Aplastic Anemia

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Chapter 4 Aplastic Anemia

Neal S. Young, Jaroslaw P. Maciejewski

Table 4-1 Differential Diagnosis of Pancytopenia

Pancytopenia With Hypocellular Bone Marrow
Acquired aplastic anemia Inherited aplastic anemia (Fanconi anemia and others) Some myelodysplasia syndromes Rare aleukemic leukemia (acute myeloid leukemia) Some acute lymphoblastic leukemias Rare lymphomas of bone marrow
Pancytopenia With Cellular Bone Marrow
Primary bone marrow diseases Myelodysplasia syndromes Paroxysmal nocturnal hemoglobinuria Myelofibrosis Some aleukemic leukemias Myelophthisis Bone marrow lymphoma Hairy cell leukemia Secondary to systemic diseases Systemic lupus erythematosus, Sjögren syndrome Hypersplenism Vitamin B₁₂, folate deficiency (familial defect) Overwhelming infection Alcohol Brucellosis Ehrlichiosis Sarcoidosis Tuberculosis and atypical mycobacteria
Hypocellular Bone Marrow ± Cytopenia
Q fever Legionnaires disease Mycobacteria Tuberculosis * Anorexia nervosa, starvation Hypothyroidism

^*Pancytopenia in tuberculosis only rarely is associated with a hypocellular bone marrow at biopsy or autopsy. Marrow failure in the setting of tuberculosis is almost always fatal; exceptional patients probably had underlying myelodysplasia or acute leukemia.

Table 4-2 A Classification of Aplastic Anemia

Acquired Aplastic Anemia
Secondary aplastic anemia Irradiation Drugs and chemicals Regular effects Cytotoxic agents Benzene Idiosyncratic reactions Chloramphenicol Nonsteroidal antiinflammatory drugs Antiepileptics Gold Other drugs and chemicals Viruses Epstein-Barr virus (infectious mononucleosis) Hepatitis virus (non-A, non-B, non-C, non-G hepatitis) Parvovirus (transient aplastic crisis, some pure red blood cell aplasia) Human immunodeficiency virus (acquired immunodeficiency syndrome) Immune diseases Eosinophilic fasciitis Hyperimmunoglobulinemia Thymoma and thymic carcinoma Graft-versus-host disease in immunodeficiency Paroxysmal nocturnal hemoglobinuria Pregnancy Idiopathic aplastic anemia
Inherited Aplastic Anemia
Fanconi anemia Dyskeratosis congenita Shwachman-Diamond syndrome Reticular dysgenesis Amegakaryocytic thrombocytopenia Familial aplastic anemias Preleukemia (e.g., monosomy 7) Nonhematologic syndromes (e.g., Down, Dubowitz, Seckel)

Table 4-3 Classification of Drugs and Chemicals Associated With Aplastic Anemia

I. Agents That Regularly Produce Bone Marrow Depression as a Major Toxic Effect When Used in Commonly Used Doses or Normal Exposures
Cytotoxic drugs used in cancer chemotherapy Alkylating agents (busulfan, melphalan, cyclophosphamide) Antimetabolites (antifolic compounds, nucleotide analogs) antimitotics (vincristine, vinblastine, colchicine) Some antibiotics (daunorubicin, doxorubicin [Adriamycin]) Benzene (and less often benzene-containing chemicals: kerosene, carbon tetrachloride, Stoddard solvent, chlorophenols)
II. Agents Probably Associated With Aplastic Anemia But With a Relatively Low Probability Relative to Their Use
Chloramphenicol Insecticides Antiprotozoals (quinacrine and chloroquine) Nonsteroidal antiinflammatory drugs (including phenylbutazone, indomethacin, ibuprofen, sulindac, diclofenac, naproxen, piroxicam, fenoprofen, fenbufen, aspirin) Anticonvulsants (hydantoins, carbamazepine, phenacemide, ethosuximide) Gold, arsenic, and other heavy metals such as bismuth and mercury Sulfonamides as a class Antithyroid medications (methimazole, methylthiouracil, propylthiouracil) Antidiabetes drugs (tolbutamide, carbutamide, chlorpropamide) Carbonic anhydrase inhibitors (acetazolamide, methazolamide, mesalazine) d-Penicillamine 2-Chlorodeoxyadenosine
III. Agents More Rarely Associated With Aplastic Anemia
Antibiotics (streptomycin, tetracycline, methicillin, ampicillin, mebendazole and albendazole, sulfonamides, flucytosine, mefloquine, dapsone) Antihistamines (cimetidine, ranitidine, chlorpheniramine) Sedatives and tranquilizers (chlorpromazine, prochlorperazine, piperacetazine, chlordiazepoxide, meprobamate, methyprylon, remoxipride) Antiarrhythmics (tocainide, amiodarone) Allopurinol (can potentiate marrow suppression by cytotoxic drugs) Ticlopidine Methyldopa Quinidine Lithium Guanidine Canthaxanthin Thiocyanate Carbimazole Cyanamide Deferoxamine Amphetamines

