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    Aplastic Anemia

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    Feb.26.2025

    Aplastic Anemia

    Synopsis

    Key Points

    • Aplastic anemia is peripheral blood pancytopenia and hypocellular bone marrow with autoimmune destruction of hematopoietic stem cells, in the absence of major dysplastic signs and marrow fibrosis
    • Acquired aplastic anemia appears to have an immunologic basis in the majority of cases; may be idiopathic or may be triggered by drugs, other toxic agents, or disease states (eg, viruses) that trigger an immune response
    • Characterized by hypocellular bone marrow and significantly decreased counts in all peripheral blood cell lines (at least 2 peripheral cytopenias must be present to meet diagnostic criteria)
    • Nonsevere aplastic anemia may be treated with supportive care, but severe aplastic anemia requires either immunosuppressive treatment or hematopoietic stem cell transplant, depending on patient age and overall condition
    • While matched sibling bone marrow transplant has been the most desirable treatment for children and young adults, excellent results can now be achieved with alternative donors r1r2
    • When relapses occur or initial immunosuppressive therapy fails, there are multiple options for rescue therapies, and prognosis for aplastic anemia has improved to the extent that most patients have an excellent chance of survival

    Urgent Action

    • Urgently obtain evaluation by a hematologist, including a bone marrow biopsy, to make a prompt diagnosis in any patient with pancytopenia
    • Immediately remove any potential offending agent (medication or toxic agent) r3
    • Promptly evaluate symptoms or signs of bleeding or infection

    Pitfalls

    • Distinction between genetic syndromes associated with bone marrow failure and acquired aplastic anemia is important because these entities may respond differently to therapies
    • If a patient is a candidate for hematopoietic stem cell transplant, it is important not to transfuse unnecessarily, as higher transfusion burden may increase the risk for graft-versus-host disease, although this risk is expected to be lower with administration of irradiated blood
    • Conversely, transfusion may be lifesaving and should not be withheld if it is necessary

    Terminology

    Clinical Clarification

    • Aplastic anemia is peripheral blood pancytopenia and hypocellular bone marrow with autoimmune destruction of hematopoietic stem cells, in the absence of major dysplastic signs and marrow fibrosis r3r4
      • At least 2 cell lines must be affected, and 2 of following criteria need to be met to diagnose aplastic anemia: r3
        • Hemoglobin level less than 10 g/dL
        • Neutrophil count less than 1.5 × 10⁹/L
        • Platelet count less than 50 × 10⁹/L
      • Either acquired or inherited, but disease manifestations are the same

    Classification

    • By cause
      • Idiopathic (60% of cases) r4
        • Immune-mediated, via abnormal T-cell response leading to overproduction of bone marrow–inhibiting cytokines;r5r6 genetic predisposition is suspected
        • No trigger can be found
        • Slowly progressive course
      • Secondary r4
        • Drug, virus, or other toxic agent triggers T-cell–mediated immune response to hematopoietic stem cells
        • Onset is more abrupt than idiopathic aplastic anemia
    • By severity, as defined by the modified Camitta criteria r7
      • Nonsevere aplastic anemia r8
        • Decreased bone marrow cellularity and peripheral blood cytopenia (for age)
        • Does not fulfill criteria for severe or very severe aplastic anemia
      • Severe aplastic anemia r8
        • Bone marrow cellularity less than 25% of reference range
        • Meets at least 2 of the following criteria:
          • Neutrophil count less than 0.5 × 10⁹/L
          • Platelet count less than 20 × 10⁹/L
          • Absolute reticulocyte count less than 60 × 10⁹/L (using an automated reticulocyte count)
      • Very severe aplastic anemia r8
        • Meets criteria of severe aplastic anemia, plus
        • Neutrophil count less than 0.2 × 10⁹/L

    Diagnosis

    Clinical Presentation

    History

    • Can be an incidental finding if severity is mild
    • Most commonly, patients present with complaints related to bleeding or anemia; presentation with complaints of fever or infection are less common r4r9
      • Easy bruising c1
      • Bleeding gums c2
      • Menorrhagia c3
      • Episodic epistaxis c4
      • Petechiae over the extremities c5
      • Fatigue c6
      • Dyspnea c7
      • Angina pectoris, if anemia is severe c8
    • Systemic symptoms such as weight loss, pain, and loss of appetite are not generally associated with aplastic anemia and suggest an alternative diagnosis r4c9c10
    • A recent infection, new medication, or possible toxic exposure may be reported c11c12c13
      • If associated with drug exposure or viral infection, latent period of 6 to 8 weeks is common r4
      • Idiopathic aplastic anemia has a more gradual onset of several months r4
    • Suggestive personal or family history of physical anomalies, or a history of chronic multilineage low blood counts since childhood, suggests an inherited syndrome (of which aplastic anemia is a component) rather than idiopathic aplastic anemia r4
      • Fanconi syndrome c14c15
      • Dyskeratosis congenita and related short-telomere syndromes c16c17
      • Shwachman-Diamond syndrome r4c18c19

