Chapter 3: Aplastic Anemia: Acquired and Inherited

• Pancytopenia with markedly hypocellular marrow and normal marrow cell cytogenetics.

• Incidence worldwide is 2 to 5 cases/million population per year and 5 to 12 cases/million population per year in the United States (and in other industrialized countries). Incidence is approximately twice as high in Asian countries.

• Peak incidence between ages 15 and 25 and 65 to 69 years.

• The definitions for range of severity of aplastic anemia are shown in Table 3–1.

Pathogenesis

• Immune suppression of marrow by autoreactive T lymphocytes.

• Toxic injury to stem and/or progenitor cells (e.g., certain chemotherapy or drugs) (see Table 3–2).

• Inherited intrinsic stem cell defect (e.g., Fanconi anemia).

Etiologic Classification

Acquired

• Acquired T lymphocyte mediated autoimmune suppression of hematopoietic stem cells and/or progenitor cells in most cases (~70%).

• Paroxysmal nocturnal hemoglobinuria (PNH) (frequently associated with hypoplastic marrow).

• Chemicals, e.g., benzene. Rare today in countries with workplace regulations limiting exposure.

• Drugs, e.g., chloramphenicol (see Table 3–2 for most frequent offenders; see also Williams Hematology, 8th ed, Chap. 34, Table 34–3, p. 467 for a more complete list).

• Viruses, e.g., Epstein-Barr; non-A,-B,-C,-D,-E, or G hepatitis; HIV.

• Immune and connective tissue diseases: e.g., eosinophilic fasciitis, Hashimoto thyroiditis, Graves disease, systemic lupus erythematosus.

• Pregnancy.

• Iatrogenic or accidental, e.g., intensive radiation to marrow-bearing bones, intensive marrow-suppressive chemotherapy.

Inherited

• Fanconi anemia

  — Autosomal recessive.

  — Any of 13 gene mutations, FANCA through FANCN, account for about 95 percent of cases.

  — Macrocytosis and poikilocytosis may precede cytopenias.

  — Cytopenias, sometimes starting with thrombocytopenia, develop after age 5 to 10 years.

  — Marrow hypocellularity explains cytopenias.

  — Short stature; abnormal skin pigmentation (café-au-lait spots); skeletal abnormalities (e.g., dysplastic radii and thumbs); heart, kidney, and eye anomalies; microcephaly; and hypogonadism in different combinations often noted.

  — Chromosome fragility, especially after exposure to DNA cross-linking agents such as diepoxybutane (used as a diagnostic test).

  — Androgens occasionally may improve hematopoiesis.

  — Allogeneic hematopoietic stem cell transplantation can be curative.

  — Risk of acute myelogenous leukemia and other cancers.

• Dyskeratosis congenita

  — Autosomal dominant, autosomal recessive, and X-linked inheritance patterns may be present (see Williams Hematology 8th ed, Chap. 34, Table 34–9, p. 478).

  — Gene mutations identified in 60 percent of cases.

  — Mutations involving genes encoding proteins in the telomerase complex.

  — Resulting abnormalities in telomere length.

  — Mucocutaneous (e.g., skin hyperpigmentation or hypopigmentation, alopecia leukoplakia) and finger and toenail abnormalities (ridging and longitudinal splitting, atrophy) in childhood.

  — Pulmonary (e.g., fibrosis), gastrointestinal (e.g., esophageal webs), urogenital (e.g., hypospadius), neurologic (e.g., learning impairment), skeletal (e.g., hypoplasia of mandible) findings.

  — Aplastic anemia in early adulthood. Principal cause of death.

  — Increased incidence of various mucosal cancers (e.g., squamous cell carcinoma of mouth, nasopharynx, esophagus, rectum, vagina, others).

• Shwachman-Diamond syndrome

  — Caused by mutation in SBDS gene (Shwachman-Bodian-Diamond syndrome) on chromosome 7.

  — Exocrine pancreatic insufficiency and neutropenia. Pancreatic endocrine function (insulin secretion) generally remains intact (see Chap. 33).

  — Neutropenia with functionally abnormal neutrophils (defective chemotaxis) present in virtually all patients.

  — Anemia and thrombocytopenia less common.

  — Elevated hemoglobin F in most patients.

  — Pancytopenia in about 20 percent of patients.

  — Patients usually present in early infancy with malabsorption; steatorrhea; failure to thrive; and deficiencies of fat-soluble vitamins A, D, E, and K.

  — Approximately 50 percent of patients regain exocrine pancreatic function during later childhood.

  — Skeletal anomalies are present in about 75 percent of patients. Short stature, osteochondrodysplasia (cartilage and bone anomalies), osteoporosis.

  — Recurrent bacterial infections (e.g., upper respiratory tract infections, otitis media, sinusitis, pneumonia, paronychia, osteomyelitis, bacteremia) occur.

  — Enzyme replacement therapy for exocrine pancreatic insufficiency.

  — Progression to multicytopenia, hypoplastic marrow, myelodysplasia, or acute myelogenous leukemia can occur.

  — Allogeneic hematopoietic stem cell transplantation can be curative.

For other rare causes of aplastic anemia see Williams Hematology 8th ed, Chap. 34, Table 34–8, p. 477.

• Fatigue, pallor, dyspnea on exertion, bleeding, or infections as a consequence of the cytopenias.

• Physical examination generally is unrevealing except for signs of anemia, bleeding, or infection.

