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Treatment of aplastic anemia in adults
Author:
Stanley L Schrier, MD
Section Editor:
William C Mentzer, MD
Deputy Editor:
Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: May 16, 2017.

INTRODUCTION — Aplastic anemia (AA) is a disorder of hematopoietic stem cells that causes pancytopenia and a hypocellular bone marrow without splenomegaly. Affected patients typically present with recurrent infections due to neutropenia, bleeding episodes due to thrombocytopenia, and fatigue due to anemia. Patients with AA are at risk of life-threatening complications, especially when pancytopenia is severe. Thus, a long-term approach to therapy is needed.

This topic reviews the treatment and prognosis of AA in adults. Additional topics discuss the diagnosis of AA, the management of inherited and acquired AA in children and adolescents, and the role of hematopoietic cell transplantation (HCT) for AA:

Adults

Diagnosis – (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Role of HCT – (See "Hematopoietic cell transplantation for aplastic anemia in adults".)

Children and adolescents

Diagnosis – (See "Acquired aplastic anemia in children and adolescents", section on 'Diagnosis' and "Clinical manifestations and diagnosis of Fanconi anemia" and "Dyskeratosis congenita and other short telomere syndromes".)

Treatment – (See "Inherited aplastic anemia in children and adolescents" and "Acquired aplastic anemia in children and adolescents" and "Management and prognosis of Fanconi anemia" and "Dyskeratosis congenita and other short telomere syndromes", section on 'Management' and "Hematopoietic cell transplantation for idiopathic severe aplastic anemia and Fanconi anemia in children and adolescents".)

INITIAL CONSIDERATIONS — Management of patients with AA depends on the underlying cause and the severity of pancytopenia (algorithm 1). The following issues must be addressed as part of treatment planning [1-4]:

Possibility of an inherited bone marrow failure syndrome – Inherited bone marrow failure syndromes include Fanconi anemia (FA), dyskeratosis congenita (DC), congenital amegakaryocytic thrombocytopenia (CAMT), Shwachman-Diamond syndrome (SDS), and severe congenital neutropenia (SCN). These usually present in childhood but rarely may be seen adults. Additional features of these syndromes that suggest their presence, and the appropriate diagnostic evaluations, are presented separately. If one of these syndromes is present, additional considerations may apply to therapy, as discussed in detail separately. (See "Inherited aplastic anemia in children and adolescents" and "Clinical manifestations and diagnosis of Fanconi anemia" and "Dyskeratosis congenita and other short telomere syndromes" and "Shwachman-Diamond syndrome" and "Congenital neutropenia".)

Possibility of hypoplastic MDS – Myelodysplastic syndromes (MDS) typically are associated with increased bone marrow cellularity; however, in some cases (eg, therapy-associated MDS) the bone marrow may be hypocellular. The possibility of a hypoplastic MDS must be evaluated, especially in older adults (see 'Over age 50' below), because therapy differs [5]. Bone marrow findings consistent with MDS rather than AA are described separately. (See "Clinical manifestations and diagnosis of the myelodysplastic syndromes".)

Underlying cause – If an associated underlying cause such as a drug reaction or infection is identified (table 1), the potentially offending agent should be withdrawn and/or treated as appropriate. However, prolonged delay in therapy while awaiting spontaneous recovery generally is not advised because it increases the risks of serious complications of cytopenias [3]. We generally do not wait longer than two to three months, although data are lacking regarding the typical interval for spontaneous recovery after drug discontinuation.

Disease severity – As discussed in detail separately, AA is classified according to disease severity based on bone marrow cellularity and peripheral blood cytopenias. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic criteria'.)

Severe AA (sAA) is characterized by bone marrow cellularity <25 percent of normal, which varies by age, and at least two severe peripheral cytopenias, such as neutropenia with absolute neutrophil count [ANC] <500 cells/microL (calculator 1), thrombocytopenia with platelet count <20,000/microL, and/or anemia with absolute reticulocyte count <20,000 cells/microL [6]. Other criteria have also been used [7]. In our practice, we use bone marrow cellularity <10 percent and severe neutropenia, especially ANC <200/microL, which represents very severe AA (vsAA). Moderate AA (also called nonsevere AA) is used for patients with bone marrow cellularity <25 percent and depression of at least two cell lines in the peripheral blood but without criteria for sAA.