    Physical examination

    • Patients typically do not appear severely ill, but they can appear toxic depending on severity of illness c20
    • Depending on the severity of cytopenias, physical findings include:
      • Signs of thrombocytopenia
        • Ecchymoses (most often unexplained by the patient) c21
        • Petechiae on pretibial surface of lower legs, dorsal forearms, wrists, and in oropharynx c22c23
        • Nose or gum bleeding may be witnessed, although this is an uncommon presentation c24c25
        • Heme-positive stool c26
        • Retinal hemorrhages may be seen in patients with severe thrombocytopenia c27
      • Signs of anemia
        • Pallor c28
        • Tachypnea and tachycardia, if anemia is severe or has developed rapidly c29c30
      • Signs of leukopenia
        • If there is infection, fever c31c32
    • Usually do not see cachexia, splenomegaly, or lymphadenopathy; these suggest an alternative diagnosis c33c34c35
    • If the pancytopenia occurs in the setting of an inherited bone marrow failure syndrome, a variety of physical findings can assist in the diagnosis; these syndromes may have different treatments and prognoses c36
      • Fanconi syndrome r10
        • Thumb and radial malformations c37c38
        • Café au lait spots c39
        • Short stature c40
      • Telomere diseases (dyskeratosis congenita and related syndromes) r11
        • Nail dysplasia c41
        • Leukoplakia c42
        • Skin hypopigmentation c43
        • Premature graying of hair c44
      • Shwachman-Diamond syndrome
        • Growth retardation with short stature c45

    Causes and Risk Factors

    Causes

    • Idiopathic (most cases) r8c46
      • Immune-mediated destruction of hematopoietic cells
    • Secondary
      • Injury to stem cells from drug or toxic exposure r4
        • Agents that predictably depress bone marrow in commonly used doses/exposures
          • Benzene and benzene-containing chemicals (benzene binds to bone marrow DNA, inhibits synthesis, and introduces DNA breaks, acting as a mitotic poison); negligible risk in most countries now but remains a risk in China c47
          • Cytotoxic cancer chemotherapeutic agents result in direct marrow toxicity and short-term bone marrow failure, but this is not generally considered aplastic anemia, as it resolves within weeks c48c49c50
        • Agents associated with aplastic anemia but with lower probability (idiosyncratic drug reaction)
          • Chloramphenicol (oral formulation withdrawn from US market owing to aplastic anemia risk) c51
          • Some anticonvulsants (hydantoins, carbamazepine, phenacemide, ethosuximide) c52c53c54c55
          • NSAIDs (phenylbutazone, indomethacin, ibuprofen, diclofenac, naproxen, sulindac, fenoprofen, piroxicam, aspirin) c56c57c58c59c60c61c62c63c64
          • Gold salts and heavy metals (arsenic, bismuth, mercury) c65c66c67
          • Antithyroid drugs (methimazole, methylthiouracil, propylthiouracil) c68c69c70
          • Sulfonamides c71
          • Antiprotozoals (chloroquine, quinacrine) c72c73
          • Drugs treating diabetes (tolbutamide, chlorpropamide, carbutamide) c74c75c76
          • Carbonic anhydrase inhibitors (acetazolamide, mesalazine, methazolamide) c77c78c79
          • Insecticides (chlordane, lindane) c80c81
      • Injury to stem cells from radiation exposure r6r12r13c82
        • Primarily occurs in victims of radiation accidents or atomic bombs
        • Aplastic anemia has not been found in unexpected numbers in patients receiving radiation therapy for cancer or in people working at or living near nuclear power plants
      • Autoimmune hepatitis c83

    Risk factors and/or associations

    Age
    Genetics
    • Inherited bone marrow failure syndromes (ie, Fanconi syndrome, dyskeratosis congenita, Shwachman-Diamond syndrome) have clinical overlap with aplastic anemia, but these are separate disease entities with additional clinical features r14c89
      • Loss-of-function germline mutations result in physical anomalies and bone marrow failure, which classically manifest in childhood
    • Aplastic anemia not associated with 1 of these syndromes is an acquired disorder; however, somatic clonal mutations may be present
      • Up to one-half of patients with aplastic anemia have a small clonal population of cells deficient in glycosylphosphatidylinositol-linked proteins that characterize paroxysmal nocturnal hemoglobinuria; this is caused by a mutation in the PIGA gene c90
        • Only a small percentage of patients develop classic paroxysmal nocturnal hemoglobinuria
        • In patients with only aplastic anemia (but not clinical paroxysmal nocturnal hemoglobinuria) with a PIGA mutation, a mutant hematopoietic stem cell clone has not expanded; however, in patients with both aplastic anemia and paroxysmal nocturnal hemoglobinuria, it has r14
    Ethnicity/race
    • Highest incidence is reported in Asia r15c91
    Other risk factors/associations
    • Generally, aplastic anemia is a rare disease; however, differences in prevalence may be explained by environmental factors r4
      • Two per 1 million people in Europe and North America
      • Four to 5.6 per 1 million people in Asia
    • Paroxysmal nocturnal hemoglobinuria r16r17c92
      • Approximately 20% to 30% of patients will go on to develop aplastic anemia r17
    • Hepatitis r18c93c94
      • Uncommon but distinct association, usually in young boys r18
      • Sometimes associated with hepatitis A or B, but most cases are associated with seronegative, autoimmune hepatitis r19r20c95c96c97
      • Pancytopenia with hypocellular marrow develops 2 to 3 months after acute hepatitis r18
    • Epstein-Barr virus or cytomegalovirus infection r4r18r21r22c98c99
      • Rare but distinct association
      • Pancytopenia develops soon after clinical symptoms of infection
      • Believed to be immune mechanism
    • Autoimmune connective tissue disease r4
      • Aplastic anemia can be part of eosinophilic fasciitis, an autoimmune infiltration of macrophages and lymphocytes into skin and muscle, sometimes responsive to corticosteroids or other immunosuppressive therapy c100c101
      • Aplastic anemia can also complicate scleroderma, systemic lupus erythematosus, or rheumatoid arthritis, but it is unclear if medication used to treat disease is a confounding factor
    • Posttransfusion graft-versus-host disease r4
      • Caused by transfusion of competent lymphocytes into immunodeficient hosts c102
      • Resistant to immunosuppressive therapy and usually fatal
    • Pregnancy r23c103
      • While pregnancy does appear to present a rare risk of developing aplastic anemia, the mechanism is poorly understood
      • While it is believed to be autoimmune, immunosuppressive therapy is not an option because of fetal toxicity
      • Stem cell transplant is also not an option; therefore, only supportive care is available during pregnancy

