A. Characteristics

1. Overall, this is a rare disease (1-2 per 1 million persons per year)
2. Most common form is acquired; genetic syndromes rare (see below)
3. Acquired form most commonly affects young persons age 15-25
4. May be transient, particularly when associated with drug or virus or toxin
5. Acquired form should be considered autoimmune syndrome directed at CD34+ progenitors
6. Associated with other bone marrow failure syndromes (see below)
   1. Myelodysplasia (clonal)
   2. Paroxysmal Nocturnal Hemoglobinuria (PNH, clonal)
   3. Agranulocytosis
   4. Pure red cell aplasia
   5. Amegakaryocytic thrombocytopenia
   6. Large granular lymphocytic leukemia (clonal)

B. Etiology

1. Nearly all forms of acquired AA have autoimmune component
   1. In AA, T cells of Th1 class likely kill bone marrow stem cells (CD34+ cells)
   2. These Th1 cells secrete interferon gamma, interleukin 2, and other cytokines
   3. Antigen specificity of these cells is not known
2. Severe disease occurs when stem cells have been reduced to ~1% of normal levels [2]
3. Telomerase Mutations [1,3]
   1. Mutations in various components of human telomerase found
   2. Mutations in TERC, the gene for RNA component of telomerase, found in congenital AA
   3. Mutations in TERT, gene for telomerase reverse transciptase, found in ~5% acquired AA
4. Drug Induced
   1. Cancer Chemotherapy
   2. Chloramphenicol
   3. Carbamazapine (Tegretol®)
   4. Ticlopidine (Ticlid®) - about 2%
   5. Clozepine (Clozaril®) - about <0.2%
   6. Phenothiazines
   7. Nonsteroidal anti-inflammatory drugs
   8. Sulfonamides
   9. Allopurinol
   10. Gold
   11. Penicillamine
5. Other Autoimmune Associations
   1. Graft-versus-host disease (GVHD)
   2. Eosinophilic fasciitis
   3. Hyperimmunoglobulinemia
   4. Thymoma (thymic carcinoma)
6. Viruses
   1. Epstein-Barr Virus
   2. Non-A, B, C, G Hepatitis Virus (post-severe viral hepatitis)
   3. HIV
   4. Human parvovirus B19 infection - possible
7. PNH [4]
   1. Characterized by loss of glycosylphosphatidylinositol (GPI)-anchored proteins
   2. Loss of CD59 decay accelerating factor from red cell surface leads to hemolysis
   3. Nearly 25% of patients with AA have lost these proteins as well
   4. PNH and AA are related, with ~25% overlap of syndromes
   5. In AA, likely that PNH clones arise due to somatic mutation of GPI enzyme
   6. Many patients with long term recovery from AA develop PNH
   7. Unclear why PNH clones have selective growth advantage over normal stem cells
   8. Autologous stem cell transplant reduces risk of PNH development in AA patients
8. Myelodysplasia (MDS)
   1. Related series of 5 syndromes with refractory anemia
   2. Tend to behave as either preleukemia or bone marrow failure syndromes
   3. Increased risk of acute myelocytic leukemia (AML) and AA
   4. About 25% of patients with MDS have lost GPI-anchored proteins [4]
   5. Autologous stem cell transplant reduces risk of MDS development in AA patients
9. Genetic Syndromes with AA
   1. Fanconi Anemia - autosomal recessive; ~10 distinct genes cause phenotype
   2. Dyskeratosis congenita - three distinct types
   3. With striking nail abnormalities - autosomal recessive, abnormal skin pigmentation
      1. X-linked recessive, DKC1 mutations
      2. hTERC mutations, autosomal dominant
   4. Ataxia-pancytopenia syndrome
   5. Amegakaryocytic thrombocytopenia - c-MPL mutations, autosomal recessive
   6. Schwachan-Diamond Syndrome - SRDS mutations, autosomal recessive, exocrine pancreatic deficiency, metaphyseal dysostosis, increased rate of MDS/leukemia

C. Presentation and Diagnosis

1. Generally present with symptoms of thrombocytopenia or anemia
2. Occasionally present with severe infection due to neutropenia
3. Severe AA
   1. Absolute Neutrophil Count (ANC) <500/µL
   2. Corrected Reticulocyte Count <1%
   3. Platelet Count <20,000/µL
   4. Diagnosis of "severe" AA requires at least 2 of the above criteria
4. Diagnosis
   1. Bone marrow aspiration and examination
   2. Marrow is hypocellular typically with fat replacement (in severe disease)
   3. Bone marrow stroma may be normal
   4. Numbers of all cell lineages are reduced

