Aplastic Anemia

Back

Practice Essentials

Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia (see the image below). Although the anemia is often normocytic, mild macrocytosis can also be observed in association with stress erythropoiesis and elevated fetal hemoglobin levels.



View Image

Low power, H and E showing a hypocellular bone marrow with increased adipose tissue and decreased hematopoietic cells in the marrow space.

Signs and symptoms

The clinical presentation of patients with aplastic anemia includes symptoms related to the decrease in bone marrow production of hematopoietic cells. The onset is insidious, and the initial symptom is frequently related to anemia or bleeding, although fever or infections may be noted at presentation.

Signs and symptoms of aplastic anemia may include the following:

A subset of patients with aplastic anemia present with jaundice and evidence of clinical hepatitis.[1, 2]

See Presentation for more detail.

Diagnosis

Testing

Laboratory testing for suspected aplastic anemia includes the following:

Procedures

Bone marrow biopsy is performed in addition to aspiration to assess cellularity qualitatively and quantitatively. Bone marrow culture may be useful in diagnosing mycobacterial and viral infections; however, the yield is generally low.

See Workup for more detail.

Management

Severe or very severe aplastic anemia is a hematologic emergency, and care should be instituted promptly. Clinicians must stress the need for patient compliance with therapy. The specific medications administered depend on the choice of therapy and whether it is supportive care only, immunosuppressive therapy, or hematopoietic cell transplantation.[3]

Pharmacotherapy

The following medications are used in patients with aplastic anemia:

Nonpharmacotherapy

Nonpharmacologic management of aplastic anemia includes the following:

Surgical option

Central venous catheter placement is required before the administration of hematopoietic cell transplantation.

See Treatment and Medication for more detail.

Background

Paul Ehrlich introduced the concept of aplastic anemia in 1888 when he reported the case of a pregnant woman who died of bone marrow failure. However, it was not until 1904 that Anatole Chauffard named this disorder aplastic anemia. (See Etiology.)

The British Society for Standards in Haematology has issued guidelines on diagnosis and management of aplastic anemia in adults[5]  and pediatric patients.[6] The Pediatric Haemato-Oncology Italian Association has issued guidelines on diagnosis and management of acquired aplastic anemia in childhood.[7]

For more information, see the following Medscape articles:

Etiology

The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment.[8, 9, 10, 11]  The distinction between acquired and inherited disease may present a clinical challenge, but more than 80% of cases are acquired. Clinical and laboratory observations suggest that acquired aplastic anemia is an autoimmune disease.

On morphologic evaluation, the hematopoietic elements in the bone marrow are less than 25%, and they are largely replaced with fat cells. Flow cytometry shows that the CD34 cell population, which contains the stem cells and the early committed progenitors, is substantially reduced.[9, 12] Data from in vitro colony-culture assays suggest profound functional loss of the hematopoietic progenitors, so much so that they are unresponsive even to high levels of hematopoietic growth factors.

Previously, it had been hypothesized that aplastic anemia may be due to a defect at various levels, such as an intrinsic defect of hematopoietic cells; external injury to hematopoietic cells; and defective stroma, which is critical for normal proliferation and functioning of hematopoietic cells. Theoretically, all of these mechanisms could be responsible for aplastic anemia. This theory was the basis of many in vitro stem cell culture experiments using a crossover design in which stem cells from patients with aplastic anemia were cultured with normal stroma and vice versa. The conclusions from these studies led to the understanding that stem cell defect is the central mechanism in the majority of patients with aplastic anemia.[13, 14]

In patients with severe aplastic anemia, stromal cells have normal function, including growth factor production. Adequate stromal function is implicit in the success of hematopoietic cell transplantation (HCT) in aplastic anemia, because the stromal elements are almost entirely (frequently) of host origin.

The role of an immune dysfunction was suggested in 1970, when autologous recovery was documented in a patient with aplastic anemia who failed to engraft after HCT. Mathe proposed that the immunosuppressive regimen used for conditioning promoted the return of normal marrow function. Since then, numerous studies have shown that, in approximately 70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function.[10, 15, 16, 17, 18]

Immunity is genetically regulated (by immune response genes), and it is also influenced by environment (eg, nutrition, aging, previous exposure).[19, 20] Although the inciting antigens that breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte antigen (HLA)-DR2 is overrepresented among European and United States patients with aplastic anemia, and its presence is predictive of a better response to cyclosporine.

Suppression of hematopoiesis is likely mediated by an expanded population of CD8+ HLA-DR+, cytotoxic T lymphocytes (CTLs) that are frequently detectable in the blood and bone marrow of patients with aplastic anemia. These cells produce inhibitory cytokines, such as gamma-interferon and tumor necrosis factor, which can suppress progenitor cell growth. Polymorphisms associated with an increased immune response are more prevalent in these cytokine genes in patients with aplastic anemia. These cytokines suppress hematopoiesis by affecting the mitotic cycle and cell killing by inducing Fas-mediated apoptosis.

In addition, such cytokines induce nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and the elimination of hematopoietic cells. Hirano et al reported that CD8+ cytotoxic T cells raised against kinectin-derived peptides suppress colony forming units (CFUs) in an HLA class I–restricted fashion, findings that suggest kinectin may be a candidate autoantigen in the pathophysiology of aplastic anemia.[21]

Constitutive expression of Tbet, a transcriptional regulator that is critical to type 1 T helper cell (Th1) polarization, occurs in a majority of aplastic anemia patients.[15] Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural-killer cells. Mutations in the perforin gene are responsible for some cases of familial hemophagocytosis[22] ; mutations in SAP, a gene encoding for a small modulator protein that inhibits undefined-interferon production, underlie X-linked lymphoproliferation, a fatal illness associated with an aberrant immune response to herpesviruses and aplastic anemia. Perforin and SAP protein levels are markedly diminished in some cases of acquired aplastic anemia.

The transcription factors FOXP3 and NFAT1 have key roles in regulatory T-cell (Treg) development and function, and Tregs play a role in autoimmunity. Tregs are decreased at presentation in almost all patients with aplastic anemia; FOXP3 protein and mRNA levels also are significantly lower in patients with this condition, whereas NFAT1 protein levels are decreased or absent.[23]

Variations in telomere length have been reported in severe aplastic anemia, but their clinical significance is unknown. However, although telomere length was unrelated to response, it was associated with the risk of relapse, clonal evolution, and overall survival in patients with severe aplastic anemia.[24]

Congenital or inherited causes

Congenital or inherited causes of aplastic anemia are responsible for at least 25% of children with this condition and for perhaps up to 10% of adults.[25] Patients may have dysmorphic features or physical stigmata, but marrow failure may be the initial presenting feature. Several loci have been identified that are associated not only with increased susceptibility to aplastic anemia but also with other physical findings.

Fanconi anemia

Fanconi anemia is characterized by the following:

Dyskeratosis congenita

Dyskeratosis congenita is characterized by the diagnostic physical triad of dysplastic nails, lacy reticular pigmentation of the upper torso, and oral leukoplakia. However, over the past decade, it has been increasingly recognized that patients may have dyskeratosis congenita without the triad. The following are also features of this condition:

Familial aplastic anemia

This is an isolated aplastic anemia. Mutations have been found in the TERC and TERT genes and are thought to confer a susceptibility to aplastic anemia. These genes encode proteins that are part of the telomerase apparatus that restores repeated regions in the telomere.[26]

Cartilage-hair hypoplasia

Cartilage-hair hypoplasia, which is caused by mutations in the RMRP gene, is inherited in an autosomal recessive manner. This condition is characterized by the following:

Pearson syndrome

Pearson syndrome causes sideroblastic anemia and exocrine pancreatic dysfunction. This condition results from mitochondrial deoxyribonucleic acid (DNA) deletions.

Thrombocytopenia-absent radius syndrome

Thrombocytopenia-absent radius (TAR) syndrome is characterized by deletions located at chromosome 1q21.1 (which are typically about 200kb in size). Patients have bilateral absence of the radii with presence of the thumbs, as well as thrombocytopenia. Other congenital anomalies can also occur (eg, cardiac disease, skeletal anomalies, urogenital anomalies).

Shwachman-Diamond syndrome

Shwachman-Diamond syndrome is caused by mutations in the SBDS gene and is inherited in an autosomal recessive manner. This disease is characterized by dysfunction of the exocrine pancreas with malabsorption and growth failure, as well as cytopenias of single or multiple lineage. Patients with Shwachman-Diamond syndrome also have an increased risk of MDS and AML.[27]

Dubowitz syndrome

Dubowitz syndrome is caused by an as-yet unknown gene. This condition is characterized by intrauterine growth retardation, extremely short stature, and wizened facial appearance. Patients also have microcephaly and mild developmental delay. Dubowitz syndrome is also associated with eczema, immune deficiency, and aplastic anemia. Malignancy is more common with this disorder, particularly lymphoma and neuroblastoma.

Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is characterized by a normochromic macrocytic anemia that can be isolated, or it can be associated with growth retardation or congenital malformation in the upper limbs, heart, and genitourinary systems. In a small minority of patients, DBA can progress to aplastic anemia. Nine genes have been found to be causative for DBA, and they are inherited in an autosomal dominant manner.[28] Approximately 50% of cases are inherited from a parent, and about 50% result from de novo mutations.

Acquired causes

Acquired causes of aplastic anemia (80%) include the following:

Drugs and elements (eg, chloramphenicol, phenylbutazone, gold) may cause aplasia of the marrow. The immune mechanism does not account for the marrow failure in idiosyncratic drug reactions. In such cases, direct toxicity may occur, perhaps due to genetically determined differences in metabolic detoxification pathways. For example, the null phenotype of certain glutathione transferases is overrepresented among patients with aplastic anemia.

PNH is caused by an acquired genetic defect affecting the PIGA gene and limited to the stem cell compartment. Mutations in the PIGA gene render cells of hematopoietic origin sensitive to increased complement lysis. Approximately one third of patients with aplastic anemia have evidence of PNH at presentation, as detected by means of flow cytometry.[30] Furthermore, patients whose disease responds after immunosuppressive therapy may recover with clonal hematopoiesis and PNH.

Epidemiology

United States statistics

No accurate prospective data are available regarding the incidence of aplastic anemia in the United States. Findings from several retrospective studies usually overlap those from Europe and suggest that the incidence is 0.6-6.1 cases per million population; this rate is largely based on data from retrospective reviews of death registries.

