces immunosuppression by inhibiting the first phase of T-cell activation. Response to immunosuppressive therapy is slow and progressive and may not be detected until 12 weeks after administration. Response rates and post-treatment survival correlate with severity of the disease; patients with very severe forms have a lower response rate.

Of the 60 to 80% of patients responding to immunosuppression, about 20 to 30% achieve a complete and durable recovery of blood counts. The other 50 to 70% achieve a partial response and become transfusion independent with platelet counts exceeding 20,000/mL and neutrophil counts exceeding 500/mL. About 10 to 40% of responders to immunosuppressive therapy require chronic immunosuppression with cyclosporine therapy to maintain adequate blood counts.

Of the 20 to 40% of patients who fail to respond to an initial course of combined immunosuppressive therapy with ATG and cyclosporine, about 75% may respond to second course of immunosuppression with rabbit ATG and cyclosporine. Similarly, 30 to 50% of patients who initially respond to immunosuppressive therapy later relapse, particularly if they have achieved only a partial response. Retreatment with a second course of immunosuppressive therapy can induce a second response in more than 50 to 75% of patients.

Overall, the quality of the initial response is a strong predictor of ultimate outcome. Of patients who achieve a complete remission, 90% survive event free. In contrast, only 50 to 60% of patients who have partial responses or relapse survive 5 years.

Major long-term complications of immunosuppressive therapy include the development of overt myelodysplastic syndrome or PNH in 20 to 30% of patients many months to years after therapy; both are markedly more frequent in patients who achieve only a partial response. ATG is associated with a higher incidence of secondary solid tumors, similar to what is observed in patients who have aplastic anemia and are prepared for allogeneic stem cell transplantation with radiation-containing regimens. Whether there is an increase in the incidence of solid tumors in patients treated with more intensive immunosuppression remains to be determined.

High-dose cyclophosphamide (50 mg/kg/day for 4 days) has also been used successfully to treat patients with aplastic anemia who lack a suitable donor, but experience with this approach is limited. In a prospective randomized trial, a standard course of ATG plus cyclosporine was better than cyclophosphamide plus cyclosporine, which caused more toxicity, fungal infections, and deaths. Although very high-dose corticosteroids (10 to 20 mg/kg) can induce responses in a small proportion of patients with aplastic anemia, corticosteroids are no longer used as single agents because of their side effects and the better response rates achieved with ATG and cyclosporine. Treatment with androgens is not beneficial in aplastic anemia.

Allogeneic Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation from an HLA-compatible sibling is curative in patients with aplastic anemia ( Chapter 184 ). Unfortunately, this approach is applicable only to a minority of patients because the proportion who have an HLA-matched sibling is on the order of 25 to 30%. Current survival rates are about 70 to 90%.

The preparative regimen that is currently considered the standard of care for allogeneic transplantation in patients with aplastic anemia consists of pretransplant immunosuppression with high-dose cyclophosphamide and ATG, followed by post-transplant immunosuppression with cyclosporine and methotrexate as prophylaxis against GvHD. Marrow transplants from HLA-matched siblings administered with this regimen are associated with a low (<5%) incidence of graft failure and a 30 to 50% incidence of grade III/IV acute GvHD; the long-term survival rate is up to 90% at 2 years after transplantation.

Marrow or peripheral blood stem cell transplants from a related single HLA allele–mismatched donor or from an HLA-matched unrelated donor are an accepted form of therapy for aplastic anemia when patients have no histocompatible siblings, have failed immunosuppressive therapy, and are refractory to platelet transfusions. Transplants from such donors are associated with a higher incidence of acute and chronic GvHD, as well as a high incidence of transplant-related complications. As a result, the usually reported survival rates (30 to 50%) have not been as good as those achieved after HLA-matched sibling transplants. Nevertheless, these survival rates are superior to those seen in otherwise refractory patients maintained on supportive therapy. The outcome of unrelated donor transplants has improved as a result of the use of less toxic preparative regimens and better selection of donors by high-resolution DNA-based HLA typing.