For patients with sAA or vsAA without an alternative underlying treatable cause of bone marrow failure, we stratify initial treatment according to patient age and the availability of a bone marrow donor. (See 'First-line therapy' below.)

For patients with nonsevere (moderate) AA, optimal therapy is unknown, and we use a more individualized approach based on the patient’s age, clinical status, and degree of cytopenias. Treatment similar to that for sAA may be appropriate for patients with progressive cytopenias, severe neutropenia, or transfusion dependence. Observation and supportive care may be associated with better outcomes and quality of life for individuals who are older or have mild or stable cytopenias.

Clonal evolution – Individuals with AA are at risk for clonal evolution, which in some cases is associated with progression to MDS or acute leukemia. (See 'Clonal disorders' below.)

Our approach is similar to a 2009 guideline from the British Committee for Standards in Hematology and the practice of other experts in the United States, although practice continues to evolve [3,4].

MANAGEMENT OF CYTOPENIAS — Appropriate supportive care for cytopenias is an integral component of therapy for patients with AA [8]. Transfusions, antibiotics, and, rarely, growth factors may be required. In very elderly individuals or those with moderate pancytopenia, these interventions may be the only therapy used. Importantly, however, these interventions do not alter the course of disease and should not be considered substitutes for appropriate therapy for individuals with severe AA who require (and can tolerate) definitive treatment [3].

Transfusions — Patients with severe anemia or thrombocytopenia may require transfusions of red blood cells (RBCs) and/or platelets. Of note, for any patient who is a potential candidate for hematopoietic cell transplantation (HCT), transfusions should be used selectively in order to reduce the risks of sensitization to donor antigens. Blood products from a sibling or family donor should be avoided scrupulously in potential HCT candidates to minimize the risk of graft failure caused by an immune reaction to donor antigens. Equally importantly, however, transfusions should not be withheld in patients with symptomatic/severe anemia or bleeding/severe thrombocytopenia. Appropriate transfusion thresholds, which may depend on patient symptoms and comorbidities, are presented separately:

RBCs – (See "Red blood cell transfusion in infants and children: Indications" and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)

Platelets – (See "Clinical and laboratory aspects of platelet transfusion therapy".)

As a general rule, we use leukoreduced products for patients with AA to reduce the risk of febrile nonhemolytic transfusion reactions. (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic reactions'.)

Infection treatment/prevention — Fever and neutropenia (eg, absolute neutrophil count [ANC] <500 cells/microL) in a patient with AA is a medical emergency. Treatment is discussed in detail separately. (See "Overview of neutropenic fever syndromes" and "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Treatment of infection' and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

There are no uniform guidelines regarding prophylactic antibacterial or antifungal therapy in patients with severe AA. Some experts have suggested administration of prophylactic antifungal therapy with voriconazole or posaconazole in individuals with an ANC <200 cells/microL based on improved survival with their use in patients with other hematopoietic stem cell disorders (eg, post-hematopoietic cell transplantation, acute leukemia) [8]. Decisions regarding prophylactic antibacterials are more challenging because certain agents have been shown in other patient populations to reduce mortality but also to increase the risk of antibacterial resistance and deleterious changes in intestinal microflora; additionally, some antibacterials are myelosuppressive [8].

Additional strategies to reduce the risk of infection are also presented separately. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Preventing infection' and "Immunizations in hematopoietic cell transplant candidates and recipients" and "Vaccination for the prevention of shingles (herpes zoster)".)

Role of growth factors — Levels of hematopoietic cytokines (growth factors) are generally quite high in individuals with AA at baseline, and growth factors generally are not used as part of routine management. Exceptions include the possible use of granulocyte colony-stimulating factor (G-CSF) in individuals with frequent or severe infections, and the use of thrombopoietin (TPO) receptor agonists in individuals with refractory disease. A potential role for TPO receptor agonists in improving hematopoietic stem cell function during initial therapy is under investigation.

Granulocyte colony-stimulating factor (G-CSF) – G-CSF is not standard therapy in AA. There is no evidence that G-CSF corrects the underlying hematopoietic stem cell defect in AA. Further, the addition of G-CSF to immunosuppressive therapy (IST) has not been associated with improvements in response rates or survival. (See 'Modifications of the standard regimen' below.)