    Diagnostic Procedures

    Primary diagnostic tools

    • Suspect diagnosis based on signs or symptoms suggesting anemia, thrombocytopenia, or leukopenia c104
    • Obtain CBC to confirm at least 2 of the 3 following findings: r3c105c106
      • Hemoglobin level less than 10 g/dL
      • Neutrophil count less than 1.5 × 10⁹/L
      • Platelet count less than 50 × 10⁹/L
    • Obtain routine laboratory studies to further evaluate pancytopenia, including absolute reticulocyte count, Hb F percentage, vitamin B₁₂ and folate levels, liver function tests r8c107c108c109
    • Definitive diagnosis requires bone marrow aspiration and trephine biopsy c110
      • Aplastic anemia is characterized by hypocellular, fatty marrow with cellularity less than 30% of reference range, in the absence of major dysplastic signs and marrow fibrosis r4
    • Additional investigations for underlying cause and alternative diagnoses may include: r8
      • Anti-nuclear antibody and anti–double-stranded DNA
      • Viral serologies: hepatitis A/B/C/E, EBV, CMV, HIV, and parvovirus B19
      • Abdominal ultrasound scan to evaluate for enlarged spleen and/or lymph nodes, which may indicate hematological malignancy
      • Chest radiograph to exclude infection
      • Radiographs of the hands, forearms, and feet may be indicated if an inherited bone marrow failure syndrome is suspected
      • High-resolution chest CT to evaluate for lung fibrosis if suspect constitutional bone marrow failure syndrome
    • Complete certainty of acquired aplastic anemia, rather than aplastic anemia as a component of an inherited or clonal syndrome, requires additional testing in consultation with a hematologist in inherited bone marrow failure syndromes
      • Chromosomal breakage testing on peripheral blood to screen for Fanconi syndrome r8
        • Indicated for patients younger than 50 years (can screen older patients if Fanconi anemia is clinically suspected), all patients who are transplant candidates, and patients who have siblings with Fanconi anemia
      • Flow cytometry testing of peripheral blood to identify patients with paroxysmal nocturnal hemoglobinuria clones r8c111
      • Cytogenetics and molecular testing of bone marrow c112
        • Testing for known genes associated with Fanconi syndrome (to confirm a positive chromosomal breakage test result) and dyskeratosis congenita is reasonable in adult patients with moderate, chronic pancytopenia and in children and adolescents r6
          • Some patients may lack physical anomalies, and genetic syndrome may be otherwise unrecognized
          • However, in severe cases with no family history, genetic test results are likely to be negative r6
    • HLA typing for future treatment purposes is recommended at time of diagnosis and is usually accomplished by urgent referral (especially for children and younger adults) to transplant specialist center r3c113

    Laboratory

    • CBC c114
      • Pancytopenia (or cytopenia of least 2 cell lines)
        • Isolated thrombocytopenia may occur in early stage
      • Relative lymphocytosis is common
    • Peripheral blood smear r4c115
      • Usually demonstrates paucity of all cell lines
      • RBC macrocytosis and anisopoikilocytosis r8
      • May show toxic granulations in neutrophils
    • Absolute reticulocyte count c116
      • Reference range: 50 to 100 × 10⁹/L
      • Count will be low, owing to decreased hematopoiesis
      • Used along with CBC results and bone marrow examination to determine if disease falls into severe category (Camitta criteria) r3
        • Severe aplastic anemia
          • Bone marrow cellularity less than 25% of reference range
          • At least 2 of the following:
            • Neutrophil count less than 0.5 × 10⁹/L c117
            • Platelet count less than 20 × 10⁹/L c118
            • Absolute reticulocyte count less than 20 × 10⁹/L
        • Very severe aplastic anemia
          • Fulfills criteria of severe aplastic anemia, plus
          • Neutrophil count less than 0.2 × 10⁹/L
    • Vitamin B₁₂ and folate levels r8c119c120
      • Deficiencies must be documented (and corrected) before diagnosis of aplastic anemia can be confirmed, although bone marrow aplasia from this cause is rare
    • Liver function tests and viral serologies c121c122
      • Liver function tests detect recent or ongoing hepatitis
      • Viral serologies (if liver function test results or history suggest current or antecedent infection)
        • Some experts recommend routine hepatitis serologies in all patients in whom disease appears to be idiopathic r4
          • Majority of cases are associated with infection not stemming from hepatitis A, B, or C r19
          • Posthepatitis aplastic anemia has worse prognosis r20
        • Epstein-Barr virus, cytomegalovirus, HIV, and parvovirus B19 are rare causes of aplastic anemia
    • Flow cytometry c123
      • Identifies paroxysmal nocturnal hemoglobinuria clones
      • Uses monoclonal antibodies, most commonly anti-CD59 (because it is expressed on all cell lineages), to detect deficiency of glycosylphosphatidylinositol anchor proteins, which are consistent with a paroxysmal nocturnal hemoglobinuria clone r17
    • Peripheral blood leukocyte telomere length r8c124
      • Screening test for telomere-maintenance gene mutations associated with dyskeratosis congenita
      • Telomere length analysis is performed
      • Test methods include flow cytometric fluorescence in situ hybridization or multiplex quantitative polymerase chain reaction
    • HLA typing r20c125
      • Because of time delay in finding an HLA-suitable donor for those patients who will be treated with bone marrow transplant, typing is usually obtained as part of initial evaluation after diagnosis