D. Treatment [1,5]

1. Transfusions avoided when possible
   1. Transfusions sensitize recipient to donor antigens ("allosensitization")
   2. Receipt of transfusions is a poor prognostic factor
2. Acute Immunosuppressive Therapy [6]
   1. Immunosuppression with ALG/ATG and CsA or stem cell transplantation (SCT)
   2. ATG + CsA associated with 55% 7 year survival [7]
   3. Anti-lymphocyte globulin (ALG) specific for (T) lymphocytes
   4. Anti-thymocyte globulin (ATG) has nonspecific activities
   5. ATG 40mg/kg daily for 4 days is superior to cyclophosphamide (CTX) [8]
   6. Transplantation superior to ATG/CsA only when HLA-identical sibling donor is available
   7. High dose glucocorticoids
   8. Cyclosporin A (CsA) - acute and chronic along with ALG or ATG
   9. Responses (60-80%) generally seen within 75 days
   10. Of the non-responders, ~50% will respond to additional courses of ATG
   11. Mycophenolate mofetil may also be useful and is very well tolerated
3. Cyclosphosphamide (CTX, Cytoxan®) [9]
   1. Immunoablative dose CTX may be used instead of ATG
   2. Randomized comparison trial against ATG showed that ATG is better tolerated and may be more effective than immunoablative cyclosphosphamide [8]
   3. Dose is 50mg/kg/day x 4 days (premedication with ondansetron)
   4. Does not require additional immunosuppression
   5. Stem cell reinfusion is not required (avoids need for SCT)
   6. Growth factor, prophylactic antibiotics, and blood product support is needed
   7. CTX treated patients have excellent 4 year [9] and longer term (>10 year) responses
   8. Overall, CTX had 84% 2 year survival [9]
4. Chronic Immunosuppressive Therapy
   1. Cyclosporin A
   2. Methotrexate - not generally used acutely
   3. Intermittent glucocorticoids
5. Stem Cell Transplantation (SCT)
   1. Allogeneic transplantation is required
   2. ~30% of persons are candidates for stem cell (bone marrow) transplant (BMT)
   3. With HLA matching, appears to provide better outcome than immunosuppression [6]
   4. Matched unrelated donor BMT is superior to mismatched related donor BMT for AA [10]
   5. Preconditioning is generally required unless donor is HLA-identical sibling
   6. Overall, 10 year survival in AA with BMT is >80% (with matched donor)
   7. Chronic graft versus host disease (GVHD) is a major problem
   8. Methotrexate and cyclosporine reduce risk of chronic GVHD
   9. Acute GVHD is fairly well treated with glucocorticoids, CsA, ATG/ALG
6. Growth Factors
   1. Occassionally, growth factors will improve blood counts
   2. Often useful following immunosuppressive or BMT therapy
   3. G-CSF or GM-CSF - stimulates neutrophil (and monocyte) lineages
   4. G-CSF administration to AA patients does not increase malignancy risk [11]
   5. Erythropoietin (EPO) used occasionally
   6. Thrombopoietin (TPO) and IL-11 are experimental
7. Pregnancy Outcomes [12]
   1. Successful pregnancy with normal outcome possible in AA patients treated with immunosuppression
   2. Complications of pregnancy more likely in patients with low platelet counts
   3. Pregnancy complications also increased in patients with PNH associated AA

E. Prognosis [6]

1. Good Prognostic Factors [6]
   1. Lower age
   2. Receipt of SCT for patients <40 years of age
   3. Absence of pre-therapy transfusions
   4. Pre-therapy ANC>200/µL
   5. Rescue with growth factors
   6. Earlier initial and longer duration of response to CsA+ATG [7]
2. Overall Prognosis [13]
   1. Patients <50 years: 60-80% remission rates, 72% overall 5 year survival
   2. Patients 50-59 years: 57% 5 year survival
   3. Patients 60 or more years: 50% 5 year survival
   4. Neutrophil count <200/µL is a poor prognostic indicator
   5. No difference between older or younger patients in response to immunosuppression
   6. Relapse typically 15-20%
3. Long Term Complications [1,4]
   1. Many patients have genetic abnormalities at diagnosis
   2. Frank chromosomal abnormalities are uncommon
   3. Clonal dysplastic disorders occurred in 20% over 10 year followup
   4. Risk of conversion to PNH or myelodysplasia is ~20% at 7-10 years
4. Overall good survival with current treatment regimens
5. For CsA+ATG, 7 year survival 55% [7]

References

1. Brodsky RA, Jones RJ. 2005. Lancet. 365:1647
2. Young NS. 2002. Ann Intern Med. 136(7):534
3. Yamaguchi H, Calado RT, Ly H, et al. 2005. NEJM. 352(14):1413
4. Dunn DE, Tanawattanacharoen P, Boccuni P, et al. 1999. Ann Intern Med. 131(6):401
5. Abkowitz JL. 2001. Ann Intern Med. 135(7):524
6. Doney K, Leisenring W, Storb R, et al. 1997. Ann Intern Med. 126(2):107
7. Rosenfeld S, Follmann D, Nunez O, Young NS. 2003. JAMA. 289(9):1130
8. Tisdale JF, Dunn DE, Geller N, et al. 2000. Lancet. 356(9241):1554
9. Brodsky RA, Sensenbrenner LL, Smith BD, et al. 2001. Ann Intern Med. 135(7):477
10. Grunebaum E, Mazzolari E, Porta F, et al. 2006. JAMA. 295(5):509
11. Locasciulli A, Arcese W, Locatelli F, et al. 2001. Lancet. 357(9249):43
12. Tichelli A, Socie G, Marsh J, et al. 2002. Ann Intern Med. 137(3):164
13. Tichelli A, Socie G, Henry-Amar M, et al. 1999. Ann Intern Med. 130(3):193