International statistics

The annual incidence of aplastic anemia in Europe, as detailed in large, formal epidemiologic studies, is 2 cases per million population.[31] Aplastic anemia is thought to be more common in Asia than in the West. The incidence was accurately determined to be 4 cases per million population in Bangkok,[32] but based on prospective studies, it may actually be closer to 6 cases per million population in the rural areas of Thailand. This increased incidence may be related to environmental factors, such as increased exposure to toxic chemicals, rather than to genetic factors, because this increase is not observed in people of Asian ancestry who are living in the United States.

Race-, sex-, and age-related demographics

Although no racial predisposition for aplastic anemia is reported in the United States, the prevalence is increased in the Far East. The male-to-female ratio for acquired aplastic anemia is approximately 1:1, although there are data to suggest that a male preponderance may be observed in the Far East.

Although aplastic anemia occurs in all age groups, a small peak in the incidence is observed in childhood because of the inclusion of inherited marrow-failure syndromes. A second peak is observed in people aged 20-25 years.

Prognosis

The outcome of patients with aplastic anemia has substantially improved because of improved supportive care. The natural history of aplastic anemia suggests that a small number of patients may spontaneously recover with supportive care[33] ; however, observational and/or supportive care therapy alone is rarely indicated.

The estimated 10-year survival rate for the typical patient receiving immunosuppression is 68%, compared with 73% for hematopoietic cell transplantation (HCT).[34] However, there is a significantly improved outcome for HCT over time, for matched sibling and alternative donors, and with younger age.[34] In cases of immunosuppression, relapse and late clonal disease are risks.

In a single-institution analysis of 183 patients who received immunosuppressive treatments for severe aplastic anemia, the telomere length of peripheral blood leukocytes was unrelated to treatment response.[24] In a multivariate analysis, however, telomere length was associated with risk of relapse, clonal evolution, and overall survival.[24] Additional studies are needed to validate these findings and to determine how this information might be incorporated into treatment algorithms.

Mortality/morbidity

The major causes of morbidity and mortality from aplastic anemia include infection and bleeding. Patients who undergo HCT have additional issues related to acute and chronic toxicity from the conditioning regimen and graft versus host disease (GVHD), as well as a potential for graft failure.[20, 35, 36, 37, 38, 39] In approximately 25-30% of patients with aplastic anemia, the condition does not respond to immunosuppression. In cases with a treatment response, relapse and late-onset clonal disease, such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and leukemia, are risks—regardless of the treatment response or degree of response.[16, 40, 41, 42, 43]

Kulasekararaj and colleagues reported that the presence of somatic mutations (including ASXL1, DNMT3A, and BCOR) in patients with aplastic anemia for more than 6 months was associated with 40% risk of transformation to MDS. Nearly a fifth of patients with aplastic anemia have mutations in genes typically seen in myeloid malignancies that predicted for later transformation to MDS.[44]

In a Japanese study of 427 patients (16-72 years old) with aplastic anemia who underwent unrelated-donor bone marrow transplantation, outcome was significantly inferior in patients whose donors were 40 years of age or older than in those with younger donors. In the older donor group, overall survival was significantly inferior (adjusted hazard ratio, 1.64), the incidence of fatal infection was significantly higher (13.7% vs. 7.5%), and primary engraftment failure and acute GVHD occurred significantly more often (9.7% vs. 5.0% and 27.1% vs. 19.7%, respectively).[45]

An Australian population-based cohort study of adults receiving allogeneic HCT reported an elevated secondary cancer risk in several patient groups, including those transplanted for severe aplastic anemia. Overall, in patients alive 2 years after transplantation (n=1463), the cumulative incidence of late mortality was 22.2% at 10 years and the risk of death relative to the matched general population was 13.8.[46]

History

The clinical presentation of patients with aplastic anemia includes symptoms related to the decrease in bone marrow production of hematopoietic cells. The onset is insidious, and the initial symptom is frequently related to anemia or bleeding, although fever or infections may be noted at presentation. Specific manifestations include the following:

Most cases of aplastic anemia are idiopathic,[5] and the search for an etiologic agent is often unproductive. Obtain an appropriately detailed work history, with emphasis on solvent exposure, as well as a family, environmental, and infectious disease history.

In the absence of obvious phenotypic features, the presentation of a patient with an inherited marrow-failure syndrome is subtle, and a thorough family history may first suggest the condition, as well as potentially identify rarer inherited marrow-failure syndromes.

With regard to environmental agents, the time course of aplastic anemia and exposure to the offending agent varies greatly, and only rarely is an environmental etiology identified.

Physical Examination

Physical examination may show signs of anemia (eg, pallor, tachycardia) and of thrombocytopenia (eg, petechiae, purpura, ecchymoses). Overt signs of infection are usually not apparent at diagnosis. A subset of patients with aplastic anemia present with jaundice and evidence of clinical hepatitis.[1, 2] Findings of adenopathy or organomegaly should suggest an alternative diagnosis (eg, hepatosplenomegaly and supraclavicular adenopathy are observed more frequently in cases of leukemia and lymphoma than in cases of aplastic anemia).

In any case of suspected aplastic anemia, look for physical stigmata of inherited marrow-failure syndromes, such as the following:

The oral pharynx, hands, and nail beds should be carefully examined for clues of inherited bone marrow-failure syndromes. Oral leukoplakia in dyskeratosis congenita is shown in the image below.



View Image

Oral leukoplakia in dyskeratosis congenita.

Approach Considerations

Aplastic anemia is diagnosed with blood and bone marrow studies. This condition is defined by the finding of a hypoplastic bone marrow that has fatty replacement and that may have relatively increased nonhematopoietic elements, such as mast cells. Careful examination is necessary to exclude metastatic tumor foci on biopsy, as occasionally metastatic tumor deposits may cause pancytopenia. Carefully consider dysplasia to rule out myelodysplastic syndrome (MDS), although some degree of dysplasia may be present in aplastic anemia.

Complete Blood Cell Count and Peripheral Smears

A paucity of platelets, red blood cells (RBCs), granulocytes, monocytes, and reticulocytes is found in patients with aplastic anemia. Mild macrocytosis is occasionally observed. The degree of cytopenia is useful in assessing the severity of aplastic anemia.

A peripheral blood smear may be helpful in distinguishing aplasia from infiltrative disease causes. Teardrop poikilocytes and leukoerythroblastic changes suggest an infiltrative process.

Peripheral Blood Testing

Peripheral blood tests in patients with suspected aplastic anemia may include the following:

Hemoglobin electrophoresis and blood-group testing may show elevated levels of fetal hemoglobin and red cell I antigen, suggesting stress erythropoiesis. These findings are observed in aplastic anemia and in other marrow-failure states and are often proportional to the macrocytosis. A positive Coombs test may point to autoimmune hemolytic anemia.

Although a biochemical profile has limited value in examination of the etiology and differential diagnosis of aplastic anemia, an analysis of kidney function, as well as measurement of transaminase, bilirubin, and lactate dehydrogenase (LDH) levels, can indicate relevant renal or hepatic diseases. Liver function test (LFT) results can indicate hemolysis.

Serologic testing for hepatitis and other viral entities, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human immunodeficiency virus (HIV), may be useful. An autoimmune-disease evaluation for evidence of collagen-vascular disease may be performed.

Aplastic anemia often occurs together with paroxysmal nocturnal hemoglobinuria (PNH).[47] Although the Ham test, or the sucrose hemolysis test, was frequently performed in the past to diagnose PNH, it has been replaced by FACS profiling of phosphatidylinositol glycan class A (PIGA) anchor proteins, such as CD55 and CD59. This study is more accurate than the Ham test for excluding PNH.

FLAER is also a highly sensitive flow cytometry test for PNH that uses whole blood and binds specifically to glycophosphatidylinositol (GPI) anchor proteins in peripheral blood granulocytes.[48, 49] In PNH, mutation of the PIGA anchor proteins results in a lack of the GPI anchors. Thus, the lack of FLAER binding to granulocytes is sufficient for the diagnosis of PNH.[48, 49] The disadvantage of the test is in measuring binding in the absence of adequate granulocytes—such as in severe aplastic anemia when the number of circulating granulocytes is extremely low.

Diepoxybutane incubation is performed to assess chromosomal breakage in Fanconi anemia and is available only in reference laboratories. This test is required even in the absence of phenotypic features of Fanconi anemia, because up to 50% of patients may not have any clinical stigmata.

Histocompatibility testing should be conducted early to identify potential related donors, especially those for young patients. Because the extent of previous transfusion has been shown to significantly affect the outcomes of patients undergoing hematopoietic cell transplantation (HCT) for aplastic anemia, the rapidity with which these data are obtained is crucial.

Hosokawa et al identified three microRNAs that are dysregulated (>1.5-fold change) in acquired aplastic anemia, compared with healthy controls, and could be used in diagnosis: miR-150-5p, miR-146b-5p, and miR-1. Plasma levels of miR-150-5p and miR-146b-5p are elevated in aplastic anemia, whereas levels of miR-1 are decreased. Because miR-150-5p expression decreased significantly after successful immunosuppressive therapy, but did not change in non-responders, these authors propose that miR-150-5p could be used for disease monitoring.[50]

In a study of pediatric patients with very severe aplastic anemia, Fang et al found that the percentage of CD20+ B cells in peripheral blood was higher than that in healthy children (P < 0.01), whereas the percentage of regulatory T cells (Tregs) was lower than that in healthy children (P < 0.001). After treatment, the percentage of CD20+ B cells was decreased, and the percentage of Tregs was significantly increased. The authors suggest CD20+ B cells and Tregs as potential markers for evaluating therapeutic efficacy and prognosis in these cases.[51]

Bone Marrow Aspiration and Biopsy

Bone marrow biopsy is performed in addition to aspiration to assess cellularity qualitatively and quantitatively. In aplastic anemia, the specimens are hypocellular. Aspiration samples alone may appear hypocellular because of technical reasons (eg, dilution with peripheral blood), or they may appear hypercellular because of areas of focal residual hematopoiesis.

By comparison, core biopsy better reveals cellularity. The specimen is considered hypocellular if it is less than 30% cellular in individuals younger than 60 years or if it is less than 20% cellular in those older than 60 years (see the following image). Some dyserythropoiesis with megaloblastosis may be observed in aplastic anemia.



View Image

Low power, H and E showing a hypocellular bone marrow with increased adipose tissue and decreased hematopoietic cells in the marrow space.

Bone marrow culture may be useful in diagnosing mycobacterial and viral infections. However, the yield is generally low. Currently, alternative studies include polymerase chain reaction (PCR) assay, but the value of this technique is unclear in this setting. Leukemia and metastatic cancers may also be diagnosed with bone marrow examination.

