Current Diagnosis

•   Patient must all meet hematologic criteria.

•   Assess severity.

•   Adequate cytogenetic analysis is essential.

•   Consider diagnoses with treatment implications:

    •    Causes of transient pancytopenia.

  •   Evaluate for inherited bone marrow failure syndromes, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes.

   •   Evaluate for malignancy (leukemia, lymphoma), HIV.

Current Therapy

•   Minimize interval between diagnosis and initiation of treatment.

•   Determine if an MSD is available.

•   If the patient is young and has an MSD, proceed to HCT with non- TBI regimen.

•   If the patient has no MSD or is older, proceed to IST with CSA/ATG/steroid.

•   For treatment failure, reconsider IST versus HCT options.

Abbreviations: ATG = antithymocyte globulin; CSA = cyclosporine; HCT = hematopoietic cell transplantation; IST = immunosuppressive therapy; MSD = matched sibling donor; TBI = total body irradiation.

The survival of patients with aplastic anemia has improved dramatically in the past several decades. Improved testing for underlying acquired and congenital genetic defects has served to better segregate patients with idiopathic aplastic anemia from those with the very different prognoses associated with inherited bone marrow failure syndrome (IBMFS) and myelodysplasia (MDS). For patients in the idiopathic (or acquired) aplastic anemia group, advances in transfusion medicine and other supportive care have also certainly contributed. Refinements in both major arms of treatment, immunosuppressive therapy (IST), and allogeneic hematopoietic cell transplantation (HCT), have also contributed to current outcomes (Figure 1). Although IST survival curves have been stable in the last decade, survival after HCT regardless of donor source has continued to improve. Greater understanding of pathophysiology and long-term treatment outcomes are having the largest impact on triage of therapy and standards of practice.

FIGURE 1    The actuarial survival of 2479 patients with  acquired severe aplastic anemia. Group A received immunosuppressive therapy (IST) (solid line) as first-line therapy and Group B underwent hematopoietic stem cell transplant (BMT) (dashed line). Ten-year survival was 73% with BMT and 68% with IST (p < 0.002). (Data from Locasciulli A, Oneto R, Bacigalupo 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;92:11–18.)


There is no pathognomonic diagnostic test for aplastic anemia. Accordingly, aplastic anemia continues to be diagnosed by a combination of inclusion and exclusion criteria. The definition established by the International Agranulocytosis and Aplastic Anaemia Study states that patients must have bone marrow hypocellularity with two or more of the following: hemoglobin of less than 10 g/dL, platelet count of less than 50 × 109/L, and neutrophil count of less than 1.5 × 109/L. Most commonly, patients said to have aplastic anemia in fact have severe aplastic anemia, which is defined by the absolute neutrophil count (ANC) as shown in Box 1. Severity grading has become part of the diagnostic algorithm and is increasingly used as one predictor of outcome.

Box 1
Severity Classification of Aplastic Anemia

Bone marrow cellularity <25%


Two peripheral blood findings:

•   Absolute neutrophil count <0.5 × 109/L

•   Platelet count <20 × 109/L

•   Reticulocyte count <20 × 109/L

Very Severe

Same criteria as for severe


Peripheral blood absolute neutrophil count <0.2 × 109/L

Nonsevere (Moderate)

Hypocellullar bone marrow


Peripheral blood cytopenias not meeting criteria for severe aplastic anemia

Differential Diagnosis

Because many conditions can fulfill these inclusion criteria, care must be taken to consider infectious, metabolic, and toxic exposures that could result in transient pancytopenia. Specific considerations are listed in many current reviews. These diagnoses are wide ranging and include hypoplastic presentations of lymphoma, leukemia, and MDS (including the subtype refractory cytopenia of childhood); anorexia; and transient severe bone marrow suppression due to drug exposure or, albeit rarely, a spectrum of acute viral illnesses.