• Pancytopenia.

• Red cells may be macrocytic.

• Markedly hypocellular marrow (see Fig. 3–1).

• Abnormal clonal cytogenetic findings suggest hypoplastic myelodysplastic syndrome (clonal myeloid disease) rather than aplastic anemia.

• Infrequent blast cells in marrow suggest hypoplastic acute myelogenous leukemia.

• Flow cytometry of CD55, CD59 on blood cells to rule out PNH.

Table 3–3 indicates important diagnostic procedures.

• Aplastic anemia.

• Hypoplastic myelodysplastic syndrome or hypoplastic acute myelogenous leukemia.

• PNH.

• Hypoplastic antecedent phase of acute lymphocytic leukemia (especially in children).

• Hypoplastic antecedent of hairy cell leukemia, lymphoma, large granular lymphocytic leukemia (rare).

Table 3–4 lists important initial steps in management.

• Allogeneic hematopoietic stem cell transplantation is often curative.

• Indicated in patients < 55 years with a suitable donor and without serious comorbid conditions. Age for transplantation may increase with advances in transplantation.

• Less than one-third of patients in United States have a matched sibling donor.

• Success of transplantation is a function of age and whether related donor is used. Best results in patients < 20 years with a related donor.

Immunosuppressive Therapy

• Is the most successful therapy in patients unsuitable for allogeneic hematopoietic stem cell transplantation.

• Antithymocyte globulin (ATG) or antilymphocyte globulin (ALG)

  — ATG prepared in horses or rabbits from human thymocytes and ALG prepared in horses or rabbits from human thoracic duct lymphocytes.

  — Fifty percent response rate when used as single agent.

  — Dose: 15 to 40 mg/kg daily intravenously for 4 to 10 days.

  — Fever, chills common on first day of treatment.

  — Accelerated platelet destruction with thrombocytopenia frequent.

  — Serum sickness can occur with fever, rash, and arthralgias 7 to 10 days after beginning treatment.

  — Moderate dose of methylprednisolone is usually used to decrease allergic reactions.

• Cyclosporine

  — Treatment in patients if refractory to ATG.

  — Dose: 3 to 7 mg/kg daily orally for at least 4 to 6 months.

  — Dose adjusted to maintain appropriate blood levels (trough blood levels of 300 to 500 ng/mL).

  — Renal impairment is common side effect.

  — Twenty-five percent of patients respond overall.

• High-dose glucocorticoids

  — For example, 5 to 10 mg/kg methylprednisolone for 3 to 14 days.

  — Very severe side effects: glycosuria, gastric distress, insomnia, psychosis, infection, aseptic necrosis of the femoral head.

  — Little evidence for efficacy of glucocorticoids used alone.

  — Usually used in lower doses (2 mg/kg and then taper) as adjunct to ATG.

• High-dose cyclophosphamide (e.g., 45 mg/kg per day for 4 doses).

• Androgen therapy

  — Danazol, 5 mg/kg per day for 6 months, as primary therapy has not been efficacious in severe or moderate aplastic anemia.

  — Androgen therapy combined with ALG and cyclosporine is being assessed.

  — Androgens can induce severe masculinization and liver damage.

• G-CSF as primary therapy not efficacious.

  — Transient improvement in neutrophil counts has been observed with GM-CSF or — G-CSF treatment in some patients but not sustained.

  — G-CSF used in combined therapy with ATG and cyclosporine has not improved remission or survival rates in most studies.

• IL-3 or IL-1 is not effective as primary treatment.

• Combination therapy: ATG and cyclosporine yield an improved response rate over either alone.

• Results of immunosuppressive therapy

  — Sixty to 80 percent of patients get marked hematologic improvement.

  — Long-term problems after immunosuppressive therapy may occur, such as continued moderate anemia and thrombocytopenia, recurrent aplasia, PNH, acute myelogenous leukemia, or myelodysplastic syndrome.

Supportive Care

• Immediate HLA typing of patient and siblings as possible stem cell donors.

• Minimal or no transfusions in potential transplant recipients, if possible.

• If transfusions are needed, do not use family donors in a potential transplant recipient.

• Transfuse platelets based on assessment of risk of bleeding and not solely on platelet count.

• Leukocyte-depleted, ABO blood group-compatible single-donor platelets should be used, if possible, to minimize HLA sensitization, subsequent refractoriness, and other problems.

• ∊-Aminocaproic acid, 4 to 12 g/d, may decrease thrombocytopenic bleeding.

• Transfuse packed RBCs (irradiated, leukocyte-depleted) when hemoglobin level is less than 8 g/dL. Use a higher threshold if comorbid conditions require.

• Obtain CMV serology for prospective transplant recipients; transfuse only CMV-negative blood products until these results are known. If the patient is CMV-positive, can discontinue these precautions. Use of leukocyte depletion filters also decreases risk of CMV acquisition.

• Neutropenic precautions for hospitalized patients with absolute neutrophil counts of less than 500/μL.

• Prompt institution of broad-spectrum intravenous antibiotics for fever after appropriate cultures have been obtained.

• Median survival of untreated severe aplastic anemia is 3 to 6 months (20% survive longer than 1 year). Allogeneic hematopoietic transplantation can cure a very large proportion of patients depending on their age at transplantation and the immunologic similarity of the donor (see Figure 3–2). Combined immunotherapy with ATG and cyclosporine can result in 10-year survival rate of 70 to 80 percent.