Myelodysplastic syndrome

Aplastic anemia must be differentiated from myelodysplastic syndrome (MDS) The bone marrow in patients with aplastic anemia may have hyperplastic pockets, which can sometimes be confused with MDS; moreover, hypoplasia of bone marrow may be present in some cases of MDS.[52] However, in aplastic anemia,  CD34 evaluation always reveals a low count; further, ringed sideroblasts,  myeloblasts, and dysplastic megakaryocytes are never seen in aplastic anemia but are often seen in MDS.

Characteristic bone marrow abnormalities that are often found in MDS include the following:

Myelodysplastic features are usually observed in hematopoietic precursors and progeny. Islands of immature cells or abnormal localization of immature progenitors (ALIP) indicate MDS. Patients with MDS may have megakaryocytic abnormalities (micromegakaryocytes, megakaryocytes with dyskaryorrhexis), greater than 5% ring sideroblasts (observed only on iron stains), and granulocytic abnormalities (pseudo–Pelger-Huët cells, hypogranulation, excess of blasts). On occasion, marrow fibrosis may be observed. Monocytes are similarly hypogranular, and their nuclei may contain nucleoli.

Chromosomal rearrangements are considered diagnostic of MDS, with trisomies of 8 and 21 and deletions of 5, 7, and 20 being the most common. However, the conventional karyotype technique reveals abnormalities in only about 50% of patients with MDS. Additionally, fluorescence in situ hybridization (FISH) may be used to visualize chromosomal abnormalities in interphase cells. Note that in hypoplastic marrows, obtaining sufficient sample for karyotyping is often difficult.

Magnetic Resonance Imaging

Although aplastic anemia is characterized by hypocellularity of bone marrow, a small minority of patients have pockets of hypercellularity, and a bone marrow biopsy may give misleading results if the sample is taken from one of those hypercellular areas. Overall bone marrow cellularity may be assessed by evaluation of magnetic resonance imaging (MRI) scans of the marrow areas of the axial skeleton.

Matcuk et al reported that calculations of bone marrow cellularity based on T1 signal intensity measurements from MRI show statistically significant correlation with determinations of cellularity from bone marrow biopsy. Cellularity increased from T11 to S1 and decreased with patient age.[53]

Staging

Staging of aplastic anemia is based on the criteria of the International Aplastic Anemia Study Group (IAASG).

Severe aplastic anemia (SAA) is defined as marrow cellularity < 25% (or 25–50% with < 30% residual hematopoietic cells), plus at least two of the following peripheral blood findings:

Very severe aplastic anemia (VSAA) is defined as as marrow cellularity < 25% (or 25–50% with < 30% residual hematopoietic cells), plus at least two of the following peripheral blood findings:

 

Approach Considerations

Therapy for aplastic anemia may consist of supportive care only, immunosuppressive therapy, or hematopoietic cell transplantation (HCT). Severe and very severe aplastic anemia (SAA and VSAA, respectively; see Workup) have a mortality rate of greater than 70% with supportive care alone[54] and are therefore a hematologic emergency. Treatment should be instituted promptly for SAA or VSAA, and clinicians must stress the need for patient compliance with therapy.

Inpatient care for patients with aplastic anemia may be needed during periods of infection and for specific therapies, such as antithymocyte globulin (ATG) or HCT. In addition, iron chelation may be required in chronically transfused patients who develop elevated serum ferritin levels above 1000 µg/L.[5]

The British Committee for Standards in Haematology recommends treating infection or uncontrolled bleeding before administering immunosuppressive therapy, including in patients scheduled for HCT.[5] In the presence of severe infection, however, it may be necessary to proceed directly to HCT to provide the patient with the best chance for early neutrophil recovery.[5]  

Both the British Committee for Standards in Haematology and the Pediatric Haemato-Oncology Italian Association recommend HCT from a matched sibling donor for severe aplastic anemia. If a matched donor is not available, options include immunosuppressive therapy or unrelated donor HCT.[6, 7]

Approximately one third of patients with aplastic anemia do not respond to immunosuppression. The thrombopoietin receptor agonist eltrombopag is approved for use in patients with severe aplastic anemia who fail to respond adequately to immunosuppressive therapy. Independent of response or degree of response, risks include relapse and late-onset clonal disease, such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or leukemia.[16, 40, 41, 42, 43]

Pregnant women with aplastic anemia have a 33% risk of relapse.[5] Provide supportive care in these patients, maintain the platelet count above 20 × 109/L, if possible, and consider administering cyclosporine.[5]

Note that monotherapy with hematopoietic growth factors (eg, recombinant human erythropoietin [rHuEPO], granulocyte colony-stimulating factor [G-CSF]) is not recommended for newly diagnosed patients.[5]

Frequent outpatient follow-up for patients with aplastic anemia is needed to monitor blood counts and any adverse effects of various drugs. Transfusions of packed red blood cells (RBCs) and platelets are administered on an outpatient basis.

Transfer considerations

Patients with aplastic anemia should be treated by physicians who are experts in the care of immunocompromised patients and in consultation with a hematologist and/or an HCT physician.

Blood Transfusion

Patients with aplastic anemia require transfusion support until the diagnosis is established and specific therapy can be instituted. The British Committee for Standards in Haematology recommends prophylactic transfusions in patients whose platelet counts fall below 10 × 109/L (or < 20 × 109/L in febrile patients).[5] However, it is important that transfusions be guided by the patient’s clinical status and not by numbers alone. Avoiding transfusions from family members is important because of possible sensitization against non-HLA (human leukocyte antigen) tissue antigens of potential donors.

For patients in whom hematopoietic cell transplantation (HCT) may be attempted, transfusions should be used judiciously because minimally transfused subjects have achieved superior therapeutic outcomes.

If using blood-bank support, attempt to minimize the risk of cytomegalovirus (CMV) infection. The blood products should, if possible, undergo leukocyte reduction to prevent alloimmunization and CMV transmission and should be irradiated to prevent transfusion-associated graft versus host disease (GVHD) in HCT candidates.

The British Committee for Standards in Haematology also recommends irradiated blood products for all patients receiving antithymocyte globulin (ATG) therapy. In patients with life-threatening neutropenic sepsis, the committee suggests consideration of irradiated granulocyte transfusions.[5]

Development of a transfusion plan in consultation with a physician who is experienced in the management of aplastic anemia is essential.

Treatment of Infections

Infections are a major cause of mortality in patients with aplastic anemia.[55, 56] Risk factors include prolonged neutropenia and the indwelling catheters used for specific therapy. Fungal infections, especially those due to Aspergillus species, pose a major risk. Patients should maintain hygiene to reduce infection risk.

The British Committee for Standards in Haematology recommends prophylactic antibiotic and antifungal agents for patients whose neutrophil counts are below 0.2 ×109/L.[5] Empirical antibiotic therapy should be broad based, with gram-negative and staphylococcal coverage based on local microbial sensitivities. Especially consider including antipseudomonal coverage at the start of treatment for patients with febrile neutropenia; also consider early introduction of antifungal agents for individuals with persistent fever.

However, the strategy of empiric antibiotic use has also resulted in the development of resistant organisms and thus is not favored by some clinicians.[57]

Cytokine support with granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) may be considered in refractory infections, although this therapy should be weighed against its cost and efficacy.[9, 58, 59, 60] Discontinue cytokine support after 1 week if the neutrophil count doesn’t rise.[5]

Hematopoietic Cell Transplantation

Central venous catheter placement is required prior to hematopoietic cell transplantation (HCT). Note that the following recommendations do not apply to patients with Fanconi anemia and other types of inherited marrow failure;[5] these patients require special consideration.

HCT using an HLA-matched sibling donor

Human leukocyte antigen (HLA)-matched sibling-donor HCT is the treatment of choice for a young patient with severe or very severe aplastic anemia (SAA or VSAA, respectively), being generally accepted for patients younger than 50 years.[5] Persons undergoing this procedure do not require irradiation-based conditioning regimens.[5]

A study of 692 German patients with SAA who received transplants from HLA-matched siblings, noted that bone-marrow grafts were preferable to peripheral blood progenitor cell (PBPC) grafts in patients younger than 20 years.[61] A multinational study of patients with SAA who received HCT from an HLA-matched sibling donor concluded that although bone marrow should definitely be the preferred graft source for these patients, PBPCs may be an acceptable alternative in countries with limited resources where patients present later in their disease course and risks of graft failure and infective complications are high.[62]

Although evidence suggests that stem cells from bone marrow afford better outcomes compared with PBPCs, an additional consideration is the perspective of the donor, who must be informed of the difference between the methods of harvesting. Bone marrow harvesting is usually performed with the donor under general anesthesia, while with PBPC harvesting the donor is awake and connected via large-bore intravenous catheters to an apheresis machine, which separates out the stem cells (for descriptions of the two methods, see Bone Marrow Donor Procedure).

Along with the risks associated with anesthesia, bone marrow donors typically experience moderate pain for several days following the procedure. PBPC donors usually experience bone pain, which may be severe, from the filgrastim-induced bone marrow stimulation used to mobilize stem cells in advance of the procedure.

One of the major problems of HCT in aplastic anemia is the high rate of rejection (10%; range, 5-50%). This is positively correlated with the number of transfusions the patient received and the duration of his or her disease, prior to transplantation.

Previously, a higher stem cell dose, as well as the addition of total body irradiation to cyclophosphamide conditioning, was tried. Although it was associated with a reduced incidence of graft rejection, the benefit was negated by high transplant-related mortality (TRM) due to an increase in graft versus host disease (GVHD).

Currently, antithymocyte globulin (ATG) with cyclophosphamide is a commonly used conditioning regimen for transplantations in aplastic anemia. The addition of ATG to cyclophosphamide for conditioning has resulted in infrequent graft rejections, as well as improved overall survival.[18, 58, 59, 63]

Fludarabine- and cyclophosphamide-based reduced-intensity conditioning (RIC) regimens with or without ATG reduced rejection and improved outcome in Indian patients undergoing allogeneic HCT for SAA.[64] When compared with 26 patients previously transplanted using cyclophosphamide/antilymphocyte globulin, there was faster neutrophil engraftment (12 vs 16 days, respectively), with significantly lower rejection rates (2.9% vs 30.7%, respectively), and superior event-free (82.8% vs 38.4%, respectively) and overall (82.8% vs 46.1%, respectively) survival rates.[64]

Standard conditioning regimens use a cyclophosphamide dose of 200 mg/kg, which is known to be associated with significant organ toxicity. In a multicenter phase 1-2 study of adult patients with SAA receiving bone marrow grafts from unrelated donors, Anderlini et al found that a regimen of cyclophosphamide in doses of 50 or 100 mg/kg, combined with TBI 2 Gy, fludarabine, and ATG, provided effective conditioning and few early deaths.[65]

The occurrence of GVHD as a complication of HCT is positively correlated with increasing age of the patient. Grafts depleted of T cells reduce the risk of GVHD but increase the risk of graft failure. The addition of cyclosporine along with methotrexate is the standard GVHD approach for matched siblings.[63] However, very few comparative data exist, and no data have reported an alternative approach to be superior to this regimen.