Patients should be carefully evaluated for other conditions that can require an alternative management approach. A fraction of pancytopenic and hypocellular patients have clonal cytogenetic abnormalities despite well-reviewed histology that appears to be free of any evidence of dysplasia or infiltrative disease. Accordingly, best practice should include both fluorescent in situ hybridization (FISH) and routine cytogenetics, because the yield for the latter analysis may be inadequate given the hypocellularity of the bone marrow compartment.

Although the prognostic relevance of clonal cytogenetics remains somewhat debatable, evidence of clonality at diagnosis should certainly provoke consideration of MDS as an alternative diagnosis and mandate an aggressive plan of follow-up and determination of HCT donor status. Clonality also potentially alters immediate treatment depending on the clinical setting and most current literature. Among infectious problems, perhaps the most important consideration from a diagnostic and management perspective is HIV. However, viruses rarely cause a true aplastic picture, and their diagnosis, at present, does not have much therapeutic importance.

Aplastic anemia can occur or recur during pregnancy and can resolve with either delivery or termination.

The most important alternative diagnosis is an inherited bone marrow failure syndrome (IBMFS) (Table 1), which should be considered in virtually all patients and certainly in all pediatric patients. Such a diagnosis has important implications for medical management of the extended family, for genetic counseling, for the choice of therapy, for prognosis of the patient, and, in the setting of HCT, for donor evaluation. A meticulous patient and family history and physical examination should be performed, although uninformative results do not eliminate the possibility of an IBMFS. IBMFS diagnosis by functional testing for cell surface molecules, telomere length, and chromosomal breakage has markedly improved. Genetic testing is available for some IBMFSs; however, it is clear that these syndromes are polygenic, and not all relevant genetic defects have been defined. Therefore, testing might not be diagnostic.

Moreover, new genetic defects associated with aplastic anemia are still being discovered. As additional mutations are described and their epidemiology becomes better elucidated, this information should be of increasing value.

Table 1

Inherited Bone Marrow Failure Syndromes Commonly Associated with Pancytopenia*

* Diamond-Blackfan anemia, as well as less common disorders such as Pearson, Seckel, and Noonan syndromes; cartilage–hair hypoplasia; and reticular dysgenesis, can progress to marrow failure meeting the definition of aplastic  anemia.

† Clinically approved mutation testing is becoming increasingly available, but not all genetic defects have been defined for any of these  disorders.

In addition to IBMFS, an evaluation for paroxysmal nocturnal hemoglobinuria (PNH) should be undertaken. A small clonal population of cells deficient in glycosylphosphatidylinositol (GPI)-linked proteins that characterize PNH can be found in 20% to 50% of both children and adults with aplastic anemia without a concurrent history of clotting or hemolysis. The presence of such cells does not imply a diagnosis of classic PNH, although some patients with apparent aplastic anemia do develop classic PNH. Ongoing clinical investigation into the relation of aplastic anemia and PNH might yield further information that will assist in therapeutic decision making.

Supportive Care

The goals of supportive care in aplastic anemia are alleviating symptoms of anemia and addressing the risks of hemorrhage and infection that result from pancytopenia. Appropriate precautions for minimizing alloimmunization should be taken, such as use of leukodepletion techniques and conservative transfusion goals.

Preemptive counseling can play as important a role as symptom management. There are few evidence-based guidelines for activities of daily living, such as the quality of diet, extent of exercise, and travel restrictions. The best standard is frequent, open communication between physician and patient. Some practical issues, however, are common. For example, the menstrual status of female patients should be ascertained immediately on diagnosis. Because severe menorrhagia can occur in the setting of protracted thrombocytopenia, use of hormonal therapy to suppress menstruation should be addressed with patients and with families of younger patients. Particular regard should be paid to anticipation of menarche in pubertal girls.

With regard to infectious risks, standards widely vary by practitioner and institution. Although the largest single cause of death in patients undergoing either HCT or IST is infection, there is no current standard for infection prophylaxis in aplastic anemia. Clinical trials to define the best possible approaches to this issue, including the role of novel broad-spectrum anti-infectives and their schedule of use, would be very important. At the least, a detailed history taken in the context of exposure and lifestyle issues should be used to develop a plan for fever and infection prophylaxis with which the patient can be compliant.

