Basics
Description
Aplastic anemia represents a heterogenous group of disorders characterized by peripheral pancytopenia and bone marrow hypocellularity. �
Epidemiology
Incidence
- Estimated incidence of 2:1,000,000 per year in Western Hemisphere and Europe with increased incidence of 5-7:1,000,000 per year in Far East and those of Asian descent
- In the pediatric population, most commonly presents between ages 15 and 25 years
Risk Factors
Genetics
Patients with a number of inherited bone marrow failure syndromes are at increased risk of developing aplastic anemia, but there is no known genetic mutation associated with acquired aplastic anemia. �
General Prevention
There are no preventive measures for acquired aplastic anemia. �
Pathophysiology
- Most instances of acquired aplastic anemia are thought to occur through a T-cell dependent autoimmune process leading to apoptosis of hematopoietic stem or progenitor cells.
- Additionally, exposure to certain toxins, chemicals, medications (classically chloramphenicol), and high doses of radiation can also lead to marrow aplasia.
Etiology
- Acquired
- Idiopathic (70% of cases)
- Toxin: exposure to arsenic, benzene, radiation, organophosphates, organochlorines
- Drugs: chloramphenicol, numerous chemotherapeutic agents
- Radiation
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Seronegative hepatitis (non-A, non-B, and non-C)
- HIV-1, Epstein-Barr virus (EBV), human herpes virus-6, cytomegalovirus (CMV)
- Malnutrition
- Pregnancy
Commonly Associated Conditions
- Congenital or inherited bone marrow failure syndromes
- Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, dyskeratosis congenita, congenital amegakaryocytic thrombocytopenia, Pearson syndrome
- Acquired
- Differentiating aplastic anemia from refractory cytopenia of childhood (RCC), defined by thrombocytopenia/neutropenia with impaired maturation of erythroid lineage and increased proerythroblasts in bone marrow, is crucial.
- Differentiating RCC from aplastic anemia can be difficult but important as RCC should be considered a form of myelodysplastic syndrome (MDS) and evaluated for hematopoietic stem cell transplantation (HSCT).
Diagnosis
History
- Detailed history including birth history, growth trajectory, antecedent illnesses, infections, environmental exposures
- Comprehensive review of systems with emphasis on neurologic (including developmental delay and learning disabilities), dermatologic, cardiac, pulmonary, endocrine (hypogonadism, growth delay), and hematologic systems
- Family history of cancer predisposition, excessive toxicity to chemotherapy, unexplained fetal loss, anemia/cytopenias, or congenital anomalies
Physical Exam
- Thorough physical exam combined with plotting of growth curves
- Head: evaluate for eye, epicanthal folds, jaw, palate abnormalities, oral mucosal lesions/bleeding, thrush
- Cardiopulmonary: auscultation for cardiac anomalies, dyspnea, diminished aeration, asymmetry
- GI: hepatosplenomegaly, palpation for masses
- GU: renal/urinary/ureter abnormalities, gonadal abnormalities, or undescended testes
- Skeletal: dysmorphisms, forearms, thumbs, vertebral anomalies, osteopenia
- Skin: pigmentation changes, eczematous rash, nail abnormalities, bruising, petechiae, pallor
- Lymphadenopathy
Diagnostic Tests & Interpretation
Lab
To confirm the diagnosis: �
- Diagnosis requires exclusion of other disease processes associated with pancytopenia (see "Etiology"� and "Differential Diagnosis"� sections) as well as the following:
- Empty or hypoplastic bone marrow
- 2 out of 3 of the following: absolute neutrophil count (ANC) <1,500 � 106/L, platelets <50,000 � 106/L, hemoglobin (Hgb) <10 g/dL
- Severe aplastic anemia (sAA)
- Bone marrow cellularity <25%
- 2 out of 3 of the following: ANC <500 � 106/L, platelets <20,000 � 106/L, absolute reticulocyte count <20 � 109/L
- Very severe aplastic anemia: the criteria are the same as for sAA, except for ANC <200 � 106/L.