    Procedures

    Bone marrow aspiration and trephine (core) biopsy c126c127
    General explanation
    • Under local anesthesia, a small incision is made over the posterior iliac crest (anterior may be used if posterior is unavailable because of injury or obesity) under sterile conditions r24
    • Aspiration: a hollow needle is inserted through bone into the marrow; using a syringe attached to the needle, a sample of the liquid bone marrow is withdrawn
    • Trephine biopsy: a small amount of the spongy bone marrow is removed r24c128
    Indication
    • All patients with pancytopenia r24
    Contraindications
    • No absolute contraindications r24r25
    • Thrombocytopenia is not a contraindication in itself, although many favor performing the procedure when platelet count is greater than 10 × 10⁹/L or during a platelet transfusion r24r25
    • Significant hypocoagulability should be corrected before bone marrow aspiration and/or biopsy if possible r24
    Complications
    • Serious adverse events are rare and have been reported in less than 0.05% of procedures r25
    • Adverse events r25
      • Bleeding (occurs primarily in patients with coagulation defects)
      • Infection
      • Persistent pain at biopsy site
    Interpretation of results
    • Trephine biopsy specimen will show the following: r3
      • Hematopoietic hypocellularity
        • Bone marrow hypocellularity less than 30% in children or young adults
          • Older adults may show more hypocellularity on basis of age alone; this cutoff may not be applicable
        • Remaining cells are morphologically normal
      • Fatty marrow without fibrosis or infiltration with malignant cells
    • Evaluate aspirate r3
      • Check cellular morphology
        • Often shows signs of dyserythropoiesis, but dysplasia of megakaryocytes and granulocytes should not be present
      • Perform cytogenic and molecular analysis
        • To rule out inherited genetic syndrome, myelodysplastic syndrome, or other malignancy
    • Send bone marrow sample for cytogenic and molecular testing
      • Next-generation sequencing and gene panels are performed to identify/confirm the following: r20r26
        • Inherited bone marrow failure syndromes
        • Acquired somatic mutations typical of myeloid malignancies and myelodysplastic syndrome

    Differential Diagnosis

    Most common

    • Myelodysplastic syndrome c129
      • Group of bone marrow failure syndromes usually characterized by hypercellular bone marrow with ineffective hematopoiesis, with variable risk for progression to leukemia r27
        • Some forms of myelodysplastic syndrome have hypocellular bone marrow with excessive cell death accounting for cytopenias; this makes differentiation from aplastic anemia more difficult
        • Diagnostic criteria include meaningful cytopenia (hemoglobin level less than 11 g/dL; absolute neutrophil count less than 1500/mm³; or platelet count less than 100,000/mm³) plus at least 1 of the following:
          • Greater than 5% blasts in bone marrow
          • Greater than 10% of cells in any given hematopoietic lineage that appear dysplastic
          • Abnormal bone marrow karyotype
          • Other evidence of clonal hematopoiesis
        • On physical examination, splenomegaly is usually present in myelodysplastic syndrome but absent in aplastic anemia
        • Maintain a high degree of suspicion of a myelodysplastic syndrome when an elderly patient presents with pancytopenia
      • Differentiate from aplastic anemia by morphologic and cytogenetic analysis of bone marrow cells r27
    • Acute myelogenous leukemia c130d1
      • Replacement of bone marrow by neoplastic cells can result in pancytopenia
      • Although uncommon, hypoplastic anemia may precede onset of acute leukemia by several months
      • Differentiate from aplastic anemia by morphologic and cytogenetic analysis of bone marrow cells
    • Primary myelofibrosis c131
      • Clonal stem cell disorder characterized by myeloproliferation, atypical megakaryocytic hyperplasia, bone marrow fibrosis, and extramedullary hematopoiesis r28
      • Clinically manifests with anemia but usually not other cytopenias r27
      • Splenomegaly and hypercatabolic symptoms may be seen in primary myelofibrosis but not in aplastic anemia r28
      • Differentiate from aplastic anemia with examination of bone marrow (often not aspirable), which shows fibrosis not fatty marrow, as in aplastic anemia r28
    • Inherited bone marrow failure syndromes, of which aplastic anemia is a component
      • Important for therapeutic implications
      • Acquired and inherited forms of aplastic anemia look identical under the microscope and are differentiated by history, physical findings, and genetic studies
        • Fanconi syndrome r3r4r10c132
          • Recessive genetic disorder (up to 0.5% of population are heterozygous) with diverse congenital malformations, progressive pancytopenia, and predisposition to hematologic malignancies and solid tumors r10
          • Like acquired aplastic anemia, presentation may include progressive pancytopenia
          • Two-thirds of patients with Fanconi syndrome have major congenital abnormalities, with wide phenotypic variability, involving any organ system r10
          • One-third of patients with Fanconi syndrome have only subtle growth or endocrine abnormalities that go unrecognized; these include abnormalities of growth parameters (eg, decreased height, weight, or head circumference) r10
            • In these patients, Fanconi syndrome may not be suspected, and pancytopenia may erroneously be attributed to acquired aplastic anemia
          • Differentiate from acquired aplastic anemia with chromosomal fragility testing (quantification of chromosomal breakage with exposure to DNA cross-linking agents), which will show excessive chromosomal breakage with Fanconi syndrome; can be confirmed with cytogenetic testing r10
        • Dyskeratosis congenita r11c133
          • Inherited bone marrow failure syndrome characterized by abnormal nail appearance, reticular skin pigmentation, and oral leukoplakia
          • Patients may develop bone marrow aplasia, myelodysplasia, leukemia, or solid tumors; sometimes presents with aplastic anemia as initial manifestation
          • Telomeres in germline cells are very short; 50% of patients have been found to have mutations in genes encoding proteins that maintain function of telomeres
          • Important to distinguish from acquired aplastic anemia, as these patients do not respond to immunotherapy as patients with aplastic anemia do, and they may not do well with stem cell transplantation
          • Differentiate from acquired aplastic anemia with telomere length analysis r26
        • Shwachman-Diamond syndrome r29c134
          • Autosomal recessive disease characterized by pancreatic insufficiency, skeletal abnormalities, and bone marrow dysfunction
          • May lead to bone marrow failure, myelodysplasia, or leukemia
          • Bone marrow failure in Shwachman-Diamond syndrome does not respond to immunosuppressive treatment, but can be treated with hematopoietic stem cell transplant
          • Differentiate from acquired aplastic anemia with genetic testing, which shows mutation on chromosome 7 in the gene coding for the SBDS protein, which is expressed in multiple organ systems