Benefit from the use of hematopoietic growth factors to support the ANC, or indeed any lineage, has been unclear in patients with idiopathic aplastic anemia. Prior concerns about the association of long-term use of granulocyte colony-stimulating factor (G-CSF) (Neupogen)1 by pediatric aplastic anemia patients, in particular, and subsequent development of MDS and acute myelogenous leukemia (AML), have not been confirmed in recent multicenter data.

Monitoring of iron status should be routine for patients with ongoing red cell transfusion needs. Chelation should be initiated according to accepted guidelines to minimize complications of iron overload.


Observation is not a successful treatment option for patients with severe aplastic anemia; older, retrospective data demonstrate a 1-year mortality with supportive care alone of more than 80%, although current transfusion and support strategies should improve on this outcome. Nonetheless, a recent large report from the European Group for Blood and Marrow Transplantation demonstrates that decreased time from diagnosis to treatment, whether IST or HCT, is a highly significant predictor of survival. A triage of therapy is shown in Figure 2.

FIGURE 2    Triage of aplastic anemia (AA) therapies. The age  limit suggested by young/old is variable from report to report, but generally sits in the 30- to 40-year-old range. Abbreviations: AML = acute myelogenous leukemia; HCT = hematopoietic cell transplant; MDS = myelodysplasia.

Immunosuppressive Therapy

It is generally held that a significant percentage of aplastic anemia has an immune pathogenesis. A variety of data on immune effector cell function and repertoire, cell surface phenotype, and cytokine production support this belief. In practice, this hypothesis is also supported by the observation that IST with cyclosporine (Neoral)1 (CSA), antithymocyte globulin (ATG), and corticosteroids results in response in roughly 75% of patients. Horse ATG was shown to be superior to rabbit ATG in a recent randomized trial.

Younger patients generally have a higher likelihood of response.

Children (<16 years) on IST with very severe aplastic anemia have better survival rates than similarly affected adults. Age does not affect the relative survival rate of patients with less severe aplastic anemia.

Randomized studies have demonstrated better response when IST agents are used in combination. Meta-analysis has also shown decreased all-cause mortality. In addition to their general immunomodulatory capacity, the immunologic effects of IST may be specific, because direct lympholytic and bone marrow stimulatory activities have been described. The addition of further immunosuppressive medications, such as mycophenolate or sirolimus, to this regimen has thus far not improved outcomes.

IST responses can be of varying degree and duration and can take 3 to 6 months to become evident. Often, responding patients continue to manifest some evidence of bone marrow failure, with mild degrees of cytopenia or residual macrocytosis commonly observed. Slow taper of CSA in IST responders is advisable, generally over longer than 6 months, and a significant fraction of patients demonstrate prolonged dependence on CSA for persistent hematologic improvement. A second course of IST in patients who failed a first course can produce response in 12% to 50% of patients. Complete or partial loss of response occurs in an appreciable number of patients, approximately one third, and can become manifest years after cessation of IST or immediately on CSA taper. Re-treatment with the same or a similar regimen is often successful.

Recent studies demonstrate that eltrombopag (Promacta), a thrombopoietin mimetic, has potential for multilineage efficacy in patients with severe aplastic anemia refractory to IST, and it has been FDA-approved for this indication.

Hematopoietic Cell Transplantation

HCT is the only truly curative therapy for aplastic anemia and produces stable survival rates in the range of 65% to 90%, depending on donor type and other HCT variables (Figure 3). In young patients with matched sibling donors (MSDs), a short interval from diagnosis to HCT, and little prior therapy, survival rates up to 97% have been recently reported. Conversely, prior IST or excessive transfusion (or both) are associated with worse outcome. Thus, the general recommendation is for young patients with MSDs to proceed to HCT as soon as the diagnosis is confirmed. The age cutoff for this decision varies somewhat, but the recommendation certainly holds for patients younger than 30 years and is often implemented for those younger than 40 years.