Although horse ATG is better than rabbit ATG as an immunosuppressive therapy, a multinational study that included 546 HLA-matched sibling HCT transplants for severe aplastic anemia, 3-year overall survival rates were not significantly different with rabbit versus horse ATG used as part of the conditioning regimen. However, the day-100 incidences of both acute and chronic GVHD were higher with horse than with rabbit ATG (acute GHVD, 17% versus 6%, respectively, p< 0.001; chronic GVHD, 20% versus 9%, p< 0.001). The authors concluded that these support the use of rabbit ATG for bone marrow conditioning.[66]

Early referral to a transplantation center at diagnosis is recommended for all young patients, even if they lack a suitable related donor, because transplant planning needs to be done even if patients are receiving immunosuppressive therapy due to a significant number of failures.[19]

Fertility

Patients receiving high-dose cyclophosphamide conditioning in allogeneic HCT from an HLA-identical sibling donor for aplastic anemia have relatively well-preserved fertility.[5] Provide these patients with appropriate contraceptive advice to prevent unintended pregnancies.

Longer-term data are limited for patients with fludarabine-based regimens. Therefore, discussions related to potential fertility preservation, including cryopreservation of sperm and oocytes/embryos, is recommended.[5] Cyclosporine is safe for use in pregnancy.

HCT using an unrelated donor

Unrelated-donor HCT is currently justified only if the donor is a full match and only if immunosuppressive therapy fails (failure of ≥1 course of ATG and CSA) or treatment as part of a clinical trial fails.[5]

High-resolution allelic matching, however, has improved outcomes in unrelated-donor HCT, especially in younger patients. Maury et al found that results for young patients who are fully HLA matched at the allelic level with their donor are comparable to those observed after stem cell transplantation from a related donor.[67]

GVHD

In the first cohorts transplanted, HCT using an unrelated donor was associated with very high mortality due to high rates of graft failure, infection, and GVHD. This poor outcome resulted primarily from the use of less stringent HLA matching in addition to the fact that these first patients had long-term disease, a history of infection, iron overload, transfusion resistance, and other related factors. However, more recent reports suggest a better outcome after unrelated transplants, an improvement that is due mainly to high-resolution HLA testing, optimization of the conditioning regimen, better supportive care, and better management of GVHD.

A retrospective study of comparative data from Japan indicated similar overall survival in children and young adults with aplastic anemia who received transplants from either a sibling or an unrelated donor, although rates of acute and chronic GVHD were significantly higher in the group receiving unrelated transplants.[68]

Due to the rates of GVHD in unrelated donor transplantation, this procedure is not preferred over immunosuppressive therapy.[36]

Partial T-cell depletion may decrease the risk of severe GVHD while still maintaining sufficient donor T lymphocytes to ensure engraftment.[36]

In a multinational study that included 287 patients with severe aplastic anemia who received ATG as part of their conditioning regimen for unrelated-donor HCT, rabbit ATG resulted in a lower incidence of acute (but not chronic) GVHD and better survival (3-year overall survival, 83% for rabbit ATG versus 75% for horse ATG P=0.02). The authors concluded that these data support the use of rabbit ATG in this setting.[66]

Graft failure

In a study that evaluated data for unrelated matched HCT versus mismatched transplants, the probability of graft failure at 100 days after using a 1-antigen mismatched, related donor was 21%, whereas the probability was 25% for a greater-than-1-antigen mismatched, related donor; 15% for a matched, unrelated donor; and 18% for a mismatched, unrelated donor.[19]

Pharmacotherapeutic regimens in HCT

In unrelated-donor transplantation, radiation, along with cyclophosphamide, may be used to reduce graft rejection. Fludarabine-based conditioning regimens have been studied,[37] along with ATG and cyclophosphamide.

It should be noted, however that early results from a cyclophosphamide deescalation study in a fludarabine-based conditioning regimen for unrelated donor HCT demonstrated life-threatening adverse events (excessive organ toxicity) at predefined cyclophosphamide dose levels.[69] The investigators reported an association between such toxicity and cyclophosphamide 150 mg/kg plus total body irradiation at 2 Gy, fludarabine at 120 mg/m2, and ATG.[69]

Although the optimal regimen for unrelated-donor HCT remains unclear, the British Committee for Standards in Haematology indicates that a non–irradiation-based fludarabine regimen appears to be favored for younger patients.[5]

According to a study by Samarasinghe et al, a conditioning regimen with fludarabine, cyclophosphamide, and alemtuzumab with matched unrelated-donor (MUD) HCT appears to be very well-suited in children with severe aplastic anemia and has excellent outcomes.[70] The investigators suggested that MUD HCT may be a reasonable alternative when immunosuppressive therapy fails.[70]

Hamad and colleagues reported on HCT using a conditioning regimen with intermediate-dose alemtuzumab (50 to 60 mg) and high-dose cyclophosphamide or fludarabine in 41 adult patients with aplastic anemia, and reported excellent survival with a favorable impact on GVHD and long-term health outcomes, but frequent viral complications. At 3 years, survival was 96% in patients younger than 40 years of age and 67% in those 40 years and older.[71]

Haploidentical HCT

A pilot study by Clay and colleagues in the United Kingdom reported successful use of nonmyeloablative peripheral blood haploidentical stem cell transplantation as rescue therapy. The study included eight patients with refractory severe aplastic anemia who lacked a matched sibling or unrelated donor or who had failed unrelated-donor or umbilical cord blood transplant.[72]

Six of the eight patients engrafted; graft failure occurred in patients with donor-directed HLA antibodies, although they had undergone intensive desensitization with plasma exchange and rituximab.The European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party will be evaluating this protocol in a future observational study[72]

Umbilical Cord Blood Transplantation

Umbilical cord blood transplantation (CBT) is not yet recommended as first- or second-line therapy for aplastic anemia. This treatment should be used as experimental therapy for patients who do not have a human leukocyte antigen (HLA)–matched donor and who have 1-2 courses of failed immunosuppressive therapy, and it should be evaluated only through prospective clinical trials.[73] Controlled trials are needed to better define the role and timing of CBT in aplastic anemia.[74, 75, 76]

Immunosuppressive Therapy

Immunosuppressive therapy using antithymocyte globulin (ATG) and cyclosporine is associated with an overall response rate of 60-80% and a 5-year survival rate of 75% in most reports, but event-free survival rates are in the range of 35-50%.

Immunosuppressive therapy using ATG plus cyclosporine is being administered as first-line therapy[77] for patients with severe or very severe aplastic anemia (SAA or VSAA, respectively) who are older than 50 years (35-50 years in presence of comorbidities) and as second-line therapy in younger patients with SAA or VSAA if a human leukocyte antigen (HLA)–matched sibling donor is not available. Immunosuppressive therapy is also recommended in patients with nonsevere aplastic anemia who are transfusion dependent.[5]

Central venous catheter placement may be required before the administration of immunosuppressive therapy, and patients with these catheters should be treated as inpatients. Patients may require blood product support during ATG therapy, as well as close monitoring for allergic or anaphylactic signs and symptoms and for prophylaxis and treatment of fevers.[5]

ATG and cyclosporine

Scheinberg et al reported that a large difference was observed in patients with aplastic anemia in the rate of hematologic response at 6 months in favor of horse ATG (68%), as compared with rabbit ATG (37%).[78] Overall survival at 3 years also differed, with a survival rate of 96% in the horse-ATG group, compared with 76% in the rabbit-ATG group when data were censored at the time of stem-cell transplantation, and 94% versus 70% in the respective groups when stem-cell–transplantation events were not censored.[78]

A review by Risitano also demonstrated that immunosuppression with rabbit ATG, as well as cyclophosphamide and alemtuzumab, in patients with aplastic anemia or immune-mediated bone marrow failure syndromes had an inferior outcome relative to horse ATG.[79] Therefore, rabbit ATG, cyclophosphamide, and alemtuzumab are not recommended as first-line therapy in these patients.[79]

In other studies of ATG, responses have been defined as complete responses (CRs) when all blood counts return to normal, and as partial responses (PRs) when there is an improvement in blood counts with transfusion independence. In these analyses, response to ATG is slow, usually taking 10-12 weeks for a response to occur; and the response may also continue to improve or occur later. If the patient has not responded to a first course of ATG, then a second course may be given, using either the same preparation or another one. Approximately 30-60% of patients may respond to a second course of ATG.[80, 81, 82, 83, 84, 85, 86]

In one study, response rates to cyclosporine alone were 45% overall, 16% for VSSA, 47% for SAA, and 85% for moderate aplastic anemia.[87] Therefore, the only predictor of response to cyclosporine was an absolute neutrophil count (ANC) of less than 200/mm3. Adding granulocyte colony-stimulating factor (G-CSF) to ATG and cyclosporine in patients with an ANC of over 200/mm3 does not provide any additional advantage in reducing the infection rate or in increasing survival or therapeutic responses.

A meta-analysis by Hayakawa et al of 13 studies comparing horse ATG with rabbit ATG for immunosuppressive therapy in severe aplastic anemia concluded that horse ATG results in a higher respnse rate (p=0.015); further, a sensitivity analysis showed that there was higher early mortality with rabbit ATG.[88] Hence, horse ATG is the preferred choice in this setting.

Time to response and relapse

The treatment response in aplastic anemia, unlike in other autoimmune diseases, is slow. At least 4-12 weeks is usually needed to observe early improvement, and the patient may continue to improve slowly thereafter. About 50% of patients respond by 3 months after ATG administration, and about 75% respond by 6 months. Most patients improve and become transfusion independent, but many still have evidence of hypoproliferative bone marrow.

Although the initial response rate is good, durable responses with no relapse or clonal evolution are observed in 50% of the patients.[89] To reduce the risk of relapse, continue cyclosporine for a minimum of 12 months after achieving maximal hematologic response, with a very slow tapering thereafter.[5] Approximately one third of patients have a relapse, most of whom have a relapse at the time of cyclosporine taper. About one third of responders are cyclosporine dependent. Of patients without a response or who relapse, 40-50% respond to a second course of immunosuppressive therapy.