Supportive Therapy

Red cell and platelet transfusions should be used with caution because of short- and long-term complications. The risk of bleeding should be carefully assessed, and platelet transfusions should be given only when the platelet count is less than 10,000/mL or if there is active bleeding with a higher platelet count ( Chapter 183 ). Pooled-donor platelets are generally used until sensitization occurs. Ideally, single-donor platelets should be used from the beginning to minimize the risk for sensitization, but in practice this alternative is difficult to implement. Refractoriness to platelet transfusions is a major problem with long-term transfusion support; such patients may require HLA-compatible platelet transfusions. Menstruating patients should be placed on a regimen of suppressive doses of birth control pills to avoid severe blood loss.

Packed red cells should also be transfused when the hemoglobin concentration is less than 7 g/dL. Younger patients may tolerate lower values, whereas a higher threshold may be clinically indicated in older patients. To reduce sensitization, packed red cells should be filtered to remove leukocytes and platelets. Chronic administration of red cell transfusions results in secondary hemochromatosis because each unit has approximately 200 to 250 mg of iron. Serum ferritin values should be monitored, and chelation therapy with deferoxamine should be given to treat iron overload ( Chapter 231 ).

Patients with aplastic anemia in whom sepsis or other severe bacterial or fungal infections develop require intensive treatment with parenteral antibacterial and antifungal agents ( Chapter 303 ). Leukocyte transfusions are indicated only in severely neutropenic (<200/mL) patients who have documented fungal or bacterial infections that are caused by organisms resistant to first-line antifungal or antibacterial therapy. Prophylactic use of antibiotics in afebrile neutropenic patients has no benefit and increases the emergence of resistant strains.

A common drawback to immunosuppressive treatment is that recovery of blood counts does not occur until 12 to 16 weeks after ATG treatment. The resulting significant early mortality is usually due to infections. Hematopoietic growth factors, particularly granulocyte colony-stimulating factor (G-CSF), may stimulate more rapid correction of severe neutropenia. However, when patients with aplastic anemia have been maintained on long-term G-CSF, the long-term incidence of myelodysplastic syndromes with clonal chromosomal abnormalities is increased.

When used as first-line therapy, recombinant hematopoietic growth factors improve blood counts, particularly the neutrophil count, in only a small proportion of patients. Unfortunately, these increments are entirely dependent on the presence of residual hematopoietic progenitors, so patients with very severe neutropenia (<200/mL) rarely respond to growth factors. In patients who do respond, blood counts drop to pretreatment values after discontinuation of growth factor administration.

Prognosis

The pancytopenia of aplastic anemia is progressive and life-threatening. The prognosis at diagnosis is closely correlated with the severity of neutropenia. The risk for infection (mainly bacterial and fungal) and associated mortality is high in patients with very severe aplastic anemia.

HLA-matched related bone marrow transplantation is curative in 80 to 90% of patients, but it carries a substantial risk for early morbidity and mortality ( Chapter 184 ). Furthermore, a proportion of long-term survivors may have chronic GvHD. In contrast, immunosuppressive therapy has fewer early risks and can induce at least partial remission in 60 to 80% of patients. However, it is not curative, so a large proportion of patients may relapse and secondary clonal diseases can develop. The success of allogeneic bone marrow transplantation correlates with age and degree of matching. The upper age limit for marrow transplantation continues to increase as better approaches are developed to prevent or treat transplant-related complications. However, allogeneic bone marrow transplantation should be used as first-line of therapy only in younger patients. There is no consensus regarding the definition of a younger patient, but it is well accepted that patients who are younger than 20 years and who have an HLA-matched sibling should undergo allogeneic stem cell transplantation. It is also well accepted that patients older than 50 years should be treated with immunosuppressive therapy. Patients who do not respond to immunosuppression can be maintained with supportive therapy, but their prognosis is poor. Transplants from partially matched family members or matched unrelated donors are an increasingly effective option for these patients. However, at this time, the higher rates of transplant-associated morbidity and mortality with such grafts continue to argue against their use in the front-line management of severe aplastic anemia.