To exclude other causes: �
- Complete blood count, + reticulocyte count
- Peripheral blood smear
- Hgb F %
- Liver function tests, lactate dehydrogenase (LDH), uric acid
- Direct and indirect Coombs assay
- Baseline serum iron, ferritin, total iron-binding capacity (TIBC)
- Flow cytometry for glycosylphosphatidylinositol (GPI)-anchored proteins CD55/CD59
- Vitamin B12, folate, copper levels
- Viral studies: hepatitis A, B, and C; EBV, CMV, HIV, human herpesvirus 6 (HHV-6), varicella-zoster virus (VZV), parvovirus
- Antinuclear antibody (ANA), anti-double stranded DNA (dsDNA)
- Acid-fast bacillus (AFB) staining of bone marrow aspirate
- Human leukocyte antigen (HLA) typing of patient and family members
- Ruling out inherited bone marrow failure syndromes:
- Chromosomal breakage (mitomycin C or diepoxybutane): Fanconi anemia
- Telomere length: dyskeratosis congenita
- Exocrine pancreatic testing: serum trypsinogen and pancreatic isoamylase: Shwachman-Diamond syndrome
- Erythrocyte adenosine deaminase: Diamond-Blackfan anemia
- c-MPL mutation: congenital amegakaryocytic thrombocytopenia
Imaging
- Chest x-ray
- Abdominal ultrasound (US)
- Echocardiogram
Diagnostic Procedures/Other
- Bone marrow aspirate and biopsy
- Cytogenetics of bone marrow with fluorescence in situ hybridization (FISH) for monosomy 5, 7, 8
Diagnostic Procedures/Other
Bone marrow fragments are hypocellular with prominent fat spaces and reduced erythropoiesis, megakaryocytes, and granulocytes. Lymphocytes, macrophages, plasma cells, or mast cells may be prominent. Appearance of dysplasia in megakaryocyte or granulocytic lineage, blasts, hypercellularity, or increased reticulin staining are not consistent with aplastic anemia. �
Differential Diagnosis
- Myelosuppression secondary to ongoing infection (viral, tuberculosis)
- MDS (including RCC)
- Hematologic malignancy
- Nutritional deficiency: vitamin, mineral, or starvation/anorexia
- Autoimmune disease: systemic lupus erythematosus (SLE), thyroid disease, rheumatoid arthritis
- PNH
- Metastatic disease
- Hemophagocytic histiocytosis
Treatment
Treatment for aplastic anemia that does not meet the severe or very severe criteria is individualized and controversial as some patients do spontaneously improve. However, patients with severe or very severe aplastic anemia should be promptly treated because of their high risk of infection. �
Medication
First Line
In all patients with sAA who are younger than the age of 40 years and without significant comorbidities, the treatment of choice is HSCT with a matched sibling donor (MSD). Superior and durable outcomes for MSD transplants conditioned with cyclophosphamide/antithymocyte globulin (ATG) as 1st-line therapy stresses importance of timely workup and HLA typing. �
Second Line
For patients without an MSD or with significant comorbidities: �
- Immunosuppressive therapy (IST) with combination horse ATG and cyclosporine (ATG/CsA) followed by prolonged taper of cyclosporine.
- If patients do not show clinical improvement within 3-6 months, consider an alternative donor HSCT such as with a matched unrelated donor (MUD) HSCT, if available, or repeat trial of IST.
Supportive Therapy:
Patients should be transfused when symptomatic with leukocyte-reduced, irradiated PRBCs and platelets. Transfusions are weighed against the risk of alloimmunization and graft rejection with allogeneic bone marrow transplant (BMT), but most institutions will transfuse to keep Hgb >7-8 g/dL and platelets above 10,000/mm3. Transfusions should be with CMV-negative blood (if patient is CMV seronegative) if patient is likely to undergo transplant. �
Issues for Referral
Pediatric hematology/oncology/BMT: As a rare disorder, patients are typically managed by centers with hematologic experience and transplant capabilities. �
Additional Therapies
- Use of Pneumocystis carinii (jiroveci) pneumonia (PCP) prophylaxis prior to BMT is institution-dependent but some recommend use of pentamidine (with atovaquone or dapsone as second line), avoiding sulfamethoxazole/trimethoprim due to its myelosuppressive properties.
- Antifungal prophylaxis is also used by many institutions.
- Granulocyte colony-stimulating factor (G-CSF) support may be used in setting of acute infection but has not been shown to improve overall survival or remission rates.
- Supportive care, androgens, cyclosporine, or growth factors alone are not definitive therapies. Corticosteroids alone are also not proven to be effective and lead to increased susceptibility to fungal infections.
Inpatient Considerations
Initial Stabilization
- Patients should be transfused slowly initially with PRBC 5 cc/kg over 4 hours to avoid pulmonary overcirculation.
- Platelet transfusions for symptomatic bleeding
- Cultures of blood and urine should be obtained with all fevers, and empiric broad-spectrum antibiotics coverage should be started while awaiting culture results.