FIGURE 3    The actuarial survival of patients  undergoing hematopoietic cell transplantation (HCT) from matched sibling  donors

(A) or alternative donors (B) by time periods. Results improved for both donor groups in the later time period (matched sibling donors 74% vs 80%, P = 0.03) and alternative donors (38% vs 65%, P = 0.0001). (Data from Locasciulli A, Oneto R, Bacigalupo 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;92:11–18.)

HCT for aplastic anemia from MSD can be successfully achieved with radiation-free preparative regimens, of which the most standard and widely used is cyclophosphamide (Cytoxan)1 (CY) and ATG conditioning. CSA and short-course methotrexate (Trexall)1 (MTX) provide highly effective graft-versus-host disease (GVHD) prophylaxis in this setting. In a group of adults and children undergoing MSD allogeneic HCT, this classic CY/ATG/CSA/MTX regimen produced a 96% rate of sustained engraftment, 3% rate of severe acute GVHD, 26% rate of chronic GVHD, and overall survival of 88% at median follow-up of 9 years. A recent study suggests that ATG may not be as essential to this outcome as previously thought.

All stem cell sources, including sibling umbilical cord blood, have been used successfully, although use of peripheral blood stem cells appears to result in an unacceptably high rate of chronic GHVD and is not currently advised.

The dearth of alternative therapies for those who fail to respond to IST, coupled with the success of MSD HCT, have encouraged the use of alternative-donor HCT for aplastic anemia. Originally, patients coming to alternative-donor HCT were often late in their clinical course with significant aplastic anemia–associated morbidity and more aggressive regimens than those used for MSD engendered more regimen-related toxicity. Outcomes were somewhat disappointing.

Results have improved significantly over the past decade, and even more so over the past 5 years (see Figure 3B). Moving HCT treatment earlier in therapeutic triage, coupled with improvements in histocompatibility and supportive care, and the successful implementation of reduced-intensity regimens and alternative immunosuppressive strategies have produced encouraging results, with an overall survival in excess of 70% in some reports. However, the best results are seen when patients are younger, with worse outcomes in those older than 40 years.

Long-Term Complications of Treatment

All aplastic anemia treatments can be associated with significant morbidity, be it the iron-overload of chronic transfusion or the more protean problems of IST or HCT. These include, in both cases, significant regimen-related end-organ toxicity. The development of clonal cytogenetic abnormalities after IST is well described and occurs in patients of all ages, regardless of treatment response, and over a broad time frame. The rate of progression to frank AML is not predictable, although progression is most common in those with monosomy 7 or complex cytogenetic abnormalities. Patients with aplastic anemia who undergo HCT generally experience fewer toxicities than does the overall HCT population, in part due to the reduced intensity of aplastic anemia regimens. Growth and fertility may be well preserved, but persistent infectious complications, pulmonary insufficiency, dermatologic pathology, avascular necrosis, other bone and joint issues, hypothyroidism or other endocrine disturbances, and secondary malignancies can occur. Some of these conditions reflect the sequelae of chronic GVHD itself, and others reflect the toxicity of drugs used to manage GVHD. The toll of GVHD is real; decreased quality of life and overall survival are observed in the nearly one half of aplastic anemia patients experiencing chronic GVHD.


Improvements in diagnosis, supportive care, IST, and HCT have led to significant improvements in survival for patients with severe aplastic anemia. However, there are still controversies over the optimal choice of therapy for individual patients, and any given choice can lead to a number of serious regimen-related toxicities. Further insights into the pathophysiology of bone marrow failure, increased diagnostic accuracy for IBMFS, greater appreciation of the risk and epidemiology of late complications, and steady progress in therapeutics will hopefully combine to yield increasingly well-targeted and more- successful treatment.


Eva C. Guinan is a prior recipient of a Specified Established Researcher Award from the Aplastic Anemia & MDS International Foundation and the Distinguished Service Award of the Fanconi Anemia Research Foundation.


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1  Not FDA approved for this  indication.

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