Chapter 3: Aplastic Anemia: Acquired and Inherited

• Aplastic anemia is marked by pancytopenia with markedly hypocellular marrow and normal marrow cell cytogenetics.

• Incidence worldwide is two to five cases/million population per year and five to twelve 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 is between ages 15 and 25 and 65 and 69 years.

• The definitions for spectrum 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 (eg, certain chemotherapy or drugs) (see Table 3–2)

• Inherited intrinsic stem cell defect (eg, Fanconi anemia)

Acquired

• Acquired T lymphocyte–mediated autoimmune suppression of hematopoietic stem cells and/or progenitor cells in most cases (~70%) (see Table 3–3)

• Paroxysmal nocturnal hemoglobinuria (PNH) (may be manifest by cytopenias and hypoplastic marrow)

• Chemicals (eg, high-dose benzene exposure); rare today in countries with workplace and product regulations limiting exposure

• Drugs (eg, chloramphenicol; see Table 3–2 for most frequent offenders; see also Williams Hematology, 9th ed, Chap. 35, Table 35–3 for a more complete list)

• Viruses (eg, Epstein-Barr; non-A, -B, -C, -D, -E, or -G hepatitis; HIV)

• Immune and connective tissue diseases (eg, eosinophilic fasciitis, Hashimoto thyroiditis, Graves disease, systemic lupus erythematosus)

• Pregnancy

• Iatrogenic or accidental (eg, intensive radiation to marrow-bearing bones, intensive marrow-suppressive chemotherapy)

Inherited

• Fanconi anemia (see Table 3–3)

  — Inheritance is autosomal recessive.

  — Any of 16 gene mutations, FANCA through FANCQ, account for about 95% 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 (eg, dysplastic radii and thumbs); heart, kidney, and eye anomalies; microcephaly; and hypogonadism in different combinations are often noted.

  — Chromosome fragility may be present, 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.

  — There is risk of acute myelogenous leukemia and other cancers.

• Dyskeratosis congenita

  — Inheritance patterns: autosomal dominant, autosomal recessive, and X-linked (see Williams Hematology, 9th ed, Chap. 35, Table 35–10)

  — Gene mutations identified in majority of cases

  — Mutations involving genes encoding proteins in the telomerase complex

  — Resulting abnormalities in telomere length

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

  — Pulmonary (eg, fibrosis), gastrointestinal (eg, esophageal webs), urogenital (eg, hypospadias), neurologic (eg, learning impairment), skeletal (eg, hypoplasia of mandible) findings

  — Aplastic anemia in early adulthood: principal cause of death

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

• Shwachman-Diamond syndrome

  — The cause is mutation in the SBDS (Shwachman-Bodian-Diamond syndrome) gene on chromosome 7.

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

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

  — Anemia and thrombocytopenia are less common.

  — Elevated hemoglobin F occurs in most patients.

  — Pancytopenia occurs in about 20% 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% of patients regain exocrine pancreatic function during later childhood.

  — Skeletal anomalies (eg, short stature, osteochondrodysplasia [cartilage and bone anomalies], osteoporosis) are present in about 75% of patients.

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

  — Enzyme replacement therapy is given for exocrine pancreatic insufficiency.

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

  — Allogeneic hematopoietic stem cell transplantation can be curative.

• Other rare causes of aplastic anemia are shown in Table 3–4

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

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

• Pancytopenia is present.

• Red cells may be macrocytic.

• Marrow is markedly hypocellular (Figure 3–1).

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

• Blast cells in marrow suggest hypoplastic acute myelogenous leukemia.

• Presence of CD55,CD59 on blood cells by flow cytometry rules out PNH.

  Table 3–5 lists important diagnostic procedures.

Table 3–6 lists important initial steps in management.

• Allogeneic hematopoietic stem cell transplantation is often curative.

  — It is 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 the United States have a matched sibling donor.

  — Success of transplantation is a function of age and whether related donor is used (Figure 3–2). Best results are in patients younger than 20 years of age with a related donor.

Immunosuppressive Therapy

• Is the most successful therapy in patients unsuitable for allogeneic hematopoietic stem cell transplantation (see Table 3–7)

• 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 and chills common on first day of treatment

  — Accelerated platelet destruction with thrombocytopenia frequent during infusion

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

  — Moderate dose of methylprednisolone 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 300–500 ng/mL)

  — Renal impairment: common side effect

  — Response in 25% of patients overall

• Combination therapy: ATG and cyclosporine, which yield an significantly improved response rate over either agent alone

• 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 (eg, 45 mg/kg per day for 4 doses)

• Androgen therapy

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

  — Androgen therapy combined with ALG and cyclosporine being assessed

  — Can induce severe masculinization and liver damage

• G-CSF as primary therapy not efficacious

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

  — G-CSF used in combined therapy with ATG and cyclosporine: no improved remission or survival rates in most studies

• Interleukin (IL)-3 or IL-1 as primary treatment not effective

• Results of combined immunosuppressive (ATG and cyclosporine therapy)

  — Marked hematologic improvement in 60% to 80% of patients

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

• Eltrombopag. This thrombopoietin receptor agonist has been used in patients who were not successfully treated with combined immunotherapy. A significant portion (~45%) had moderate to marked improvement in one or more blood cell counts or loss of red cell and platelet transfusion requirements. A few returned to normal blood cell counts. In some so treated, these effects have persisted for more than a year of observation. The initial studies started with a dose of 50 mg, increasing to 150 mg/day over a 12-week period. Longer treatment periods and higher doses may induce remissions in some patients. These variations in treatment are currently under study.

Supportive Care

• Immediate human leukocyte antigen (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, no use of family donors in a potential transplant recipient

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

• Use of leukocyte-depleted, ABO blood group-compatible single-donor platelets, if possible, to minimize HLA sensitization, subsequent refractoriness, and other problems

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

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

• Cytomegalovirus (CMV) serology for prospective transplant recipients. Transfuse only CMV-negative blood products until these results are known. If the patient is CMV-positive, these precautions can be discontinued. Use of leukocyte depletion filters also decreases risk of CMV acquisition

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

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

Clinical Course

• 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 3–3). Combined immunotherapy with ATG and cyclosporine can result in 10-year survival rate of 70% to 80%.