    Treatment

    Goals

    • Improve hematopoiesis and blood counts; avoid transfusion dependency

    Disposition

    Admission criteria

    Bleeding complications or severe anemia requiring inpatient treatment or monitoring

    Infection requiring IV antibiotics or inpatient monitoring

    Criteria for ICU admission
    • Severe bleeding requiring ICU-level monitoring and treatment
    • Hypotension or other unstable vital signs
    • Sepsis

    Recommendations for specialist referral

    • Aplastic anemia should be treated by a hematologist-oncologist with experience treating bone marrow failure

    Treatment Options

    Management for all patients diagnosed with aplastic anemia

    • Discontinuation of potential offending drugs or other toxic agents r3
      • Be aware that removal of triggering toxic agent does not reverse aplastic anemia r4
      • Treatment should proceed promptly regardless of possible trigger removal r4
    • Transfusions, if needed to improve quality of life r26
      • To reduce risk of alloimmunization and later graft rejection after hematopoietic stem cell transplant r4
        • Blood products should be irradiated (or physically leukocyte-depleted) and should not be from a potential later bone marrow donor
        • Although large numbers of transfusions do increase the risk of graft rejection, small numbers of transfusions do not have a major adverse effect on survival; irradiation should reduce this risk
        • Transfusions should not be withheld when clearly necessary
      • Manage symptomatic anemia with packed RBC transfusions
        • Individualize transfusion threshold based on comorbidities and clinical scenario
          • Children may tolerate a hemoglobin level as low as 6 g/dL r20
          • Physically fit adults are usually asymptomatic at hemoglobin levels as low as 7 g/dL r4
          • For hospitalized stable adult patients, hemoglobin concentration of 70 to 80 g/L is recommended threshold for RBC transfusion (80 g/L for those with comorbid cardiovascular disease) r8
          • Older adults and those with cardiopulmonary disease may need target hemoglobin level over 9 g/dL to avoid symptoms r4
          • If repeated RBC transfusions are required, monitor for iron overload; consider chelation therapy when the serum ferritin is greater than 1000 mcg/L r30
      • Manage bleeding risk with platelet transfusions if necessary
        • In absence of bleeding, platelets are commonly given only when counts decline to 10 × 10⁹/L or lower r20
          • Some experts will not transfuse platelets in the absence of bleeding until counts decrease to 5 × 10⁹/L or lower r4
        • If there is active bleeding, threshold to transfuse platelets is generally set at 20 × 10⁹/L or higher r20
    • Avoidance of other bleeding risk
      • Hormonal suppression of menses in females r20
        • Continuous oral contraceptives
        • Gonadotropin-releasing hormone agonists
      • Avoidance of contact sports and activities with high risk for falls or injuries
    • Infection prevention and management
      • Good hand hygiene and avoidance of sick contacts is prudent for all patients and imperative for patients with severe aplastic anemia
      • There is no current standard for infection prophylaxis; treatment is individualized because of the long-term nature of neutropenia r9
        • Patients treated with immunosuppressive therapy require the following prophylactic antimicrobials to be administered until adequate lymphocyte recovery (absolute CD4 T cells of greater than 200 × 10³/L) and absolute neutrophil count of greater than 0.50 × 10⁹/L r31
          • Antibiotic for pneumocystis pneumonia prophylaxis (eg, atovaquone, trimethoprim/sulfamethoxazole, or pentamidine)
          • Antifungal prophylaxis (eg, mold active azole)
          • Antiviral prophylaxis for herpes simplex virus and varicella-zoster virus (eg, acyclovir or valacyclovir)
        • Broad-spectrum antibiotic with gram-negative and antipseudomonal coverage (eg, fluoroquinolone) is recommended until neutrophil recovery in allogeneic hematopoietic stem cell transplant recipients and patients treated with immunosuppressive therapy who have prolonged neutropenia (7 or more days) r31
      • Fever in the setting of a neutrophil count less than 0.5 × 10⁹/L is treated as a medical emergency with hospital admission, obtaining cultures, and administration of broad-spectrum parenteral antibiotics r4
      • Irradiated granulocytes can be considered in patients with a life-threatening infection related to severe neutropenia r8