   FANCONI’S ANEMIA AND OTHER CONGENITAL CYTOPENIA

Fanconi’s anemia is an autosomal recessive disorder characterized by progressive pancytopenia, diverse congenital abnormalities, enhanced chromosomal fragility or cellular hypersensitivity to mutagenic chemicals, and an increased predisposition to acute myelogenous leukemia and epithelial cancers, particularly of the head and neck and genitourinary system. Cells from patients with Fanconi’s anemia are uniquely hypersensitive to the clastogenic effect of DNA cross-linking agents such as diepoxybutane and cyclophosphamide; the increased chromosomal breakage resulting from exposure to diepoxybutane establishes the diagnosis. At least 12 complementation groups are now recognized within the spectrum of Fanconi’s anemia. The genes affected by mutations corresponding to 11 of these complementation groups (FANC A, B, C, D1, D2, E, F, G, J, L, and M) have been mapped and cloned, and their respective coded proteins have been characterized. It is now recognized that in response to DNA damage and during the S phase of the normal cell cycle, a complex of eight of these gene products (FANC A, B, C, E, G, L, and M) is formed and catalyzes the monoubiquitination of another Fanconi’s anemia protein, FANC D2. After monoubiquitination, FANC D2 relocalizes from a soluble nuclear compartment to foci on the chromatin, where it promotes the loading and colocalization of FANC D1 (now recognized to be identical to BRCA2) to form stable complexes of FANC D1 and D2, as well as BRCA1, on damaged chromatin. Current studies suggest that these complexes may stabilize broken replication forks and thereby foster efficient homologous recombination through the DNA repair protein RAD51. Another protein in this chromatin-bound complex, BRCA1, also contributes to DNA repair, and mutations in an associated helicase, BACH1, have recently been proposed as the basis for FANC J. Defects in any of the Fanconi anemia–associated genes forming the initial seven protein complexes or in the later proteins in this pathway will result in chromosome instability and enhanced sensitivity to DNA breakage induced by alkylating agents—the distinctive diagnostic feature of Fanconi’s anemia.

The mechanisms whereby these gene mutations induce aplasia are still unclear. However, the limitations to efficient DNA repair associated with these defects may limit the ultimate replicative potential of hematopoietic stem cells, thereby predisposing them to depletion or malignant transformation. Specific mutations within the common variant of Fanconi’s anemia, type C, are associated with earlier onset of severe aplasia. In addition, Fanconi type G and specific mutations of type A are associated with a particularly high risk for secondary myelodysplasia and acute myelogenous leukemia.

Clinical Manifestations

The most widely recognized features include short stature, cafe au lait spots, kidney and urinary tract abnormalities, microphthalmos, mental retardation, and skeletal abnormalities, most often affecting the thumb and radius. However, many patients with Fanconi’s anemia have no morphologic abnormalities, with anemia or progressive aplasia being the only manifestation of disease.

Diagnosis

Patients with Fanconi’s anemia are now most commonly detected early in life in families of known predisposition, at which time they may have normal hematologic indices, mild anemia, or neutropenia. The diagnosis is generally obvious from the pancytopenia and typical associated features.

Treatment

Initially, up to 75% of patients with moderate to severe Fanconi’s anemia may attain improved hemoglobin levels when treated with androgens, with or without corticosteroids. However, long-term androgen use in these patients is associated with significant complications, including hepatocellular carcinoma. Prompt improvements in neutrophil counts have also been observed with G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF), and daily to three times–weekly doses of these cytokines can sustain neutrophil counts for many months. However, once pancytopenia develops, these cytokines are rarely effective.

Currently, allogeneic hematopoietic cell transplantation ( Chapter 184 ) is the only curative treatment of Fanconi’s anemia. It is the treatment of choice for patients with HLA-matched related donors, in whom long-term survival rates are 70 to 90%. Transplants of T cell–depleted hematopoietic progenitor cell grafts from partially matched related and unrelated donors administered after conditioning based on the immunosuppressive activity of the antimetabolite fludarabine have resulted in extended disease-free survival rates of 75 to 82%.

