Plastic Anemia
Definition
Pancytopenia (i.e., anemia, neutropenia, and thrombocytopenia) and aplastic marrow on biopsy examination [see Figure 3] establish a working diagnosis of aplastic anemia. The biopsy specimen must not be taken from a marrow site that has been irradiated. It is essential to determine the severity of aplastic anemia. Severe aplastic anemia (SAA) is defined by (1) marrow of less than 25% normal cellularity or marrow of less than 50% normal cellularity in which fewer than 30% of the cells are hematopoiet-ic, and (2) two out of three abnormal peripheral blood values (absolute reticulocyte count < 40,000/^l, absolute neutrophil count [ANC] < 500 ^l, or platelet level < 20,000/^l). These criteria have been criticized as being relatively insensitive.
Etiology
Aplastic anemia has a number of causes [see Table 2], although in many cases the exact cause cannot be determined.
Ionizing irradiation and chemotherapeutic drugs used in the management of malignant and immunologic disorders have the capacity to destroy hematopoietic stem cells. With careful dosing and scheduling, recovery is expected. Certain drugs, such as chloramphenicol, produce marrow aplasia that is not dose dependent. Gold therapy and the inhalation of organic solvent vapors (e.g., benzene or glue) can also cause fatal marrow failure.
In 2% to 10% of hepatitis patients, severe aplasia occurs 2 to 3 months after a seemingly typical case of acute disease, usually in young men. Often, the hepatitis has no obvious cause, and tests for hepatitis A, B, and C are negative.25 There is a high incidence of aplastic anemia after liver transplantation in patients with severe non-A, non-B hepatitis.26
Several lines of evidence support the possibility that immune disorders can lead to aplasia. Marrow aplasia occurs in graft versus host disease (GVHD).27 Immunosuppressive preconditioning improves the chances of successful transplantation of syn-geneic marrow into patients with aplastic anemia,28 and im-munosuppressive therapy has been used successfully to treat id-iopathic aplastic anemia.27,28 The blood of some patients with aplastic anemia appears to contain suppressor T cells that suppress the growth of the committed progenitor cells known as colony-forming unit-granulocyte-macrophage (CFU-GM). The suppressor T cells may act by producing interferon gamma.28 The result of these complex immune mechanisms involving suppressor T cells is a profound decrease in primitive hematopoietic cells as measured by both the long-term culture-initiating cell (LTC-IC) assay and the ability to form secondary colonies from the colonies surviving 5 weeks of marrow culture.
Aplasia can also be part of a prodrome to hairy-cell leukemia [see 12:XV Chronic Lymphoid Leukemias and Plasma Cell Disorders],acute lymphoblastic leukemia [see 12:XVI Acute Leukemia], or, in rare cases, acute myeloid leukemia; or it can develop in the course of myelodysplasia [see 12:XVI Acute Leukemia].
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Table 2 Causes of Aplastic Anemia |
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irradiation |
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drugs |
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Agents whose use regularly causes myelosuppression |
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Alkylating agents: melphalan, cyclophosphamide, chlorambucil, busulfan |
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Antimetabolites: azathioprine, 6-mercaptopurine, hydroxyurea, methotrexate |
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Other antitumor agents: daunorubicin, doxorubicin, car-mustine, lomustine, amsacrine |
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Agents whose use occasionally causes myelosuppression |
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Chloramphenicol, gold compounds, arsenic, sulfonamides, mephenytoin, trimethadione, phenylbutazone, quinacrine, indomethacin, diclofenac, felbamate |
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toxins |
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Benzene, glue vapors |
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infections |
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Non-A, non-B, non-C hepatitis, infectious mononucleosis, parvovirus infection (attacks erythroid precursors), HIV |
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malignant diseases |
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Hairy-cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia (rarely), myelodysplastic syndromes |
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clonal disorders |
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Paroxysmal nocturnal hemoglobinuria |
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immune-mediated aplasia |
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Eosinophilic fasciitis |
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inherited disorders |
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Fanconi anemia |
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pregnancy |
Diagnosis
The patient with aplastic anemia may seek medical attention because of fatigue and shortness of breath. Accompanying thrombocytopenia may cause petechiae, oral blood blisters, gin-gival bleeding, and hematuria depending on the level of the platelet count. By far the major problem associated with aplastic anemia is the recurrent bacterial infections caused by the profound neutropenia. Sepsis, pneumonia, and urinary tract infections are common among patients with aplastic anemia. Invasive fungal infections may cause death, especially in patients with severe neutropenia.