    Further treatment will depend on severity of illness, patient age, and need for transfusion

    • Determine severity by modified Camitta criteria
      • Nonsevere aplastic anemia r3
        • Decreased bone marrow cellularity and peripheral blood cytopenia
        • Does not fulfill criteria for severe aplastic anemia
      • Severe aplastic anemia r8
        • Bone marrow cellularity less than 25% of reference range
        • At least 2 of the following criteria:
          • Neutrophil count less than 0.5 × 10⁹/L
          • Platelet count less than 20 × 10⁹/L
          • Reticulocyte count less than 60 × 10⁹/L
      • Very severe aplastic anemia r3
        • Fulfills criteria of severe aplastic anemia, plus
        • Neutrophil count less than 0.2 × 10⁹/L
    • Treatment of nonsevere aplastic anemia r3r4r32
      • Many patients do not require treatment r8
        • Observation with monitoring of CBC may be acceptable if patient is not transfusion dependent r3r33
      • RBC transfusions, if needed
      • Determine whether transfusion dependent
        • Definition is somewhat controversial, but RBC-transfusion dependence has been defined by an expert panel of hematologists as requiring an average of 2 units of packed RBCs per month over a 3-month period r34
      • Immunosuppressive therapy or danazol may be considered for patients who are transfusion dependent, who have bleeding or infections, or for lifestyle reasons r8
    • Treatment of severe aplastic anemia, very severe aplastic anemia, and transfusion-dependent nonsevere aplastic anemia
      • Matched sibling hematopoietic stem cell transplant, if available r3r4r6
        • First line treatment for children and adults younger than age 40 years r1r8r31r35
          • Can consider for patients aged between 40 and 50 years based on comorbidities, performance status, expertise of transplant center, and rapid availability of sibling donor
        • Second line for older adults whose condition does not respond to first line immunosuppressive therapy r8
        • In the absence of a matched sibling donor, a matched, unrelated donor hematopoietic stem cell transplant is considered a safe and feasible alternative first line treatment for children and young adults r1r2
      • Immunosuppressive therapy
        • First line treatment for adults older than 40 years and patients of any age who are medically unfit for hematopoietic stem cell transplant r8r31
        • Second line for children and young adults (first line in the absence of an appropriate donor for hematopoietic stem cell transplant) r1r8r35
        • Standard regimen consists of antithymocyte immune globulin and cyclosporine, with or without eltrombopag r31
          • Equine antithymocyte immune globulin for 4 days (days 1-4) r8
            • Precede each daily dose with the following:
              • Platelet transfusion to keep platelets greater than 20 to 30 x 10⁹/L
              • Prednisone or methylprednisolone in modest dose to ameliorate serum sickness r4
              • H1 antihistamine (eg, diphenhydramine or chlorphenamine) r35
          • Cyclosporine daily, beginning on day 1 of antithymocyte immune globulin treatment r8
            • Continue treatment while monitoring increase in blood count, slowly tapering after at least a further 12 months of therapy
          • Eltrombopag, if given, is administered beginning on day 14 and continued for 3 to 6 months r8
            • Eltrombopag is an oral synthetic thrombopoietin receptor agonist that acts as a bone marrow stimulating agent r36
            • Addition of eltrombopag to standard immunosuppressive regimen improves the rate and magnitude of hematologic response r6r37r38
            • FDA-approved for treatment of newly diagnosed severe aplastic anemic conjunction with immunosuppressive therapy in patients older than 2 years
              • However, addition of eltrombopag is not currently recommended for treatment of children as benefits are less clear than in adults r31r35
            • Requires careful monitoring for clonal evolution r8
            • Some experts avoid using in patients with clonal cytogenetic abnormalities as it may promote expansion of dormant preexisting clones with an aberrant karyotype r39
        • Antithymocyte immune globulin and cyclosporine combination is well tolerated, with improvement expected in 3 to 6 months r4
          • Response rate is 60% to 70%; addition of eltrombopag results in an overall initial response rate of around 80%r31
          • Relapse is common but not a sign of poor prognosis
      • Mismatched unrelated donor hematopoietic stem cell transplant
        • Indicated in children who fail to respond to immunosuppressive therapy and have no suitable matched donor r1
      • Options for patients who are refractory to immunosuppressive therapy and have no suitable matched/mismatched donor include: r1
        • Clinical trial, if one is available
        • Second course of immunosuppressive therapy r1
          • In transplant-ineligible children with refractory severe aplastic anemia, consider adding eltrombopag to a second trial of immunosuppressive therapy r40
        • Androgens r1
          • Generally less effective than immunosuppression but may be tried when immunosuppression fails; options include: r4r6
            • Danazol
            • Oxymetholone
            • Nandrolone decanoate
          • Hepatotoxicity may be limiting
          • Most commonly used outside of the United States in medical settings where antithymocyte immune globulin is unavailable; availability of these agents varies based on country
        • Monoclonal antibodies
          • Alemtuzumab r1
            • Monoclonal antibody against CD52
            • Alemtuzumab can been used alone in refractory cases with a response rate of 37% r41
        • Thrombopoietin receptor agonists
          • Eltrombopag
            • Oral synthetic thrombopoietin receptor agonist
            • Can be used alone for patients with severe aplastic anemia refractory to immunosuppressive therapy or for patients heavily pretreated and unsuitable for hematopoietic stem cell transplant r8
            • Hematological response reported in 50% of patients; including trilineage improvements, which are sustained after discontinuation; however, real-world response rates are lower, especially in older adults r8r42
          • Romiplostim r8r43
            • Parenteral thrombopoietin agonist r44
            • Approved to treat immune thrombocytopenia; has been suggested for refractory cases of aplastic anemia, but this is not FDA-approved and is not a routine treatment r8r44
            • Demonstrated efficacy in patients with refractory aplastic anemia in a phase 3 clinical trial r43
        • Haploidentical or unrelated umbilical cord blood hematopoietic stem cell transplant r1r40
          • Considered a reasonable and potentially curative option for patients to whom the following applies: r45
            • Are nonresponsive to immunosuppressive therapy
            • Relapsed after immunosuppressive therapy
            • Acquired a secondary clonal disorder (ie, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria) after immunosuppressive therapy
          • Preferred option for children with refractory severe aplastic anemia r40
      • Hematopoietic growth factors r46
        • Routine use of traditional hematopoietic growth factors is not recommended
        • While trials of traditional growth factors (eg, erythropoietin, granulocyte colony-stimulating factor) are sometimes used clinically, a meta-analysis of trials showed no effect on mortality, relapse, risk of malignancy, or infection, and no difference in overall hematologic response to other treatments