Although a hematopoietic stem cell graft can cure aplasia and prevent the subsequent development of myelodysplastic syndrome or acute myelocytic leukemia, the increased risk for solid tumors remains. Indeed, squamous cell carcinoma of the head and neck has developed in more than 25% of patients with Fanconi’s anemia after successful stem cell transplantation. A high proportion of these tumors are associated with the human papillomavirus ( Chapter 396 ), so trials are under way to test whether vaccination of the donor before transplantation and the host after transplantation can reduce this risk. The possibility of gene therapy for Fanconi’s anemia is also being explored.

   DYSKERATOSIS CONGENITA

Aplastic anemia also develops in a majority of patients with dyskeratosis congenita, a rare genetic disorder clinically characterized by the triad of skin hyperpigmentation, dystrophic nails, and oral leukoplakia.

Pathobiology

Autosomal dominant as well as autosomal and X-linked recessive forms are recognized. The X-linked form is ascribed to mutations in the DKCI gene encoding dyskerin, a protein contributing to telomere maintenance and the function of ribosomes. The autosomal dominant form is due to mutations in the RNA component of telomerase. These mutations result in deficiencies in the activity of telomerase, which catalyzes repair of telomeres at the end of chromosomes in germ cells and stem cells of different lineages after each cell division. Such deficiencies may result in an abnormal and progressive shortening of telomeres, thereby limiting the progenitor cell’s ultimate proliferative potential. In patients with dyskeratosis congenita, the degree of shortening is directly correlated with the severity of clinical manifestations. The autosomal dominant form is characterized by the phenomenon of “disease anticipation,” in which the severity of clinical manifestations increases and occurs earlier in successive generations. Average age-adjusted telomere lengths are also shorter in children of affected probands.

Clinical Manifestations

The typical pancytopenia, skin pigmentation, dystrophic nails, and oral leukoplakia are often associated with short stature; structural abnormalities of the gastrointestinal, genitourinary, and pulmonary systems; and a predisposition to myelodysplastic syndrome, acute myelocytic leukemia, and epithelial malignancies. The diagnosis is usually clear from the characteristic clinical findings.

Treatment

The cytopenia in dyskeratosis congenita can be treated for varying periods with androgens, erythropoietin, G-CSF or GM-CSF, and transfusion support. However, progressive aplasia commonly requires hematopoietic cell transplantation from a normal HLA-compatible related or unrelated allogeneic donor, which can provide full and durable reconstitution of normal hematopoiesis.

   SCHWACHMAN-DIAMOND SYNDROME

Schwachman-Diamond syndrome is a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, short stature, and neutropenia. More than 36% of cases progress to aplastic anemia, myelodysplasia, or overt acute myelocytic leukemia by the age of 30 years. In most (80%) but not all cases, the disease has been ascribed to mutations in the Schwachman-Bodian-Diamond gene, which is located on 7q11 and produces a protein that is concentrated in pseudopods and may contribute to normal chemotaxis. Most patients have significant neutropenia and defective chemotaxis of phagocytes. Treatment with G-CSF (5 μg/kg/day subcutaneously) corrects the neutropenia in most patients, and long-term treatment must be continued. For patients in whom aplastic anemia, myelodysplastic syndrome, or acute myelocytic leukemia develops, the only curative option is hematopoietic cell transplantation from a normal HLA-compatible allogeneic donor. Recent results of marrow and cord blood transplants, mostly from unrelated donors, indicate an extended disease-free survival rate of 64%.

   PURE RED CELL APLASIA

Pure red cell aplasias (PRCAs) are rare disorders that selectively affect the growth and differentiation of erythroid precursors in bone marrow. Affected patients have varying degrees of anemia. Myeloid, megakaryocytic, and lymphoid lineages appear normal. Several distinctive forms of red cell aplasia are recognized, including a congenital form, Blackfan-Diamond anemia, which is usually diagnosed at or shortly after birth, and acquired forms, which may have their onset at any time but are generally first detected in older children and adults.