The diagnosis of aplastic anemia requires a marrow aspirate and biopsy [see Figure 3], as well as a thorough history of drug exposures, infections, and especially symptoms suggesting viral illnesses and serologic test results for hepatitis, infectious mononucleosis, HIV, and parvovirus [see Figure 4]. Measurement of red cell CD59 is helpful in the diagnosis of paroxysmal nocturnal hemoglobinuria.
It is also important to determine the severity of aplastic anemia [see Aplastic Anemia, Definition, above]. Severe cases are associated with a very low rate of spontaneous remission and a mortality of 70% within 1 year. In contrast, 80% of patients who have milder forms of aplastic anemia survive for 1 year.24
Differential Diagnosis
The differential diagnosis of pancytopenia includes chronic lymphocytic leukemia, systemic lupus erythematosus, and congestive splenomegaly. In these diseases, however, the marrow is not aplastic but rather shows hyperplasia of the involved cell lines. Other conditions that cause pancytopenia include hy-poplastic myelodysplastic syndrome, acute leukemia, mega-loblastosis, and large granular lymphocytic leukemia.30
Treatment of Mild Aplastic Anemia
Treatment of milder forms of aplastic anemia involves removing the offending agent and providing supportive therapy, primarily transfusion therapy, anticipating that the remaining pluripotent stem cells will repopulate the marrow.
Figure 4 Giant pronormoblast, evident on this marrow smear, strongly suggests a diagnosis of parvovirus infection.
Supportive therapy Thrombocytopenia is often a major problem associated with aplastic anemia. It should be managed by platelet transfusion as needed to control or prevent bleeding. Usually, a threshold of 10,000 platelets/^l is used for transfusion, but conservative treatment is best, and as few transfusions as possible are given. Extensive platelet replacement may result in allosensitization to platelets and may complicate future allo-geneic bone marrow transplantation. Red blood cell transfusions are given as required to control the symptoms and signs of anemia.
Granulocyte colony-stimulating factor (G-CSF) and granulo-cyte-macrophage colony-stimulating factor (GM-CSF) have been given to patients to raise the absolute neutrophil count and help combat infection. They are usually ineffective when used alone, because of the severe deficiency in precursor cells, which are the target for the actions of G-CSF and GM-CSF.31 It is generally preferable to proceed to definitive treatment: immunosup-pressive therapy or preferably allogeneic bone marrow transplantation if a matched sibling donor is available [see 5:XI Hematopoietic Cell Transplantation].
Definitive therapy Transplantation from a matched sibling after a preparative regimen of high-dose cyclophosphamide and antithymocyte globulin, together with the use of methotrexate and cyclosporine for GVHD prophylaxis, is a very effective regimen for patients with aplastic anemia. Current results suggest a cure rate greater than 90%.33 Results with mismatched or unrelated matched donors are somewhat worse; therefore, patients with aplastic anemia who are without sibling donors are often given a trial of immunosuppressive therapy before transplantation.
