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Aplastic Anemia

A. Idiopathic

B. Constitutional (congenital Fanconi's aplastic anemia)

C. Chemical & physical agents

1. Dose related: chloramphenicol, benzene, ionizing radiation, alkylating agents, antimetabolites, mitotic inhibitors, anthracyclines, inorganic arsenical
2. Idiosyncratic: chloramphenicol, phenylbutazone, sulfa drugs, gold compounds, organic arsenical, insecticides, hydantoin

D. Hepatitis

E. Immunologically mediated aplasia

F. Pregnancy

G. Paraxymal nocturnal hemoglobinuria

H. Misc: SLE, pancreatitis, miliary TB, viral infections, Simmond's disease.

Grand Round: Acquired Aplastic Anemia  (NEJM July 21, 1999;282:   - Neal S. Young, MD )

REF:  ACP  PIER 2002      http://pier.acponline.org/physicians/diseases/d479/diagnosis/d479-g3.5.html

Differential Diagnosis of Severe Aplastic Anemia

Disease	Characteristics	Notes
Pancytopenia and hypocellular marrow due to hypoplastic MDS	Hypocellular marrow mimics severe AA, but subtle dysplastic morphologic features and abnormal cytogenetics may help distinguish between hypoplastic MDS and severe AA	The most useful test is cytogenetics of bone marrow. However, normal cytogenetics may be seen in both MDS and severe AA. If abnormal, a diagnosis of MDS is favored
Pancytopenia and hypocellular marrow due to paroxysmal nocturnal hemoglobinuria	History of hemolytic anemia with dark urine. Positive PNH test distinguishes from severe AA	Flow cytometry is most useful test for detecting the presence or absence of PNH. Positive urine hemosiderin in Ham or sucrose lysis test support diagnosis of PNH
Pancytopenia and hypocellular marrow due to FA or dyskeratosis congenita	Presentation in childhood. Characteristic physical abnormalities, particularly bony abnormalities (Fanconi) and skin disease (dyskeratosis congenita). Abnormal cytogenetics tests showing chromosome fragility characteristic of FA	Patients with FA may evolve into severe AA. Therefore, all patients under age 40 with severe AA should have chromosome fragility testing done to exclude FA as cause of severe AA
Pancytopenia due to severe megaloblastic anemia	Deficiencies of vitamin B12 or folic acid may result in severe pancytopenia. Bone marrow aspiration and biopsy result show cellular marrow	Normal B12, folate, and cellular bone marrow aspirate and biopsy result differentiates from severe AA
Pancytopenia due to myelophthisic (marrow invasive) condition	The bone marrow biopsy shows cellular marrow with malignant cells, including acute myelogenous and lymphoblastic leukemia, myelodysplastic syndrome, Hodgkin disease, non-Hodgkin lymphoma, and multiple myeloma. Occasionally, metastatic solid tumors for breast, lung, or other cancers may cause pancytopenia excluding diagnosis of severe AA. Physical exam may show hepatosplenomegaly or lymphadenopathy, which is rare in severe AA	Invasion of bone marrow by any solid tumor or by any hematologic malignancy may result in pancytopenia. Review of blood smear and bone marrow aspirate and biopsy result excludes severe AA. Blood smear may show teardrops, nucleated erythrocytes, and immature cells consistent with marrow-invasive tumor or leukemia, lymphoma, or chronic inflammatory disease
Pancytopenia due to chronic bacterial or viral infections	Positive serologic test results for viruses and evidence of hepatitis with elevated liver function test (AST, ALT) results suggesting chronic viral infection from hepatitis B, C, infectious mononucleus, cytomegalovirus, or parvovirus. Bone marrow aspirate and biopsy result show cellular marrow	Chronic viral diseases, granulomatous diseases (tuberculosis), or, rarely, bacterial infections may cause pancytopenia with cellular marrow or may evolve into true aplastic anemia
Pancytopenia due to hypersplenism	Blood counts are not usually severely depressed. Spleen is enlarged. Frequent hepatomegaly. Cellular marrow on biopsy	Liver disease commonly associated with hypersplenism
Autoimmune pancytopenia	Patients with severe pancytopenia with maturation arrest due to antiprogenitor cell or stem cell antibodies; bone marrow aspirate is usually cellular	Rare condition caused by anti-stem cell antibodies distinguishable by presence of cellular marrow on biopsy and evidence of maturation arrest in all three lineages (12)

AA = aplastic anemia; ALT = alanine aminotransferase; AST = aspartate aminotransferase; FA = Fanconi anemia; MDS = myelodysplastic syndrome; PNH = paroxysmal nocturnal hemoglobinuria.

Non-drug Therapy    

Consider one of several non-drug therapies for the treatment of severe AA, depending on the individual clinical situation.

• Consider transfusions of packed red blood cells and platelets in certain clinical situations.
• Recognize that allogeneic bone marrow transplantation of a matched related donor is the treatment of choice for carefully selected patients under age 50.
• Use cyclophosphamide with ATG as the preparative regimen of choice for patients undergoing allogeneic bone marrow transplants with matched related donors for severe AA.
• Use immunosuppressive therapies to prevent and treat acute and chronic GVHD in patients undergoing allogeneic stem cell transplantation for severe AA.
• Consider allogeneic bone marrow transplantation with matched unrelated donors or other alternative donors for patients under age 40 who do not have a matched related donor.

Drug Therapy    

Use immunosuppressive therapy as the treatment of choice for patients with severe AA who are not candidates for allogeneic bone marrow transplantation.

• Consider therapy with ATG, with or without cyclosporine, as the treatment of choice for patients with severe AA who are not candidates for allogeneic bone marrow transplantation.
• Consider other options for patients in whom ATG, cyclosporine, or both have failed.