In rare cases, full hematologic recovery is observed, but most patients improve to a functional hematologic recovery that obviates further transfusion support. Furthermore, the risk of some form of clonal disease other than paroxysmal nocturnal hemoglobinuria (PNH) is 15-30% and may be due to the inability of these therapies to completely correct bone marrow function, a missed diagnosis of myelodysplastic syndrome (MDS), or the fact that the stem cells under proliferative stress may be more prone than other cells to mutation.

Investigational immunosuppressive therapy

At present, the use of high-dose cyclophosphamide should be limited to clinical trials.[89] Preliminary data have suggested that high-dose cyclophosphamide may result in durable remissions in some patients with aplastic anemia. However, some of these patients develop PNH and cytogenetic abnormalities on follow-up. When investigators conducted a prospective, randomized study based on the above preliminary report by using cyclophosphamide versus ATG plus CSA, the study was terminated early because of very high mortality and fungal infections in the cyclophosphamide arm.[90, 91]

Up to 50% of patients with aplastic anemia demonstrate small PNH clones in the absence of evidence of hemolysis.[5] In patients with a history of PNH-associated thrombosis, use of ATG is not recommended. In addition, because abnormal cytogenetic clones can occur in up to 12% of patients with aplastic anemia, the presence of some clones in otherwise typical cases of aplastic anemia does not necessarily signify a diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).[5] However, an exception is when the monosomy 7 clone is present, in which case there is a high risk of transformation to MDS or AML.[5]

Other promising investigational immunosuppressive therapies include alemtuzumab (monoclonal anti-CD52 antibody). However, daclizumab (monoclonal anti-CD25 antibody) was withdrawn from the market due to toxicity. Mycophenolate mofetil and sirolimus have also been used but did not result in treatment responses.

Except in the setting of prospective clinical trials, hematopoietic growth factors (eg, recombinant human erythropoietin [rHuEPO], granulocyte colony-stimulating factor [G-CSF]) is not recommended for routine long-term use following ATG and CSA therapy.[5]

Eltrombopag

In patients with aplastic anemia that is refractory to immunosuppressive therapy (IST), treatment with eltrombopag (Promacta) may be considered. Eltrombopag, a thrombopoietin receptor agonist, was approved in August 2014 for severe aplastic anemia in patients who fail to respond adequately to at least one prior IST regimen. Approval was supported by a phase II study in which 41% of patients experienced a hematologic response in at least one lineage (ie, platelets, red blood cells, neutrophils) after 12 weeks of treatment with eltrombopag.[92, 93]

In the extension phase of the study, three patients achieved a multi-lineage response. Four of those patients subsequently tapered off treatment and maintained the response (median followup 8.1 months, range 7.2-10.6 months).[92, 93]

Eltrombopag has also shown benefit as first-line therapy. Townsley et al combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia, using three different regimens. The best response was noted in patients receiving eltrombopag from day 1 to 6 months, along with horse ATG on days 1 to 4 and daily cyclosporine from day 1 to 6 months. In this cohort, at 6 months, complete responses were seen in 58% of patients and hematologic responses in 94%. This compared with 10% and 66% rates, respectively, observed in a historical cohort treated with IST alone. In addition, the improved blood counts were accompanied by increased marrow cellularity and hematopoietic progenitor numbers.[94]

Geng et al reported on upfront use of eltrombopag in two pediatric patients with non-severe aplastic anemia. Both patients achieved hematologic response with eltrombopag monotherapy.[95]

In November 2018, the FDA expanded approval for eltrombopag to include use as first-line therapy, in combination with standard IST, for adult and pediatric patients 2 years and older with severe aplastic anemia.[96]

Diet and Activity

The diet for the patient with aplastic anemia who has neutropenia or who is receiving immunosuppressive therapy should be tailored carefully to exclude raw meats, dairy products, or fruits and vegetables that are likely to be colonized by bacteria, fungus, or molds. Furthermore, a salt-limited diet is recommended during therapy with steroids or cyclosporin-A (CSA).

The patient should avoid any activity that increases the risk of trauma during periods of thrombocytopenia. Menstruating women are also advised to be on hormonal pills to avoid menstrual cycles that are likely to be heavy due to thrombocytopenia.

Inform patients of the increased risk of community-acquired infections during periods of neutropenia and lymphopenia. Patients should maintain hygiene to reduce the risks of infection.

Medication Summary

The goals of pharmacotherapy in cases of aplastic anemia are to reduce morbidity and prevent complications.

Options in immunosuppressive treatment include combination therapy, including antithymocyte globulin (ATG), cyclosporine, and methylprednisolone, with or without cytokine support. ATG or cyclosporine alone may also produce a response in aplastic anemia, but the combination improves the likelihood of a response. Nevertheless, a prospective study from India concluded that for resource-poor patients, cyclosporine monotherapy, in a dosage of 5 mg/kg/day, is a relatively safe treatment option for aplastic anemia.[97]

Hematopoietic support with eltrombopag, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) may be considered in refractory infections, although cost and efficacy of this therapy should be weighed.[9, 58, 59, 60, 92, 93]

Cyclosporine (Sandimmune, Neoral)

Clinical Context:  Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, graft versus host disease) for a variety of organs.

For children and adults, base the initial dosing on the ideal body weight and subsequently adjust for levels. Frequent monitoring of drug levels is needed. To convert to the oral dose, use an intravenous (IV)-to-oral correction factor of 1:4. The dosage and duration of therapy may vary with different protocols. When used without hematopoietic growth factor in children, ATG and cyclosporine-based immunosuppressive therapy has been shown to lead to an excellent response and survival rate with low incidence of clonal evolution.

Methylprednisolone (Medrol, Solu-Medrol)

Clinical Context:  Steroids ameliorate the delayed effects of anaphylactoid reactions and may limit biphasic anaphylaxis. In severe serum sickness (mediated by immune complexes), parenteral steroids may reduce the inflammatory effects. Hence, methylprednisolone is used with antithymocyte globulin (ATG) to decrease the adverse effects (eg, allergic reactions, serum sickness). Also, this agent has an additional immunosuppressive effect. High doses or long duration may be needed if serum sickness occurs with ATG. The doses and duration may vary with different protocols.

Alemtuzumab (Campath, MabCampath)

Clinical Context:  Alemtuzumab is a recombinant monoclonal antibody against CD52 (lymphocyte antigen). This agent promotes antibody-dependent lysis.

Lymphocyte immune globulin, equine (Atgam)

Clinical Context:  Lymphocyte immune globulin inhibits the cell-mediated immune response by altering T-cell function or by eliminating antigen-reactive cells. There is little prospective, randomized data to suggest a single schedule that is superior, but experience suggests that a 4- to 5-day infusion is associated with less toxicity than older 7- to 10-day schedules.

Cyclophosphamide (Cytoxan)

Clinical Context:  Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of deoxyribonucleic acid (DNA), which may interfere with the growth of normal and neoplastic cells. Monitor carefully; used only on an investigational basis.

Antithymocyte globulin, rabbit (Thymoglobulin)

Clinical Context:  Antithymocyte globulin (ATG) may modify T-cell function. The dose and duration of therapy vary with the investigational protocols.

Class Summary

The merits of additional immunosuppression versus the increased risk and cost should be considered. Data from a randomized, prospective study indicated that an increased proportion of patients responded to the addition of CSA to ATG but that this did not translate into a long-term survival advantage.[98] That is, failure-free survival is better with CSA, but long-term overall survival was similar between CSA and ATG.

For patients who cannot tolerate equine-based products, use of the commercially available, rabbit-based ATG product (Thymoglobulin) may be considered. This product is currently approved in the United States and has been used for the treatment of aplastic anemia in Europe (although note the different dose schedule).

Eltrombopag (Promacta)

Clinical Context:  Eltrombopag is a thrombopoietin (TPO)-receptor agonist that interacts with human TPO receptor transmembrane domain of human TPO-receptor. It initiates signaling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. It is indicated for severe aplastic anemia in patients who fail to respond adequately to at least 1 prior immunosuppressive therapy.

Sargramostim (Leukine)

Clinical Context:  A recombinant human GM-CSF, sargramostim can stimulate production of neutrophils and activate mature granulocytes and macrophages. The dose and frequency of administration vary with the investigational protocol.

Filgrastim (Neupogen)

Clinical Context:  Filgrastim is a G-CSF that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils.

Class Summary

Eltrombopag has gained FDA approval for severe aplastic anemia and may be considered in patients who fail immunosuppressive therapy. Several preliminary studies have demonstrated that the addition of cytokines (eg, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) may hasten the neutrophil recovery and that these agents may improve response rate and survival, although long-term use may increase the risk of clonal evolution.

Fludarabine (Fludara)

Clinical Context:  Fludarabine contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-b-D-arabinofuranosyladenine (ara-A) that enters the cell and is phosphorylated to form the active metabolite 2-fluoro-ara-adenosine triphosphate, which inhibits deoxyribonucleic acid (DNA) synthesis. Specifically, this agent inhibits DNA polymerase, DNA primase, DNA ligase, and ribonucleotide reductase, as well as ribonucleic acid (RNA) function, RNA processing, and mRNA translation. Fludarabine also activates apoptosis.

Class Summary

Antimetabolites are antineoplastic agent that inhibit cell growth and proliferation.

Deferoxamine (Desferal)

Clinical Context:  Deferoxamine chelates iron by forming a stable complex that prevents the iron from entering into further chemical reactions; it also chelates iron readily from ferritin and hemosiderin but not readily from transferrin. Desferoxamine does not combine with the iron from cytochromes and hemoglobin. The chelate is readily soluble and is renally excreted.

Deferasirox (Exjade)

Clinical Context:  Deferasirox chelates trivalent iron. This agent is used to treat chronic iron overload due to blood transfusions. Monitor patients' renal and hepatic function.

Class Summary

Chelating agents eliminate iron overload from transfusions.