Three forms of immunosuppression have been shown to produce partial remission in aplastic anemia.31,32,34 Antithymocyte globulin (ATG) produced sustained remission in about half of the patients in a randomized trial.32 High-dose corticosteroids improved blood counts in about 40% of treated patients, and cy-closporine was also shown to be beneficial.32 (Androgens such as oxymetholone may have a role in the treatment of severe aplas-tic anemia but are not given alone.31,34)
Although each of these agents can be used individually or consecutively in the treatment of aplastic anemia, a controlled study suggests that results are better when all three are used si-multaneously.31,32 The combination of ATG, a corticosteroid, and cyclosporine resulted in an actuarial survival of 62% at 36 months. The first signs of response occurred at about 4 weeks; the median time to remission was 60 to 82 days.32 In this study, patient outcome was related to the quality of hematologic response. An 11-year follow-up report confirmed the effectiveness of the combination of ATG, corticosteroids, and cyclosporine. The relapse rate was 38%, and clonal or malignant diseases developed in 25% of patients.
One recommendation, based on the usual availability of horse ATG in the United States,31,32 is to administer horse ATG at a dosage of 40 mg/kg/day in 500 ml of saline for 4 days over a period of 4 to 5 hours through an I.V. line equipped with a mi-croaggregate in-line filter. The toxic side effect of ATG is serum sickness, which can usually be controlled with corticosteroids. Prednisone (60 to 100 mg/day) is given orally in divided doses, or methylprednisolone (40 mg) is added to the infusion bottle, and the dose can be increased to 1 mg/kg/day. Corticosteroid therapy is adjusted to control serum sickness, but it can usually be tapered after 2 weeks and stopped after 30 days.
Cyclosporine (10 to 12 mg/kg/day) is given orally in two divided doses, with the aim of achieving whole blood trough levels of 500 to 800 ng/ml or a serum level of 100 to 200 ng/ml. After 29 days, the cyclosporine dosage can be tapered for a trough whole blood level of 200 to 500 ng/ml.31,32 The cyclosporine is continued for at least 6 months. Cyclosporine can cause hypertension, renal toxicity, hypomagnesemia, vitiligo, tremors, hypertrichosis, susceptibility to Pneumocystis carinii pneumonia (PCP), and gingival hyperplasia.31,32 In one study, 300 mg of aerosolized pentamidine was given every 4 weeks as PCP prophylaxis.
In another study, G-CSF (5 ^g/kg/day) was given subcuta-neously for the first 90 days, along with I.V. methylprednisolone (2 mg/kg/day on days 1 through 5, followed by 1 mg/kg/day on days 6 through 10, and tapered off in 30 days), with good results.
In contrast to patients who undergo allogeneic bone marrow transplantation, patients who respond to immunosuppressive therapy are not actually cured. Many of these patients continue to have moderate cytopenia37; 20% to 36% experience relapses of aplastic anemia,31,32,37 and as many as 20% to 36% eventually develop clonal disorders, such as paroxysmal nocturnal hemoglo-binuria, myelodysplastic syndrome, and acute leukemia.31,32 Patients also are at increased risk for the development of solid tumors after treatment of aplastic anemia, but the risk is the same for patients who underwent immunosuppressive therapy as it is for those who underwent allogeneic bone marrow transplanta-tion.38 More than 50% of patients who have relapses of aplastic anemia after initially responding to immunosuppressive therapy may respond to a second course of therapy. 31,32 For unresponsive patients, a trial of rabbit ATG may work. The rabbit ATG (3.5 mg/kg/day diluted in saline and infused over 6 to 8 hours for 5 consecutive days)39 is given along with cyclosporine (5 mg/kg/day p.o. on days 1 through 180, then tapered) and G-CSF (5 ^g/kg/day on days 1 through 90).
An intriguing report concerns 10 patients with severe aplastic anemia who were treated with high-dose I.V. cyclophosphamide (45 mg/kg/day) for 4 consecutive days.40 Some patients also received cyclosporine. Only one course of I.V. cyclophosphamide was given. Seven of 10 patients had a complete hematologic response, and six were still alive after a median follow-up of 10.8 years (range, 7.3 to 17.8 years). However, a trial comparing high-dose cyclophosphamide with ATG was ended early because of excessive cyclophosphamide-induced morbidity and mortality.41 Therefore, the role of high-dose cyclophos-phamide in the treatment of aplastic anemia needs extensive clarification.