Another issue related to G-CSF administration is the theoretical concern that it might promote development or evolution of a clonal population of cells with cytogenetic abnormalities or mutations that could predispose the patient to develop myelodysplasia or acute myeloid leukemia (AML). The role of G-CSF in clonal evolution (if any) is difficult to determine because patients with acquired AA have an increased baseline risk of clonal disorders. (See 'Clonal disorders' below.)

Thrombopoietin (TPO) receptor agonists – TPO receptor agonists (also called TPO mimetics) stimulate megakaryocytes well as multipotent hematopoietic stem and progenitor cells in the bone marrow. These agents have an evolving role in patients who are not transplant-eligible and those with refractory disease (eg, persistent thrombocytopenia and/or other cytopenias despite IST). (See 'Refractory disease' below.)

The role of TPO receptor agonists as a component of first-line therapy is under active investigation, as discussed below with several studies ongoing [9-11].

Erythropoietin – Erythropoietin is not used in AA, because there are insufficient erythroid precursor cells for it to be effective.

FIRST-LINE THERAPY

Overview of approach: IST versus HCT — First-line therapy is stratified according to the age of the patient, which correlates with ability to tolerate hematopoietic cell transplantation (HCT); the severity of disease; and the availability of an appropriate donor (algorithm 1).

For the majority of patients under age 50 years with severe AA who have an available donor, we suggest a strategy of up-front HCT rather than initial immunosuppressive therapy (IST) or IST plus eltrombopag. We feel more strongly about pursuing HCT in younger patients, especially those under 20 years and many under 50 years. The upper age limit for tolerating HCT and the size of the available donor pool continue to expand, and treatment-related morbidity/mortality continues to improve with advances in therapy; as a result, the proportion of individuals for whom HCT is considered appropriate therapy continues to grow. On the basis of data presented at the 2016 American Society of Hematology meeting, we have begun to incorporate the results of myeloid somatic mutation panels in these patients. Patients with mutations in ASXL1 or DNMT3 appear to have a poorer response to IST and a greater propensity for clonal evolution. It may be that such a finding should lead to more intense consideration of the appropriateness of HCT.

For individuals with a sibling donor, HCT can usually be initiated within approximately six to eight weeks, and there is not a good rationale for providing IST and/or eltrombopag during this short period. If a search for an unrelated donor must be undertaken, there may be some benefit of providing eltrombopag, with or without IST. This decision is made on a case-by-case basis depending on several factors that include the severity of cytopenias, transfusion requirements, frequency or severity of infections, and availability and cost to the patient of eltrombopag. Patients for whom HCT is appropriate but who lack a donor are treated with eltrombopag plus IST, but the donor search should continue, especially for younger patients with severe disease.  

The rationale for preferring HCT for younger patients with severe disease includes the high mortality rate of severe AA and the superior long-term outcomes (including survival) with HCT, especially in younger patients. Additionally, concerns remain regarding the degree and durability of responses with IST and a greater potential risk of clonal disorders such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) following IST. (See 'Clonal disorders' below.)

However, a strategy of initial IST may be appropriate for some individuals for whom a suitable donor is not available, for older individuals who may not tolerate HCT, and for some individuals who place a higher value on avoiding the up-front mortality of HCT compared with IST. As discussed below, initial eltrombopag plus IST is associated with excellent hematologic responses, but the duration of these responses is unknown, and this therapy does not prevent clonal evolution. (See 'Evidence for efficacy' below and 'Clonal disorders' below.)

Initial IST does not preclude later HCT, provided a donor is available and the patient remains in adequate health to tolerate the procedure.

Both HCT and IST require substantial expertise to administer. Early involvement of a transplant center or clinician with expertise in managing bone marrow failure syndromes and/or enrollment in a clinical trial is strongly encouraged [3].

Evidence to support the use of HCT comes from observational studies; IST and HCT have not been directly compared in a randomized trial.

Three prospective studies (302 patients) that compared IST with HCT were identified in a 2013 Cochrane review, in which allocation to HCT was based on availability of a sibling donor [12]. Major findings from this review were that overall mortality was similar between IST and HCT, and treatment related mortality from HCT ranged from 20 to 42 percent. However, the review noted that all three studies were performed in the 1980s and 1990s, before many of the currently available advances in therapy were made, and thus may not accurately reflect the standard of care.