What is aplastic anemia?What is the clinical presentation of aplastic anemia?What are the signs and symptoms of aplastic anemia?Which lab tests are performed in the evaluation of suspected aplastic anemia?Which procedures are performed in the evaluation of suspected aplastic anemia?What are the treatment options for aplastic anemia?Which medications are used in the treatment of aplastic anemia?What is included in the nonpharmacologic management of aplastic anemia?When is surgical care indicated in the treatment of aplastic anemia?What is the origin of aplastic anemia?Which organizations have issued guidelines on the diagnosis and management of aplastic anemia?Where can more information be found about aplastic anemia?What are the characteristics of Fanconi anemia?What percentage of aplastic anemia is acquired?What is the role of hematopoietic progenitors in the pathogenesis of plastic anemia?What is the central mechanism in the pathogenesis of aplastic anemia?What is needed for successful hematopoietic cell transplantation (HCT) in severe aplastic anemia?What is the role of immune dysfunction in the pathogenesis of aplastic anemia?What is the role of cytokines in the etiology of aplastic anemia?What is the role of protein expression in the etiology of aplastic anemia?Which transcription factors are involved in the etiology of aplastic anemia?What is the role of telomeres in the etiology of aplastic anemia?What is characteristic of congenital or inherited causes of aplastic anemia?What are features of dyskeratosis congenital-caused aplastic anemia?What causes familial aplastic anemia?What are the characteristics of cartilage-hair hypoplasia-caused aplastic anemia?What are the characteristics of Pearson syndrome-caused aplastic anemia?What are characteristics of thrombocytopenia-absent radius (TAR)-caused aplastic anemia?What are characteristics of Shwachman-Diamond syndrome-caused aplastic anemia?What are characteristics of Dubowitz syndrome-caused aplastic anemia?What are characteristics of Diamond-Blackfan anemia (DBA)?What are acquired causes of aplastic anemia?How do drugs and elements cause aplastic anemia?How does paroxysmal nocturnal hemoglobinuria (PNH) cause aplastic anemia?What is the incidence of aplastic anemia in the US?What is the global incidence of aplastic anemia?What are the racial predilections of aplastic anemia?How does the incidence of aplastic anemia vary among males and females?How does the incidence of aplastic anemia vary by age?What is the prognosis of aplastic anemia?What are the survival rates for aplastic anemia following treatment?What are the major causes of morbidity and mortality for aplastic anemia?Which factors increase the risk of myelodysplastic syndromes (MDS) in patients with aplastic anemia?How does donor age affect the survival rates following bone marrow transplantation for aplastic anemia?What effect does hematopoietic cell transplantation (HCT) have on the prognosis of aplastic anemia?What are the signs and symptoms of aplastic anemia?What is necessary to identify the etiologic agent for aplastic anemia?Which physical findings suggest aplastic anemia?What is the physical stigmata of inherited marrow-failure syndromes that may indicate aplastic anemia?Which conditions are most commonly included in the differential diagnosis of aplastic anemia?What are the differential diagnoses for Aplastic Anemia?How is aplastic anemia diagnosed?Which CBC count findings suggest aplastic anemia?What is the role of peripheral blood smear in the diagnosis of aplastic anemia?What is the role of peripheral blood tests in the diagnosis of aplastic anemia?What results of hemoglobin electrophoresis and blood-group testing suggest aplastic anemia?What is the role of serologic testing in the diagnosis of aplastic anemia?How is the Ham test used to diagnose aplastic anemia?How is paroxysmal nocturnal hemoglobinuria (PNH) differentiated from aplastic anemia?What is the role of diepoxybutane incubation in the diagnosis of aplastic anemia?What is the role of histocompatibility testing in the diagnosis of aplastic anemia?What is the role of microRNAs in the diagnosis of aplastic anemia?What is the role of bone marrow aspiration and biopsy in the diagnosis of aplastic anemia?What is the role of bone marrow culture for the diagnosis of aplastic anemia?How is aplastic anemia differentiated from myelodysplastic syndrome (MDS)?How do bone marrow abnormalities found in myelodysplastic syndrome (MDS) differ from those found in aplastic anemia?How do chromosomal abnormalities found in myelodysplastic syndrome (MDS) differ from aplastic anemia?What is the role of MRI in the diagnosis of aplastic anemia?Which criteria are used to stage aplastic anemia?How is severe aplastic anemia (SAA) defined?How is very severe aplastic anemia (VSAA) defined?What are the treatment options for severe aplastic anemia (SAA) and very severe aplastic anemia (VSAA)?When is inpatient care indicated for aplastic anemia?What are the British Committee for Standards in Haematology treatment recommendations for aplastic anemia?What is the efficacy of immunosuppressive drugs for the treatments for aplastic anemia?How are pregnant women with aplastic anemia treated?In which patient group is monotherapy with hematopoietic growth factors not recommended for the treatment of aplastic anemia?Why is frequent outpatient follow-up needed for patients with aplastic anemia?Which specialists should be responsible for treating patients with aplastic anemia?What are the British Committee for Standards in Haematology recommendations for blood transfusions to treat aplastic anemia?When is the use of irradiated blood products recommended by the British Committee for Standards in Haematology for the treatment of aplastic anemia?What is the importance of a transfusion plan in the treatment of aplastic anemia?What are the risk factors for infections in patients with aplastic anemia?What are the British Committee for Standards in Haematology guidelines for use of prophylactic antibiotic and antifungal agents in the management of aplastic anemia?What is the role of cytokine support in the treatment of aplastic anemia?When is central venous placement indicated in the treatment of aplastic anemia?What is the treatment of choice for a young patient with severe or very severe aplastic anemia (SAA or VSAA)?What is the difference between bone marrow and peripheral blood progenitor cell (PBPC) harvesting for the treatment of aplastic anemia?How is the pain associated with bone marrow donation characterized?What is a major limitation of hematopoietic cell transplantation (HCT) for treatment of aplastic anemia?What is a commonly used conditioning regimen for transplantations in aplastic anemia?What effect do reduced-intensity conditioning (RIC) regimens have on outcomes in severe aplastic anemia (SAA)?What drugs are used in standard conditioning regimens for transplantation in aplastic anemia?What increases the risk of graft versus host disease (GVHD) following hematopoietic cell transplantation (HCT) for aplastic anemia?What are the differences between horse antithymocyte globulin (ATG) and rabbit antithymocyte globulin (ATG) for immunosuppressive therapy in aplastic anemia?What is the benefit of early referral to a transplantation center following diagnosis of aplastic anemia?How is fertility affected by high-dose cyclophosphamide conditioning in patients with aplastic anemia?When is unrelated-donor hematopoietic cell transplantation (HCT) indicated for aplastic anemia?What has improved outcomes in unrelated-donor hematopoietic cell transplantation (HCT) for aplastic anemia?How likely is graft versus host disease (GVHD) following hematopoietic cell transplantation (HCT) for the treatment of aplastic anemia?What can decrease the risk of severe graft versus host disease (GVHD) following hematopoietic cell transplantation (HCT) for aplastic anemia?How do outcomes compare between horse antithymocyte globulin (ATG) and rabbit antithymocyte globulin (ATG) for conditioning in patients with aplastic anemia?What is the likelihood of graft failure for unrelated matched hematopoietic cell transplantation (HCT) versus mismatched transplants for the treatment of aplastic anemia?What can reduce the risk of graft rejection in unrelated donor transplantation for aplastic anemia?What is the optimal regimen for unrelated-donor hematopoietic cell transplantation (HCT) for aplastic anemia?Which conditioning regimens have shown good results in aplastic anemia (SAA)?What is a rescue therapy option for aplastic anemia?What is the role of umbilical cord blood transplantation (CBT) for the treatment of aplastic anemia?What are the response and survival rates for aplastic anemia treated with immunosuppressive therapy (IST)?Which immunosuppressive therapy (IST) is administered as first-line therapy in patients with severe or very severe aplastic anemia (SAA or VSAA)?What is the role of central venous catheter placement for immunosuppressive therapy (IST) for aplastic anemia?What is the difference in response to horse or rabbit antithymocyte globulin (ATG) in immunosuppressive therapy (IST) for aplastic anemia?How is complete responses (CRs) and partial responses (PRs) to immunosuppressive therapy (IST) defined for aplastic anemia?What is the preferred choice of immunosuppressive therapy (IST) for aplastic anemia?What is the treatment response in aplastic anemia?What is the treatment outcome in most cases of aplastic anemia?What is the role of high-dose cyclophosphamide in the management of aplastic anemia?What is the relationship between paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia?What immunosuppressive therapies (ISTs) are being investigated for aplastic anemia?What is the role of eltrombopag in the treatment of aplastic anemia?What are the dietary recommendations for patients with aplastic anemia?What are the activity recommendations for patients with aplastic anemia?When is the likelihood of infections increased in patients with aplastic anemia?What are the goals of drug treatment in patients with aplastic anemia?What are the treatment options for aplastic anemia?Which medications in the drug class Chelators are used in the treatment of Aplastic Anemia?Which medications in the drug class Antineoplastic Agent, Antimetabolite (purine) are used in the treatment of Aplastic Anemia?Which medications in the drug class Hematopoietic Growth Factors are used in the treatment of Aplastic Anemia?Which medications in the drug class Immunosuppressive Agents are used in the treatment of Aplastic Anemia?

Author

Sameer Bakhshi, MD, Additional Professor of Pediatric Oncology, Department of Medical Oncology, Dr BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, India

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Acknowledgements

Esteban Abella, MD Consulting Staff, Arizona Pediatric Hematology/Oncology, PLLC

Disclosure: Nothing to disclose.

David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Roy Baynes, MB, BCh, PhD, FACP Charles Martin Professor of Cancer Research, Department of Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References