Admission Criteria
Symptomatic anemia, fever, severe thrombocytopenia, or any evidence of clinical bleeding must be admitted for supportive care and monitoring. �
IV Fluids
Unless the patient has had a recent history of inadequate intake or losses, IV fluids are not usually necessary at the outset. Bear in mind that the patient will likely be receiving additional volume due to transfusions. �
Nursing
Patients should be roomed in isolation if possible. �
Ongoing Care
Follow-up Recommendations
Regardless of whether IST or BMT is chosen for treatment modality, follow-up should be lifelong given risk of recurrence of aplastic anemia or transformation to MDS or malignancy. Long-term retrospective studies have demonstrated rates of relapse of up to 38%, with incidence of clonal transformation in 10-25% of patients who undergo IST. �
Patient Monitoring
Those who undergo HSCT are expected to have hematopoietic reconstitution as they engraft. Hematologic recovery in those who undergo IST may take several months: 90% of patients who respond will do so by 3 months, but some patients may take up to 6 months from ATG to recover marrow function. �
Parameters of Recovery
- Improve overall hematopoiesis to reduce transfusion dependency and no longer fulfill criteria for sAA by 6 months. Neutrophil recovery may be the first cytopenia to improve.
- Relapse or clonal evolution commonly occurs at 2-4 years from time of IST. Some centers recommend monitoring bone marrow aspirates with biopsy at 6-month intervals for 1st year after IST, then annually.
Patient Education
- NIH site: http://www.nhlbi.nih.gov/health/health-topics/topics/aplastic/
- Aplastic Anemia & MDS International Foundation: http://www.aamds.org/about/aplastic-anemia
Diet
Recommend low bacterial content diet. �
Prognosis
- Aplastic anemia has a high rate of mortality if left untreated. Death is predominantly from infection and hemorrhage. If patients are treated with antibiotics and transfusions alone, mortality is 80% in 2 years.
- First line
- MSD: HSCT with MSD from bone marrow source has a predicted 6-year outcome of 80-91% in children younger than 20 years of age.
- Second line
- IST: Response rate of IST in children is 75%.
- Relapse/salvage: aplastic anemia refractory to IST at 6 months should be considered for salvage therapy: MUD-HSCT for younger patients; repeat IST for older patients and those with significant comorbidities.
- MUD: Recent trials have shown improved survival of >60% and as high as 94% in children who have undergone MUD-HSCT for sAA.
- Repeat IST: Patients refractory to the initial course of IST had a response rate of 30-40% at 6 months to ATG/CsA.
Complications
- Infection
- Hemorrhage
- Iron overload requiring phlebotomy or chelation therapy
- Allosensitization to transfusion products
Additional Reading
- Bacigalupo �A, Passweg �J. Diagnosis and treatment of acquired aplastic anemia. Hematol Oncol Clin North Am. 2009;23(2):159-170. �[View Abstract]
- Marsh �JC, Ball �SE, Cavenagh �J, et al. Guidelines for the diagnosis and management of aplastic anemia. Br J Haematol. 2009;147(1):43-70. �[View Abstract]
- Niemeyer �CM, Baumann �I. Classification of childhood aplastic anemia and myelodysplastic syndrome. Hematology Am Soc Hematol Educ Program. 2011;2011:84-89. �[View Abstract]
- Scheinberg �P, Nunez �O, Weinstein �B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365(5):430-438.
- Scheinberg �P, Young �NS. How I treat acquired aplastic anemia. Blood. 2012;120(6):1185-1196. �[View Abstract]
- Shimamura �A. Clinical approach to marrow failure. Hematology Am Soc Hematol Educ Program. 2009;1:329-337. �[View Abstract]
- Young �NS, Scheinberg �P, Calado �RT. Aplastic anemia. Curr Opin Hematol. 2008;15:162-168. �[View Abstract]
Codes
ICD09
- 284.9 Aplastic anemia, unspecified
- 284.89 Other specified aplastic anemias
- 284.09 Other constitutional aplastic anemia
ICD10
- D61.9 Aplastic anemia, unspecified
- D61.89 Oth aplastic anemias and other bone marrow failure syndromes
- D61.3 Idiopathic aplastic anemia
- D61.2 Aplastic anemia due to other external agents
- D61.09 Other constitutional aplastic anemia
SNOMED
- 306058006 Aplastic anemia (disorder)
- 55907008 Acquired aplastic anemia
- 191256002 Idiopathic aplastic anemia (disorder)
- 191248000 Aplastic anemia due to toxic cause (disorder)
- 30575002 Fanconis anemia (disorder)
FAQ
- Q: When starting IST, should I choose horse ATG or rabbit ATG as part of the ATG/cyclosporine/prednisone regimen?
- A: A head to head comparison of horse ATG (hATG) versus rabbit ATG (rATG) in immunosuppressive regimens showed inferiority of rATG in 1st-time treatment for sAA (Scheinberg, NEJM 2011).
- Q: When should patient and family members be HLA typed when considering aplastic anemia?
- A: HLA typing should be performed on patient and family members once peripheral pancytopenia and bone marrow hypocellularity is confirmed.
- Q: What are common side effects of the IST regimen?
- A: ATG may cause hypersensitivity reactions, whereas cyclosporine A may cause hypertension, electrolyte abnormalities, nephropathy, and hirsutism.