Treatment of Severe Aplastic Anemia
The choice of appropriate therapy for patients with SAA is influenced by age and disease severity. The European Group for Blood and Marrow Transplantation reported on the results of immunosuppressive therapy in 810 patients subdivided into three age groups: younger than 49, 50 through 59, and older than 60. The 5-year survival rates for those with SAA were 86%, 72%, and 54%, respectively; for those with VSAA, the comparable rates were 49%, 40%, and 21%.42 Older patients had more bleeding and infections.
Patients younger than 20 years Allogeneic bone marrow transplantation should be performed in patients younger than 20 years if a matched sibling donor is available. Although there are risks, including chronic GVHD and organ dysfunction caused by the conditioning program,31 50% to 80% of patients may be cured; the incidence of later clonal disorders is very low.34 Allogeneic bone marrow transplantation, along with conditioning programs consisting of cyclophosphamide and ATG, produced an actuarial survival rate of 69% after 15 years.34 Patients younger than 20 years who do not have a matched sibling donor should consider transplantation from a matched unrelated donor. Allogeneic transplantation from a matched unrelated donor initially produced a 2-year survival rate of only 29% because of severe GVHD.31 In a study of 15 patients who received unrelated-donor transplantations, all were reported alive at 2 to 86 months (mean follow-up, 51 months); only one patient developed extensive GVHD, and five (33%) developed moderate to acute GVHD. These results suggest that conditioning regimens that contain ATG and cyclophosphamide are improving the treatment outcomes for unrelated donor transplantation in this patient group.43
Patients between 20 and 45 years of age Patients between 20 and 45 years of age who are in excellent health and have a fully matched sibling donor may be able to tolerate GVHD and thus benefit from the curative potential of an allogeneic bone marrow transplant. Some experts propose that allogene-ic bone marrow transplantation should be considered for patients in this age group,34 particularly because newer conditioning programs seem to be capable of reducing the severity of GVHD.31,44 In a study of 154 patients younger than 46 years who received allogeneic transplantation, the median survival was 29 months, and the probability of overall survival at 5 years was 56%.®
Patients older than 45 years Previously it was thought that the impact of GVHD was too severe for patients older than 45 years, and it was suggested that these patients receive immuno-suppressive therapy.31,34 However, conditioning programs containing ATG and cyclophosphamide seem to be more tolerable, and even heavily pretreated patients as old as 59 years have done well after allogeneic marrow transplantation.
Acquired Pure Red Cell Aplasia
Definition
In adults, pure red cell aplasia (PRCA) is an acquired disorder. The anemia is severe (hematocrit usually less than 20%), reticulocytopenia is profound (often 0%), the absolute reticulo-cyte count is usually less than 10,000/ ^l, and marrow erythroid precursors are virtually absent. Marrow myeloid and mega-karyocytic elements are preserved, however, and the peripheral platelet and white blood cell counts are also normal.