    Drug therapy

    • Immunosuppressive therapy
      • Antithymocyte immune globulin c135c136
        • Anti-Thymocyte Immune Globulin (Equine) Solution for injection; Children and Adolescents: 40 mg/kg/dose IV once daily for 4 days. May repeat course after 6 months or longer in individuals who are refractory to initial treatment or who have relapsing disease.
        • Anti-Thymocyte Immune Globulin (Equine) Solution for injection; Adults: 40 mg/kg/dose IV once daily for 4 days. May repeat course after 3 months or longer in individuals who are refractory to initial treatment or who have relapsing disease.
      • Calcineurin inhibitor
        • Cyclosporine c137c138
          • Cyclosporine Oral capsule; Children and Adolescents: 5 to 6 mg/kg/dose PO twice daily, initially. Adjust dose based on target cyclosporine trough concentration. Taper dose after at least 6 months and complete response with stable blood counts for 3 to 6 months. May repeat course in individuals who are refractory to initial treatment or who have relapsing disease.
          • Cyclosporine Oral capsule; Adults 18 to 60 years: 2.5 to 3 mg/kg/dose PO twice daily, initially. Adjust dose based on target cyclosporine trough concentration. Taper dose by 25 mg/day every 2 to 3 months starting 12 months after blood counts plateau. May repeat course after 3 months or longer in individuals who are refractory to initial treatment or who have relapsing disease.
          • Cyclosporine Oral capsule; Adults older than 60 years: 1.25 mg/kg/dose PO twice daily, initially. Adjust dose based on target cyclosporine trough concentration. Taper dose by 25 mg/day every 2 to 3 months starting 12 months after blood counts plateau. May repeat course after 3 months or longer in individuals who are refractory to initial treatment or who have relapsing disease.
      • Corticosteroids
        • Methylprednisolone
          • Methylprednisolone Sodium Succinate Solution for injection; Children and Adolescents: 1 mg/kg/dose IV every 12 hours for 4 days, followed by oral corticosteroid taper.
          • Methylprednisolone Sodium Succinate Solution for injection; Children and Adolescents: 1 mg/kg/dose IV every 12 hours for 4 days, followed by oral corticosteroid taper.
          • Methylprednisolone Sodium Succinate Solution for injection; Adults: 1 mg/kg/dose IV once daily for 4 to 7 days, followed by oral corticosteroid taper.
        • Prednisone c139c140
          • Prednisone Oral tablet; Children and Adolescents: 2 mg/kg/dose PO once daily for 4 to 14 days starting after IV methylprednisolone, followed by taper over at least 2 weeks.
          • Prednisone Oral tablet; Adults: 0.5 mg/kg/dose PO once daily, initially, starting after IV methylprednisolone. Taper dose by one-half every 5 days based on clinical response.
    • Thrombopoietin receptor agonist
      • Eltrombopag c141
        • For treatment of severe aplastic anemia
          • Eltrombopag Olamine Oral suspension; Children 2 to 5 years: 2.5 mg/kg/dose PO once daily, or 1.25 mg/kg/dose PO once daily for individuals of East/Southeast Asian ancestry, for 6 months.
          • Eltrombopag Olamine Oral suspension; Children 6 to 11 years: 75 mg PO once daily, or 37.5 mg PO once daily for individuals of East/Southeast Asian ancestry, for 6 months.
          • Eltrombopag Olamine Oral tablet; Children and Adolescents 12 to 17 years: 150 mg PO once daily, or 75 mg PO once daily for individuals of East/Southeast Asian ancestry, for 6 months.
          • Eltrombopag Olamine Oral tablet; Adults: 150 mg PO once daily, or 75 mg PO once daily for individuals of East/Southeast Asian ancestry, for 6 months; may discontinue therapy after 3 months if complete response is achieved.
        • For treatment of refractory severe aplastic anemia
          • Eltrombopag choline
            • Eltrombopag Choline Oral tablet; Adults: 36 mg PO once daily, or 18 mg PO once daily for individuals of East/Southeast Asian ancestry, initially. Adjust dose by 36 mg/day every 2 weeks as necessary to achieve the target platelet count; use the lowest effective dose. Max: 108 mg/day.
          • Eltrombopag olamine
            • Eltrombopag Olamine Oral tablet; Adults: 50 mg PO once daily, or 25 mg PO once daily for individuals of East/Southeast Asian ancestry, initially. Adjust dose by 50 mg/day PO every 2 weeks as necessary to achieve the target platelet count; use the lowest effective dose. Max: 150 mg/day.