   Blackfan-Diamond Anemia

Blackfan-Diamond anemia is a rare form of hypoplastic anemia characterized by intrinsic abnormalities in erythroid progenitor differentiation that result in varying degrees of normochromic or macrocytic anemia, elevated levels of red cell adenosine deaminase and hemoglobin F, and either absence or severely reduced erythroid elements in the marrow. A family history consistent with an autosomal dominant disorder is detected in 10 to 20% of cases.

Pathobiology

Approximately 25% of all patients, particularly those with the autosomal dominant form, have mutations involving a gene termed DBA1 or RPS19, which is located on chromosome 19q13.2 and encodes the ribosomal protein S19. Mutations in another as yet uncloned gene, termed DBA2 and mapped to 8p23-22, have been implicated in an additional 35% of patients. An etiologic role for RPS19 mutations is suggested because transduction of CD34+ marrow progenitor cells from these patients with a retroviral vector encoding a normal gene for the S19 protein increases the formation of normal erythroid colonies in vitro by over three-fold.

Clinical Manifestations

This disorder is also associated with craniofacial dysmorphologies, malformations of the thumb or upper limbs, atrial or ventricular septal defects of the heart, and abnormalities of the urogenital system.

Diagnosis

The diagnosis is usually obvious from the characteristic clinical manifestations.

Treatment

The severity of anemia is variable. Approximately 80% of affected patients achieve partial or full remission when treated with low-dose steroids (prednisone, 2 mg/kg/day until hemoglobin increases to 10 g/dL, followed by a slow taper to alternate-day doses needed to sustain the hemoglobin level), and about 15% sustain remission off steroids. The survival rate at age 40 is 100% for patients achieving a sustained remission and 75% for those who can be maintained on steroids. However, for patients with severe or steroid-refractory anemia, only 57% survive to age 40. In phase II trials, 15 to 30% of such patients have achieved partial or complete remissions when treated with interleukin-3 (5 to 10 μg/kg/day subcutaneously) or with the prolactin-inducing drug metoclopramide (10 mg orally three times per day for 4 months). In contrast, erythropoietin is ineffective. In approximately 2% of patients leukemia ultimately develops. Stem cell transplantation from an HLA-matched sibling administered after myeloablative and immunosuppressive conditioning can reconstitute normal donor-derived hematopoiesis and provide about a 75% disease-free survival rate at 3 to 5 years after transplantation. Unfortunately, the disease-free survival rate after transplants from unrelated or HLA-disparate related donors is still poor and ranges from 17 to 39%.

   Acquired Forms

Definition and Epidemiology

Acquired PRCA may develop for unknown reasons, but more commonly it develops in association with specific types of malignancy, infection, or drugs. Most commonly, acquired PRCA develops as a complication of a neoplastic process such as a thymoma ( Chapter 448 ), B- or T-cell chronic lymphocytic leukemia ( Chapter 195 ), non-Hodgkin’s lymphoma ( Chapter 196 ), or an autoimmune disorder such as rheumatoid arthritis ( Chapter 285 ) or SLE ( Chapter 287 ).

Pathobiology

When PRCA is a complication of lymphoreticular malignancies or chronic Epstein-Barr virus infection, interferon γ–secreting T cells that inhibit erythroid colony growth in vitro can often be isolated from blood or marrow. In patients with B-cell chronic lymphocytic leukemia or autoimmune diseases in whom PRCA develops, antibodies that suppress erythropoiesis have often been identified. In rare instances, these antibodies have been shown to neutralize erythropoietin.

The emergence of T or B cells that are active against erythroid progenitors has also been hypothesized to play an etiologic role in the development of PRCA in patients treated with specific drugs such as phenytoin, chlorpropamide, isoniazid, and azathioprine. However, certain agents, such as chloramphenicol and the antibiotic linezolid, may induce a dose-dependent selective inhibition of red cell production.