  1. Breakey VR, Meyn S, Ng V, Allen C, Dokal I, Lansdorp PM, et al. Hepatitis-associated aplastic anemia presenting as a familial bone marrow failure syndrome. J Pediatr Hematol Oncol. 2009 Nov. 31(11):884-7. [View Abstract]
  2. Gonzalez-Casas R, Garcia-Buey L, Jones EA, Gisbert JP, Moreno-Otero R. Systematic review: hepatitis-associated aplastic anaemia--a syndrome associated with abnormal immunological function. Aliment Pharmacol Ther. 2009 Sep 1. 30(5):436-43. [View Abstract]
  3. Miano M, Dufour C. The diagnosis and treatment of aplastic anemia: a review. Int J Hematol. 2015 Jun. 101 (6):527-35. [View Abstract]
  4. McCormack PL. Eltrombopag: a review of its use in patients with severe aplastic anaemia. Drugs. 2015 Apr. 75 (5):525-31. [View Abstract]
  5. [Guideline] Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016 Jan. 172 (2):187-207. [View Abstract]
  6. [Guideline] Samarasinghe S, Veys P, Vora A, Wynn R. Paediatric amendment to adult BSH Guidelines for aplastic anaemia. Br J Haematol. 2018 Jan. 180 (2):201-205. [View Abstract]
  7. [Guideline] Barone A, Lucarelli A, Onofrillo D, Verzegnassi F, Bonanomi S, et al. Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP). Blood Cells Mol Dis. 2015 Jun. 55 (1):40-7. [View Abstract]
  8. Wu Y, Yu J, Zhang L, Luo Q, Xiao JW, Liu XM, et al. [Hematopoiesis support of mesenchymal stem cells in children with aplastic anemia]. Zhongguo Dang Dai Er Ke Za Zhi. 2008 Aug. 10(4):455-9. [View Abstract]
  9. Scopes J, Daly S, Atkinson R, Ball SE, Gordon-Smith EC, Gibson FM. Aplastic anemia: evidence for dysfunctional bone marrow progenitor cells and the corrective effect of granulocyte colony-stimulating factor in vitro. Blood. 1996 Apr 15. 87(8):3179-85. [View Abstract]
  10. Young NS. Pathophysiologic mechanisms in acquired aplastic anemia. Hematology Am Soc Hematol Educ Program. 2006. 72-7. [View Abstract]
  11. Luzzatto L, Risitano AM. Advances in understanding the pathogenesis of acquired aplastic anaemia. Br J Haematol. 2018 Jul 5. [View Abstract]
  12. Liu H, Mihara K, Kimura A, Tanaka K, Kamada N. Induction of apoptosis in CD34+ cells by sera from patients with aplastic anemia. Hiroshima J Med Sci. 1999 Jun. 48(2):57-63. [View Abstract]
  13. Marsh JC. Long-term bone marrow cultures in aplastic anaemia. Eur J Haematol Suppl. 1996. 60:75-9. [View Abstract]
  14. Marsh JC, Chang J, Testa NG, Hows JM, Dexter TM. The hematopoietic defect in aplastic anemia assessed by long-term marrow culture. Blood. 1990 Nov 1. 76(9):1748-57. [View Abstract]
  15. Solomou EE, Keyvanfar K, Young NS. T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood. 2006 May 15. 107(10):3983-91. [View Abstract]
  16. Socié G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Late clonal diseases of treated aplastic anemia. Semin Hematol. 2000 Jan. 37(1):91-101. [View Abstract]
  17. Nakao S. Immune mechanism of aplastic anemia. Int J Hematol. 1997 Aug. 66(2):127-34. [View Abstract]
  18. Frickhofen N, Kaltwasser JP, Schrezenmeier H, Raghavachar A, Vogt HG, Herrmann F, et al. Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group. N Engl J Med. 1991 May 9. 324(19):1297-304. [View Abstract]
  19. Passweg JR, Pérez WS, Eapen M, Camitta BM, Gluckman E, Hinterberger W, et al. Bone marrow transplants from mismatched related and unrelated donors for severe aplastic anemia. Bone Marrow Transplant. 2006 Apr. 37(7):641-9. [View Abstract]
  20. Bacigalupo A, Brand R, Oneto R, Bruno B, Socié G, Passweg J, et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience. Semin Hematol. 2000 Jan. 37(1):69-80. [View Abstract]
  21. Hirano N, Butler MO, Von Bergwelt-Baildon MS, Maecker B, Schultze JL, O'Connor KC, et al. Autoantibodies frequently detected in patients with aplastic anemia. Blood. 2003 Dec 15. 102(13):4567-75. [View Abstract]
  22. Solomou EE, Gibellini F, Stewart B, Malide D, Berg M, Visconte V, et al. Perforin gene mutations in patients with acquired aplastic anemia. Blood. 2007 Jun 15. 109(12):5234-7. [View Abstract]
  23. Solomou EE, Rezvani K, Mielke S, Malide D, Keyvanfar K, Visconte V, et al. Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia. Blood. 2007 Sep 1. 110(5):1603-6. [View Abstract]
  24. Scheinberg P, Cooper JN, Sloand EM, Wu CO, Calado RT, Young NS. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA. 2010 Sep 22. 304(12):1358-64. [View Abstract]
  25. Alter BP. Aplastic Anemia, Pediatric Aspects. Oncologist. 1996. 1(6):361-366. [View Abstract]
  26. Vulliamy T, Marrone A, Dokal I, Mason PJ. Association between aplastic anaemia and mutations in telomerase RNA. Lancet. 2002 Jun 22. 359(9324):2168-70. [View Abstract]
  27. Rothbaum R, Perrault J, Vlachos A, Cipolli M, Alter BP, Burroughs S, et al. Shwachman-Diamond syndrome: report from an international conference. J Pediatr. 2002 Aug. 141(2):266-70. [View Abstract]
  28. Doherty L, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Clinton C, et al. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2010 Feb 12. 86(2):222-8. [View Abstract]
  29. Zhang J, Yang T. [Meta-analysis of association between organophosphorus pesticides and aplastic anemia]. Zhonghua Liu Xing Bing Xue Za Zhi. 2015 Sep. 36 (9):1005-9. [View Abstract]
  30. Young NS, Maciejewski JP, Sloand E, Chen G, Zeng W, Risitano A, et al. The relationship of aplastic anemia and PNH. Int J Hematol. 2002 Aug. 76 Suppl 2:168-72. [View Abstract]
  31. Kaufman DW, Kelly JP, Levy M, Shapiro S. The Drug Etiology of Agranulocytosis and Aplastic Anemia. New York: Oxford University Press; 1991.
  32. Issaragrisil S, Sriratanasatavorn C, Piankijagum A, Vannasaeng S, Porapakkham Y, Leaverton PE, et al. Incidence of aplastic anemia in Bangkok. The Aplastic Anemia Study Group. Blood. 1991 May 15. 77(10):2166-8. [View Abstract]
  33. Young NS, Shimamura A. Acquired bone marrow failure syndromes. Handen RI, Lux SE, Stossel TP,. Blood: Principles & Practice of Hematology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003. 297.
  34. Locasciulli A, Oneto R, Bacigalupo A, Socié G, Korthof E, Bekassy A, et al. Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2007 Jan. 92(1):11-8. [View Abstract]
  35. Chan KW, McDonald L, Lim D, Grimley MS, Grayson G, Wall DA. Unrelated cord blood transplantation in children with idiopathic severe aplastic anemia. Bone Marrow Transplant. 2008 Nov. 42(9):589-95. [View Abstract]
  36. Bunin N, Aplenc R, Iannone R, Leahey A, Grupp S, Monos D, et al. Unrelated donor bone marrow transplantation for children with severe aplastic anemia: minimal GVHD and durable engraftment with partial T cell depletion. Bone Marrow Transplant. 2005 Feb. 35(4):369-73. [View Abstract]
  37. Kang HJ, Shin HY, Choi HS, Ahn HS. Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. Bone Marrow Transplant. 2004 Dec. 34(11):939-43. [View Abstract]
  38. Brodsky RA, Sensenbrenner LL, Smith BD, Dorr D, Seaman PJ, Lee SM, et al. Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia. Ann Intern Med. 2001 Oct 2. 135(7):477-83. [View Abstract]
  39. Horowitz MM. Current status of allogeneic bone marrow transplantation in acquired aplastic anemia. Semin Hematol. 2000 Jan. 37(1):30-42. [View Abstract]
  40. Kaito K, Kobayashi M, Katayama T, Masuoka H, Shimada T, Nishiwaki K, et al. Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults. Br J Haematol. 1998 Nov. 103(2):297-303. [View Abstract]
  41. Piaggio G, Podestà M, Pitto A, Sessarego M, Figari O, Fugazza G, et al. Coexistence of normal and clonal haemopoiesis in aplastic anaemia patients treated with immunosuppressive therapy. Br J Haematol. 1999 Dec. 107(3):505-11. [View Abstract]
  42. Rosti V. The molecular basis of paroxysmal nocturnal hemoglobinuria. Haematologica. 2000 Jan. 85(1):82-7. [View Abstract]
  43. Orazi A, Czader MB. Myelodysplastic syndromes. Am J Clin Pathol. 2009 Aug. 132(2):290-305. [View Abstract]
  44. Kulasekararaj AG, Jiang J, Smith AE, Mohamedali AM, Mian S, Gandhi S, et al. Somatic mutations identify a sub-group of aplastic anemia patients that progress to myelodysplastic syndrome. Blood. 2014 Aug 18. [View Abstract]
  45. Arai Y, Kondo T, Yamazaki H, Takenaka K, Sugita J, Kobayashi T, et al. Allogeneic unrelated bone marrow transplantation from older donors results in worse prognosis in recipients with aplastic anemia. Haematologica. 2016 Feb 8. [View Abstract]
  46. Vajdic CM, Mayson E, Dodds AJ, O'Brien T, Wilcox L, Nivison-Smith I, et al. Second cancer risk and late mortality in adult Australians receiving allogeneic haematopoietic stem cell transplantation: A population-based cohort study. Biol Blood Marrow Transplant. 2016 Feb 6. [View Abstract]
  47. Devalet B, Mullier F, Chatelain B, Dogné JM, Chatelain C. Pathophysiology, diagnosis, and treatment of paroxysmal nocturnal hemoglobinuria: a review. Eur J Haematol. 2015 Sep. 95 (3):190-8. [View Abstract]
  48. Brodsky RA, Mukhina GL, Li S, Nelson KL, Chiurazzi PL, Buckley JT, et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol. 2000 Sep. 114(3):459-66. [View Abstract]
  49. Krauss JS. The laboratory diagnosis of paroxysmal nocturnal hemoglobinuria (PNH): update 2010. Lab Medicine. 2012. 43:20-4.
  50. Hosokawa K, Kajigaya S, Feng X, Desierto MJ, Fernandez Ibanez MD, Rios O, et al. A plasma microRNA signature as a biomarker for acquired aplastic anemia. Haematologica. 2017 Jan. 102 (1):69-78. [View Abstract]
  51. Fang J, Lin L, Wang Y, Lin D, Liu C, Sunlong Q, et al. Regulatory T cells and CD20+ B cells in pediatric very severe aplastic anemia: possible clinical markers for evaluating the therapeutic efficacy and prognosis. Hematology. 2018 Jul 11. 1-5. [View Abstract]
  52. Brodsky RA. Acquired Aplastic Anemia. Greer JP, Arber DA, Glader B, List AF, Means RT Jr, Paraskevas F, Rodgers GM, eds. Wintrobe's Clinical Hematology. 13th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2014. 965-74.