    Nondrug and supportive care

    Procedures
    Hematopoietic stem cell transplantation c142
    General explanation
    • Patient is prepared with immunosuppressive conditioning regimen to improve engraftment by eliminating recipient lymphocytes (usually antithymocyte immune globulin and cyclosporine with or without total body irradiation, or a variation of this combination)
    • Bone marrow or peripheral blood is retrieved from donor; obtaining stem cells from bone marrow achieves lower risk of graft-versus-host disease than from peripheral blood stem cells
    • Stem cells are removed from donor tissue and infused into recipient
    Indication r3r4r9r33
    • Severe aplastic anemia
      • First line treatment in children or young adults with matched sibling; a matched unrelated donor is an alternative if matched sibling donor is not available
      • Older adults whose condition does not respond to immunotherapy, regardless of matched donor status; haploidentical donor can be considered
    Complications
    • Early
      • Graft rejection r47
        • Occurs when immunologically competent host cells destroy transplanted donor cells
        • More common in aplastic anemia than in other indications for stem cell transplant
        • Defined by failure of hematopoietic response by day 100 after hematopoietic stem cell transplant r48
      • Graft-versus-host disease r47
        • Major complication that occurs when donor immune cells from graft become sensitized to and attack host tissue
        • Acute disease characterized by rash, jaundice, and diarrhea
        • Chronic disease affects multiple organs and may lead to death
        • About one-half of patients respond to steroids or other immunosuppressive treatment
    • Late r3r4r47r49
      • Impaired gonadal function
        • Primarily in children who received total body irradiation
      • Impaired growth and development
      • Secondary malignancies
        • More common in patients who received total body irradiation
        • Lymphoid malignancies: risk decreases over time
        • Solid tumors: risk continues over time
      • Long-term follow-up of children showed complications of hepatitis C, as original treatment occurred before isolation of virus and ability to screen r49
      • Chronic graft-versus-host disease
    Interpretation of results
    • Peripheral blood counts are used to determine success; response should be seen before 100 days posttransplant r47
      • A small group of patients will see recovery between 3 and 6 months r33
      • Hematologic response is defined as no longer meeting criteria for severe aplastic anemia r33

    Allogeneic stem cell transplantation from an HLA-matched sibling donor is curative in over 90% of children and 80% of adolescents and does not require prior irradiation r6

    Well-matched alternative donor stem cells may achieve a good result but with a higher risk of graft-versus-host disease; prior irradiation decreases risk of graft-versus-host disease r3r50

    • Alternative donors are usually HLA-matched unrelated donors, but haploidentical donors may be an acceptable option for young patients when no matched donor is available
    • Umbilical cord blood transplant is a second line treatment option used mainly in children with no matched sibling donor; there is an increased rate of graft rejection r3

    Monitoring

    • Patients responsive to treatment are followed for relapse and clonal evolution
      • There are no clear guidelines, but expert opinion seems to agree on the following:
        • Regular and frequent peripheral blood counts c143
        • Peripheral blood counts should guide management, rather than marrow cellularity r33
        • Bone marrow biopsy at 6 and 12 months, then yearly after treatment to monitor for morphology and karyotype r33c144
        • Marrow is expected to remain hypocellular for long periods r33

    Complications and Prognosis

    Complications

    • Relapse after immunosuppressive therapy or hematopoietic stem cell transplant r6r33c145
      • Relapse alone is not correlated with decreased survival
      • Initially, treat with immunotherapy
      • Further treatment will be individualized
      • Relapse is most likely to occur in the first 2 to 4 years after treatment
    • Clonal evolution to myelodysplastic syndrome, acute myelogenous leukemia, or paroxysmal nocturnal hemoglobinuria r6r33c146
      • Clonality may be present as an intrinsic feature of aplastic anemia but increases after immunosuppressive therapy
        • Between 10% and 15% of adult patients will go on to develop clonal evolution after immunosuppressive therapy
          • Children have a lower rate of clonal progression r2
        • Paroxysmal nocturnal hemoglobinuria is the most common clonal hematopoietic disorder arising in patients with aplastic anemia r51
        • Most likely to occur in the first 2 to 4 years after treatment
        • Clonal evolution with the 3-drug immunosuppressive regimen (antithymocyte immune globulin and cyclosporine plus eltrombopag) appears to be similar to that with antithymocyte immune globulin plus cyclosporine alone r52
      • Hematopoietic stem cell transplant may be the only option for patients with clonal evolution
    • Chronic graft-versus-host disease after hematopoietic stem cell transplant r4c147
    • Solid tumors as late complications of hematopoietic stem cell transplant r4

    Prognosis

    • Prognosis for acquired aplastic anemia has improved over past decades with better immunosuppressive therapies, deeper knowledge of hematopoietic stem cell transplantation, and novel drug treatment r6
    • Children with matched sibling donors have a cure rate over 90%, and studies show excellent long-term quality of life for survivors r53
    • Adolescents have a cure rate of about 80% with a matched sibling donor r54
    • Matched unrelated donor transplantations are now achieving excellent results, particularly in children r55
    • Initial immunotherapy in those who are not candidates for hematopoietic stem cell transplant has a 60% to 70% response rate and, while relapse occurs in approximately 30%,r15 these patients usually respond to further immunosuppression. Addition of eltrombopag significantly increases the response rate r2r33
    • Long-term survival rate among children who respond to first line immunosuppressive therapy is comparable with those who have received an up-front matched sibling donor hematopoietic stem cell transplant r15
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