Table 4-4 Drugs Associated With Aplastic Anemia in the International Aplastic Anemia and Agranulocytosis Study *

CI, Confidence interval.

* The multivariate model included the following factors: age, gender, geographic area, date of interview, reliability of the patient, person interviewed, transfer from another hospital, history of blood disorder or tuberculosis, exposure to benzene and related chemicals, and use of other suspected drugs.

† Other than trimethoprim–sulfonamide combination.

From Kaufman DW, Kelly JP, Levy M, et al: The drug etiology of agranulocytosis and aplastic anemia. New York, 1991, Oxford University Press.

Table 4-5 Clinical Presentation of Aplastic Anemia

Adapted from Williams DM, Lynch RE, Cartwright GE: Drug induced aplastic anemia. Semin Hematol 10:195, 1973.

Table 4-6 Severity of Aplastic Anemia as Defined by Laboratory Studies

Diagnostic Algorithm in Aplastic Anemia

AA, Aplastic anemia; AML, acute myeloid leukemia; AMM, agnogenic myeloid metaplasia; BM, bone marrow; DEB, diepoxybutane; MDS, myelodysplastic syndrome; MMC, mitomycin C; PB, peripheral blood.

Table 4-7 Bone Marrow Morphologic Findings that Discriminate Myelodysplasia From Aplastic Anemia

* Ringed sideroblasts and myeloblasts are observed by definition in some of the myelodysplastic syndromes. Dyserythropoietic red blood cell precursors show bizarre forms with multiple or irregular nuclei. Megakaryocytes can show defective nuclear polyploidization and increased internuclear spaces, or they can be small with only a few nuclei and peculiar granulation.

Adapted from Bagby GC: The preleukemic syndrome (hematopoietic dysplasia). In Shahidi NT, editor: Aplastic anemia and other bone marrow failure syndromes, New York, 1990, Springer-Verlag, p 199. Provides percentages for myelodysplasia.

Treatment Algorithm in Aplastic Anemia

Algorithm-based selection of treatment for patients with aplastic anemia. ATG, Antithymocyte globulin; BMT, bone marrow transplantation; CSA, cyclosporine A; HLA, human leukocyte antigen; IS, immunosuppression; TX, treatment.

Table 4-8 Results of Matched Sibling Donor Allogeneic Marrow Transplantation for Aplastic Anemia

EBMT, European Group for Bone Marrow Transplant; GVHD, graft-versus-host disease; IBMTR; International Blood and Marrow Transplant Registry.
GVHD results are generally for grades II–IV and in patient at risk.
Only studies reporting ≥20 patients are tabulated.
In contrast to Table 4-1, response rates are not provided because, in surviving patients who do not experience primary graft rejection or secondary graft failure, full hematologic recovery with donor hematopoiesis is anticipated.

Table 4-9 Alternative Donor Stem Cell Transplantation for Severe Aplastic Anemia

ATG, Anti-thymocyte globulin; CP, Campath; Cy, cyclophosphamide; Flu, fludarabine; GVHD, graft-versus-host disease; IBMTR, International Blood and Marrow Transplant Registry; LFI, limited field irradiation; MMRD, mismatched related donor; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; TBI, total-body irradiation; TCD, T-cell depletion; TLI, total lymphoid irradiation; TT, thiotepa; UCB, umbilical cord blood.
Only studies reporting ≥5 patients are tabulated.

* GVHD results are generally for grades II-IV and in patient at risk.

Table 4-10 Intensive Immunosuppression in Severe Aplastic Anemia

Only studies of more than 20 enrolled patients are tabulated. Responses to immunosuppressive therapy are usually partial; blood counts may not become normal, but transfusions are no longer required, and the neutrophil count is adequate to prevent infection. Relapse is usually responsive to further immunosuppressive therapies. Clonal evolution is to dysplastic bone marrow changes or cytogenetic abnormalities.

* With androgens and ± granulocyte colony-stimulating factor.

† With mycophenolate mofetil.