Drug Treatment for Severe Aplastic Anemia

ATG or ALG

• Action: Immunosuppressive, lyses of T lymphocytes
• Dosage: ATG 40 mg/kg iv x 4 days.   Alternative schedule 15 mg/kg for 10 days.
  For bone marrow transplantation prep: administer as 30 mg/kg·qod x 3 doses on day 6, day 4, and day 2 before bone marrow transplantation
  ALG: 40 mg/kg iv x 4 days
• Benefit: Induces freedom from transfusion in 60%-80% of patients. Responses occurring 3 weeks to 6 months after ATG
• Side Effects: Fevers, chills, initial anaphylactic reaction, serum sickness, including serositis, skin rashes. Worsens thrombocytopenia, induces positive Coombs test result Patients should be hospitalized and infusion should be given with premedication (see table Clinical Use of Antithymocyte Globulin in Severe Aplastic Anemia) including corticosteroid coverage. Use of a large-bore iv catheter with an in-line filter recommended. Multiple preps raised in horses, goats, rabbits are available. Taper off steroid over 4 weeks.
• Note: Up to 20% relapse rates. Patients may be retreated with same or second ATG raised in different animals and should be closely monitored for anaphylactic reactions. Long-term follow-up studies show that 20%-50% of ATG responders may develop secondary myelodysplasias, PNH, or both

Cyclosporine

• Immunosuppression through modulation of T-lymphocyte function
• 3-12 mg/kg initial loading dose.  Subsequent doses are monitored by frequent blood levels to keep level at 150-300 ng/mL
• Active in inducing responses as a single agent or with ATG in up to 40%-50% of patients
• Renal toxicity, liver toxicity, hypomagnesemia, aggravates hypertension, rarely may induce seizures
• Monitor renal and liver function tests, magnesium and cyclosporine levels weekly.  A useful option as a single agent in patients who cannot tolerate ATG. Crossover studies show that it is equally as effective as ATG. Usually administered with ATG

High-dose cyclophosphamide

• Immunosuppressive and T-cell lytic agent
• 50 mg/kg x 4 for a total of 200 mg/kg.   Similar dose for bone marrow transplantation preparative regimen
• May induce remissions in untreated patients and patients in whom ATG or cyclosporine fail, and may prevent long-term bone marrow dyscrasias
• Cardiomyopathy, hemorrhagic cystitis, severe cytopenias
• At increased risk for fatal infections.
  This drug should not be routinely administered outside a transplant center or a center specializing in treatment of severe AA; should be reserved for patients in whom less toxic upfront immunosuppressive therapy fails. Data suggests that cyclophosphamide may prevent long-term myelodysplasias

Androgens oxymetholone (Anadrol-50)

• Stimulates stem-cell growth.  Increases sensitivity to erythropoietin
• 1-5 mg/kg·qd orally
• Randomized studies have shown that androgens are no more beneficial than supportive care alone and do not enhance the response to immunosuppressive agents (62). However, occasionally a patient may respond with increased blood cell production
• Hepatotoxic, including jaundice. May induce liver cysts and liver tumors. Virilizing in females, contraindicated in pregnant females and in patients with prostate or breast cancer. Increased fluid retention
• Liver function should be monitored closely.  Androgen therapy is best reserved for patients who are not candidates for immunosuppressive or bone marrow transplant therapy or in whom these therapies fail. It is better tolerated in male patients

High dose methylprednisolone

• Lyses, lymphocytes, immunosuppressive
• 20 mg/kg·qd days 1-3, 10 mg/kg·qd days 4-7, 5 mg/kg·qd days 8-11, 2 mg/kg·qd days 12-20, and 1 mg/kg·qd until day 30
• With maintenance of 0.1-0.2 mg/kg·qd. Up to 38% response rates reported
• Steroid psychosis, hyperglycemia, hypertension, aseptic necrosis, volume overload, potassium wasting, and increased risk of fungal infections
• Moderate to low doses of corticosteroids are not beneficial and potentially detrimental. Use of high-dose methylprednisolone may be useful in patients in whom ATG, cyclosporine, or both fail or who are intolerant of ATG with increased toxicity.  High-dose methylprednisolone should be reserved for patients in whom ATG and cyclosporine fails and who have no other options

Hematopoietic growth factors (G-CSF, GM-CSF)

• Stimulates committed progenitor cells, increases leukocyte counts
• Neupogen G-CSF (5 µg/kg·qd) or GM-CSF leukine (250 mcg/m2·qd)
• A useful adjunct with immunosuppressive therapy, particularly in patients with threatened infections.  May accelerate or temporarily increase leukocyte counts. Very little evidence that these growth factors induce permanent remissions
• Fever, chills, bone pain, occasional anaphylactic first-dose reactions, fluid retention
• Long-term use of growth factors may potentially induce increased risk for myelodysplastic syndrome and rarely induces trilineage recovery. Useful in raising leukocyte counts short term in patients with threatened infections.  Most hematopoietic growth factors have not induced long-term remissions in severe AA. Occasional response to stem-cell factor (C-kit ligand, an investigational drug), or IL-3.  No evidence that platelet-stimulating growth factors such as IL-11 and IL-6 are useful in severe AA

Mycophenolate mofetil (CellCept)

• T cell inhibition. Potent immunosuppression
• 1 g po bid
• Uncertain
• Diarrhea, melena, increases infection risk
• Investigational

*AA = aplastic anemia; ALG = antilymphocyte globulin; ATG = antithymocyte globulin; bid = twice daily;
G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; iv = intravenous; po = oral;
PNH = paroxysmal nocturnal hemoglobinuria; qod = every other day; qd = once daily.

10262002