Pathophysiology
In PRCA, erythropoiesis is thought to be inhibited primarily by immune mechanisms, including autoantibody-mediated and T cell-mediated suppression of erythroid progenitors, usually at a stage after the CFU-E stage of erythroid differentiation and before formation of proerythroblasts. T cells, particularly of the large granular lymphocyte (T-LGL) class, may be involved in the suppression of erythropoiesis, and in some cases, there is evidence that the suppression is caused by clonal T cells.47 Autoanti-body inhibition of erythropoietin has also been described, but it is quite uncommon.48 Two other mechanisms probably cause PRCA: (1) a specific attack on erythroid precursors by the parvovirus B19 (one report indicated that 14% of cases were caused by this virus49) and (2) an underlying hematopoietic clonal abnormality that may be a prodrome to myelodysplastic syndrome.48
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Table 3 Causes of Acquired Pure Red Cell Aplasia |
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Primary |
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Associated with thymoma in 10%-15% of cases51 |
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Idiopathic causes |
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Secondary |
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Neoplasia: chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin and non-Hodgkin lymphomas; large granular lymphocytic proliferative disorders; prodrome to myelodysplastic syndromes51 |
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Systemic lupus erythematosus or rheumatoid arthritis |
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Associated with pregnancy |
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Associated with autoimmune hemolytic anemia |
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Drugs: those most commonly associated are phenytoin, chlorpropamide, zidovudine,57 trimethoprim-sulfameth- oxazole, isoniazid51 |
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Multiple endocrine gland insufficiency |
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Primary amyloidosis |
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Infections: infectious mononucleosis, viral hepatitis, parvo-virus infection, HIV51 |
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ABO-incompatible bone marrow transplantation |
Etiology
PRCA may be caused by a variety of processes, including neo-plasia, autoimmune disorders, drugs, and infections [see Table 3].
The association of PRCA with LGL proliferation and leukemia is increasingly being recognized.30 The routine use of T cell receptor gene rearrangement studies in one series showed that nine of 14 patients had a clonal LGL disorder.50 Presumably, these LGL cells directly mediate inhibition of erythropoiesis.49,50 In perhaps as many as 20% of cases, PRCA may be a prodrome to the myelodysplastic syndromes or acute myeloid leukemia.49,51
Erythroblastopenia also occurs in a small percentage of patients with autoimmune hemolytic anemia [see 5: IV Hemoglo-binopathies and Hemolytic Anemias] and may be caused by au-toantibody attack on maturing normoblasts.
The treatment of HIV infection with zidovudine (AZT) produces, in virtually all patients, an anemia that is usually marked by significant macrocytosis.52 Moderate erythroid hypoplasia is the usual cause of this anemia, which can progress to PRCA.
Parvovirus infection is the cause of the transient aplastic crises that occur in patients who have severe hemolytic disorders. The marrow in patients with such disorders must compensate for the peripheral hemolysis by increasing its production up to sevenfold and thus typically shows an intense erythroid hy-perplasia. Although parvovirus can affect all precursor cells, the red cell precursors are the most profoundly affected.
PRCA can complicate ABO-incompatible allogeneic bone marrow transplantation; the recipient’s serum continues to express anti-A or anti-B isohemagglutinins against donor A or B antigen expressed on the surface of erythroid progenitors.51 With PRCA of pregnancy, antibodies against BFU-E usually disappear after delivery, coinciding with clinical remission.
Diagnosis
The patient with PRCA presents with symptoms characteristic of anemia—namely, weakness, fatigue, and shortness of breath. White blood cell and platelet counts are normal morphologically and functionally. A very low reticulocyte count—either a relative reticulocyte value of less than 0.2% or a very low absolute reticulocyte count of less than 10,000 ^l—should prompt the physician to order a bone marrow aspirate. In a patient with PRCA, a bone marrow aspirate and biopsy typically show normal myelopoiesis, lymphopoiesis, and megakaryocytopoiesis; erythropoiesis is virtually absent. In the absence of any apparent cause of PRCA, four conditions must be considered: idiopathic PRCA, thymoma, hypoplastic myelodysplastic syndromes (MDS), and LGL leukemia. The workup to diagnose PRCA usually includes computed tomography of the chest to evaluate the possibility of thymoma, immunophenotypic analysis of circulating blood or marrow lymphocytes to identify LGL proliferation, marrow cytogenetics to evaluate the possibility of MDS, and antibody tests for parvovirus.49 A diagnostic hallmark of par-vovirus infection is the appearance of giant pronormoblasts in the marrow [see Figure 4]. The distinction between PRCA associated with the myelodysplastic syndromes and acute myeloid leukemia may be difficult to determine at the time of diagnosis unless a typical myelodysplastic cytogenetic abnormality is detected during a bone marrow examination.