Acquired PRCA may also result from a lytic infection of erythroid progenitors by human parvovirus B19, the etiologic agent of fifth disease. Erythroid cells are selectively targeted by virtue of their expression of globoside, the blood group P antigen that is expressed on a proportion of erythroid colony-forming units and all more differentiated erythroid elements. Such infections probably occur in normal individuals, but anemia is not observed because of the rapidity of the immune response and the regrowth of normal erythroid elements. However, in patients with spherocytosis or sickle cell anemia, whose erythroid cell production is already stressed by chronic hemolysis, red cell aplastic crises may develop. Similarly, acquired PRCA may develop after parvovirus B19 infection in patients with acquired immunodeficiency syndrome (AIDS) as a result of impairment in viral clearance ascribable to their immunodeficiency.

Acquired PRCA may also be the first manifestation of a myelodysplastic syndrome ( Chapter 193 ); in this case it is a clonal disorder of erythropoiesis rather than a sequela of a secondary immune response. Consistent with this hypothesis is the low rate of response to immunosuppressive therapy in these patients.

Treatment

Treatment of acquired PRCA is usually suggested by the disorder co-associated with its development. Removal of a thymoma, treatment of an underlying malignancy, or cessation of an instigating drug may induce remission. For patients with autoimmune forms, treatment with prednisone (2 mg/kg/day with a slow taper after remission) generally improves erythropoiesis. Refractory patients may also respond to prednisone combined with cyclosporine (10 mg/kg/day divided into two doses, with dose adjustments to maintain levels of 200 to 400 μg/mL for 3 to 6 months, followed by a taper over a 3-month period) or low-dose cyclophosphamide (2 to 3 mg/kg/day until remission or 3 to 4 months). Studies indicate that the CD20-specific monoclonal antibody rituximab can induce durable remissions in patients whose PRCA is refractory to these agents. In contrast, for patients with parvovirus B19 infection–induced aplasia, brief treatment with high doses of intravenous immunoglobulin (400 mg/kg/day every 3 to 4 weeks) alone usually fosters rapid recovery of normal erythropoiesis by providing significant doses of parvovirus-specific antibody and thereby hastening viral clearance. For patients with AIDS, chronic parvoviremia may necessitate repeated doses of immunoglobulin.

   MYELOPHTHISIC ANEMIAS

Deposition of fibrous tissue in bone marrow (myelofibrosis) generally causes leukoerythroblastosis in the peripheral blood (immature granulocytes, nucleated red cells, and teardrop-shaped red cells). This process can occur as a primary hematologic disease, called myelofibrosis with myeloid metaplasia ( Chapter 177 ), or as a secondary process, called myelophthisis, which is often associated with anemia. Myelophthisis represents a reaction of the marrow tissue to invading tumor cells, infectious agents (particularly mycobacteria or fungi), lipid storage diseases (notably Gaucher’s disease [ Chapter 223 ]), or other granulomatous diseases such as sarcoidosis ( Chapter 95 ). Tumors associated with myelophthisis are of both hematopoietic (acute leukemias, chronic myeloproliferative disorders, hairy cell leukemia, Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma) and epithelial (breast, lung, prostate, and stomach adenocarcinomas) origin. Myelophthisis can also occur as a result of osteopetrosis ( Chapter 269 ), a congenital disease characterized by failure of osteoclasts to remodel bone, thereby resulting in obliteration of the marrow space with bone and fibrous tissue. Marrow fibrosis results from an overproduction of collagen by marrow stromal cells as a consequence of abnormal concentrations of cytokines produced by tumor cells or inflammatory cells that control collagen metabolism.

The blood smear in myelophthisis is characterized by a normocytic, normochromic anemia with low reticulocyte counts, teardrop-shaped red cells, and circulating erythroblasts. Platelet counts are usually decreased, whereas the granulocyte count, which includes immature forms, is normal or increased. The marrow fibrosis is often associated with extramedullary hematopoiesis and sometimes hepatosplenomegaly. Marrow often cannot be aspirated (dry tap), but biopsy reveals fibrosis. The primary process is generally apparent, but it is extremely important to exclude an infectious cause. Therapy is aimed at the primary cause; infections can be successfully treated, whereas metastatic marrow disease is more difficult to treat.

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