  53. Matcuk GR Jr, Siddiqi I, Cen S, Hagiya A, Isaacson R, Brynes R. Bone marrow cellularity MRI calculation and correlation with bone marrow biopsy. Clin Imaging. 2016 May-Jun. 40 (3):392-7. [View Abstract]
  54. Camitta BM, Thomas ED, Nathan DG, Gale RP, Kopecky KJ, Rappeport JM, et al. A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood. 1979 Mar. 53(3):504-14. [View Abstract]
  55. Valdez JM, Scheinberg P, Young NS, Walsh TJ. Infections in patients with aplastic anemia. Semin Hematol. 2009 Jul. 46(3):269-76. [View Abstract]
  56. Jancel T, Penzak SR. Antiviral therapy in patients with hematologic malignancies, transplantation, and aplastic anemia. Semin Hematol. 2009 Jul. 46(3):230-47. [View Abstract]
  57. Pournaras S, Iosifidis E, Roilides E. Advances in antibacterial therapy against emerging bacterial pathogens. Semin Hematol. 2009 Jul. 46(3):198-211. [View Abstract]
  58. Di Bona E, Rodeghiero F, Bruno B, Gabbas A, Foa P, Locasciulli A, et al. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Br J Haematol. 1999 Nov. 107(2):330-4. [View Abstract]
  59. Bacigalupo A, Broccia G, Corda G, Arcese W, Carotenuto M, Gallamini A, et al. Antilymphocyte globulin, cyclosporin, and granulocyte colony-stimulating factor in patients with acquired severe aplastic anemia (SAA): a pilot study of the EBMT SAA Working Party. Blood. 1995 Mar 1. 85(5):1348-53. [View Abstract]
  60. Dufour C, Ferretti E, Bagnasco F, Burlando O, Lanciotti M, Ramenghi U, et al. Changes in cytokine profile pre- and post-immunosuppression in acquired aplastic anemia. Haematologica. 2009 Dec. 94(12):1743-7. [View Abstract]
  61. Schrezenmeier H, Passweg JR, Marsh JC, Bacigalupo A, Bredeson CN, Bullorsky E, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood. 2007 Aug 15. 110(4):1397-400. [View Abstract]
  62. Kumar R, Kimura F, Ahn KW, Hu ZH, Kuwatsuka Y, et al. Comparing Outcomes with Bone Marrow or Peripheral Blood Stem Cells as Graft Source for Matched Sibling Transplants in Severe Aplastic Anemia across Different Economic Regions. Biol Blood Marrow Transplant. 2016 Jan 18. [View Abstract]
  63. Locatelli F, Bruno B, Zecca M, Van-Lint MT, McCann S, Arcese W, et al. Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial. Blood. 2000 Sep 1. 96(5):1690-7. [View Abstract]
  64. George B, Mathews V, Viswabandya A, Kavitha ML, Srivastava A, Chandy M. Fludarabine and cyclophosphamide based reduced intensity conditioning (RIC) regimens reduce rejection and improve outcome in Indian patients undergoing allogeneic stem cell transplantation for severe aplastic anemia. Bone Marrow Transplant. 2007 Jul. 40(1):13-8. [View Abstract]
  65. Anderlini P, Wu J, Gersten I, Ewell M, Tolar J, Antin JH, et al. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. Lancet Haematol. 2015 Sep. 2 (9):e367-75. [View Abstract]
  66. Kekre N, Zhang Y, Zhang MJ, Carreras J, Ahmed P, Anderlini P, et al. Effect of antithymocyte globulin source on outcomes of bone marrow transplantation for severe aplastic anemia. Haematologica. 2017 Mar 24. [View Abstract]
  67. Maury S, Balère-Appert ML, Chir Z, Boiron JM, Galambrun C, Yakouben K, et al. Unrelated stem cell transplantation for severe acquired aplastic anemia: improved outcome in the era of high-resolution HLA matching between donor and recipient. Haematologica. 2007 May. 92(5):589-96. [View Abstract]
  68. Yagasaki H, Takahashi Y, Hama A, et al. Comparison of matched-sibling donor BMT and unrelated donor BMT in children and adolescent with acquired severe aplastic anemia. Bone Marrow Transplant. 2010 Oct. 45(10):1508-13. [View Abstract]
  69. Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM, et al. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biol Blood Marrow Transplant. 2012 Jul. 18(7):1007-11. [View Abstract]
  70. Samarasinghe S, Steward C, Hiwarkar P, Saif MA, Hough R, Webb D, et al. Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience. Br J Haematol. 2012 May. 157(3):339-46. [View Abstract]
  71. Hamad N, Del Bel R, Messner HA, Kim D, Kuruvilla J, Lipton JH, et al. Outcomes of Hematopoietic Cell Transplantation in Adult Patients with Acquired Aplastic Anemia Using Intermediate-Dose Alemtuzumab-Based Conditioning. Biol Blood Marrow Transplant. 2014 Jul 10. [View Abstract]
  72. Clay J, Kulasekararaj AG, Potter V, Grimaldi F, McLornan D, Raj K, et al. Nonmyeloablative Peripheral Blood Haploidentical Stem Cell Transplantation for Refractory Severe Aplastic Anemia. Biol Blood Marrow Transplant. 2014 Jul 10. [View Abstract]
  73. Peffault de Latour R, Rocha V, Socié G. Cord blood transplantation in aplastic anemia. Bone Marrow Transplant. 2013 Feb. 48(2):201-2. [View Abstract]
  74. MacMillan ML, Walters MC, Gluckman E. Transplant outcomes in bone marrow failure syndromes and hemoglobinopathies. Semin Hematol. 2010 Jan. 47(1):37-45. [View Abstract]
  75. Chan KW, McDonald L, Lim D, Grimley MS, Grayson G, Wall DA. Unrelated cord blood transplantation in children with idiopathic severe aplastic anemia. Bone Marrow Transplant. 2008 Nov. 42(9):589-95. [View Abstract]
  76. Yoshimi A, Kojima S, Taniguchi S, et al. Unrelated cord blood transplantation for severe aplastic anemia. Biol Blood Marrow Transplant. 2008 Sep. 14(9):1057-63. [View Abstract]
  77. Schrezenmeier H, Korper S, Hochsmann B. Standard first-line immunosuppression for acquired severe aplastic anemia in adults. Curr Drug Targets. 2015 Jun 30. [View Abstract]
  78. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4. 365(5):430-8. [View Abstract]
  79. Risitano AM. Immunosuppressive therapies in the management of acquired immune-mediated marrow failures. Curr Opin Hematol. 2012 Jan. 19(1):3-13. [View Abstract]
  80. Doney K, Dahlberg SJ, Monroe D, Storb R, Buckner CD, Thomas ED. Therapy of severe aplastic anemia with anti-human thymocyte globulin and androgens: the effect of HLA-haploidentical marrow infusion. Blood. 1984 Feb. 63(2):342-8. [View Abstract]
  81. Marsh JC, Hows JM, Bryett KA, Al-Hashimi S, Fairhead SM, Gordon-Smith EC. Survival after antilymphocyte globulin therapy for aplastic anemia depends on disease severity. Blood. 1987 Oct. 70(4):1046-52. [View Abstract]
  82. Means RT Jr, Krantz SB, Dessypris EN, Lukens JN, Niblack GD, Greer JP, et al. Re-treatment of aplastic anemia with antithymocyte globulin or antilymphocyte serum. Am J Med. 1988 Apr. 84(4):678-82. [View Abstract]
  83. Schrezenmeier H, Marin P, Raghavachar A, McCann S, Hows J, Gluckman E, et al. Relapse of aplastic anaemia after immunosuppressive treatment: a report from the European Bone Marrow Transplantation Group SAA Working Party. Br J Haematol. 1993 Oct. 85(2):371-7. [View Abstract]
  84. Schrezenmeier H, Hertenstein B, Wagner B, Raghavachar A, Heimpel H. A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins. Exp Hematol. 1995 Jan. 23(1):81-7. [View Abstract]
  85. Stein RS, Means RT Jr, Krantz SB, Flexner JM, Greer JP. Treatment of aplastic anemia with an investigational antilymphocyte serum prepared in rabbits. Am J Med Sci. 1994 Dec. 308(6):338-43. [View Abstract]
  86. Tichelli A, Passweg J, Nissen C, Bargetzi M, Hoffmann T, Wodnar-Filipowicz A, et al. Repeated treatment with horse antilymphocyte globulin for severe aplastic anaemia. Br J Haematol. 1998 Feb. 100(2):393-400. [View Abstract]
  87. Maschan A, Bogatcheva N, Kryjanovskii O, Shneider M, Litvinov D, Mitiushkina T, et al. Results at a single centre of immunosuppression with cyclosporine A in 66 children with aplastic anaemia. Br J Haematol. 1999 Sep. 106(4):967-70. [View Abstract]
  88. Hayakawa J, Kanda J, Akahoshi Y, Harada N, Kameda K, Ugai T, et al. Meta-analysis of treatment with rabbit and horse antithymocyte globulin for aplastic anemia. Int J Hematol. 2017 Jan 11. [View Abstract]
  89. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012 Aug 9. 120(6):1185-96. [View Abstract]
  90. Brodsky RA, Chen AR, Dorr D, et al. High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. Blood. 2010 Mar 18. 115(11):2136-41. [View Abstract]
  91. Tisdale JF, Dunn DE, Geller N, et al. High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial. Lancet. 2000 Nov 4. 356(9241):1554-9. [View Abstract]
  92. Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012 Jul 5. 367(1):11-9. [View Abstract]
  93. Promacta (eltrombopag) prescribing information [package insert]. Research Triangle Park, NC 27709: GlaxoSmithKline. August 2014. Available at
  94. Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017 Apr 20. 376 (16):1540-1550. [View Abstract]
  95. Geng W, Kearney S, Nelson S. Upfront eltrombopag monotherapy induces stable hematologic remission in pediatric patients with nonsevere idiopathic aplastic anemia. Pediatr Blood Cancer. 2018 Jun 22. 23 (7):e27290. [View Abstract]
  96. Supplement Approval. U.S. Food & Drug Administration. Available at https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/022291Orig1s021ltr.pdf. November 16, 2018; Accessed: January 14, 2019.
  97. Mandal PK, Baul S, Dolai TK, De R, Chakrabarti P. Outcome of Cyclosporine Monotherapy in Patients of Aplastic Anemia: Experience of a Tertiary Care Hospital in Eastern India. Indian J Hematol Blood Transfus. 2017 Mar. 33 (1):144-147. [View Abstract]
  98. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood. 2003 Feb 15. 101(4):1236-42. [View Abstract]

Low power, H and E showing a hypocellular bone marrow with increased adipose tissue and decreased hematopoietic cells in the marrow space.

Oral leukoplakia in dyskeratosis congenita.

Low power, H and E showing a hypocellular bone marrow with increased adipose tissue and decreased hematopoietic cells in the marrow space.

Oral leukoplakia in dyskeratosis congenita.

Low power, H and E showing a hypocellular bone marrow with increased adipose tissue and decreased hematopoietic cells in the marrow space.