A retrospective study involving 395 adults and children found that actuarial survival at 15 years was superior with HCT (69 versus 38 percent) (figure 1) [13]. Those who underwent HCT (using bone marrow) had an engraftment rate of 89 percent; IST produced a response rate of 44 percent (complete, partial, and minimal responses). The median age of patients undergoing HCT was 22 years (range 2 to 54) and the median age for IST was 25 years (range 1 to 74).

The ongoing reductions in HCT-related morbidity and mortality over time has been illustrated in various case series. In a review of 1305 patients with AA who underwent HCT during different time periods, five-year survival increased progressively, from 48 percent (1976 to 1981) to 66 percent (1988 to 1992) [14]. The improved survival was due primarily to decreased mortality in the first three months after transplant. Risks of graft-versus-host disease (GVHD) and interstitial pneumonia were also decreased. Similar improvements have been reported in other studies during this and subsequent time periods [15]. (See "Hematopoietic cell transplantation for aplastic anemia in adults", section on 'Survival and quality of life'.)

Information regarding donor selection, conditioning regimen, and GVHD prophylaxis is presented in detail separately. (See "Hematopoietic cell transplantation for idiopathic severe aplastic anemia and Fanconi anemia in children and adolescents" and "Hematopoietic cell transplantation for aplastic anemia in adults".)

As discussed separately, the pool of available donors is expanding, and patients for whom HCT is considered appropriate should have an ongoing donor search, which may include a search for an unrelated donor or an evaluation of the possibility of haploidentical transplantation. (See "Hematopoietic cell transplantation for aplastic anemia in adults", section on 'Overview of HCT considerations'.)

Severe AA — Severe AA requires definitive therapy due to its extremely high mortality rate. The decision between HCT and IST must balance the relative toxicities and long-term efficacy of the therapies, which differ over time (eg, higher up-front mortality but greater chance of cure with HCT) and according to patient age.

Under age 20 — For patients under the age of 20 years with severe AA, we suggest allogeneic HCT. This should be performed as promptly as possible once an appropriate donor (preferably a fully HLA-matched family member) is identified. Specific information regarding conditioning regimen, donor selection, and GVHD prophylaxis in this age group is presented separately. (See "Hematopoietic cell transplantation for idiopathic severe aplastic anemia and Fanconi anemia in children and adolescents", section on 'Idiopathic severe aplastic anemia'.)

If an appropriate donor is not available, the patient may be treated with eltrombopag plus IST while an aggressive search for a donor continues. (See 'Initial immunosuppressive therapy' below.)

Ages 20 to 50 — The approach to adults 20 to 50 years of age is shifting due to improvements in HCT outcomes, especially reductions in GVHD, and to an expansion of the donor pool to unrelated donors.

For patients ages 20 to 50 who are otherwise in good health (ie, without other major comorbidities), we suggest HCT. However, some patients may choose eltrombopag plus IST due to the up-front risks of HCT, which may be greater than for children and adolescents. Specific information regarding conditioning regimen, donor selection, and GVHD prophylaxis in this age group is presented separately. (See "Hematopoietic cell transplantation for idiopathic severe aplastic anemia and Fanconi anemia in children and adolescents", section on 'Idiopathic severe aplastic anemia'.)

If an appropriate donor is not available, the patient may be treated with eltrombopag plus IST while an aggressive search for a donor continues. (See 'Initial immunosuppressive therapy' below.)

Over age 50 — Patients over the age of 50 years with AA experience increased toxicities of treatment compared with younger patients with AA. However, in many cases eltrombopag plus IST is appropriate. The decision to use IST rather than supportive care alone, and more intensive versus less intensive IST, is individualized based on the patient’s overall health, comorbidities, and preferences. We often use full-dose IST in patients over 50 years.

The following additional considerations may apply to individuals over age 50 [3,5]:

Individuals with potentially poor-prognosis mutations such as mutations in ASXL1 or DNMT3A tend to have worse outcomes from IST, and we may be more likely to suggest HCT for these individuals. (See "Cytogenetics and molecular genetics of myelodysplastic syndromes", section on 'Gene mutations'.)

The choice of therapy is difficult and must be made between the more intensive eltrombopag plus standard IST versus a less intensive regimen such as single agent eltrombopag or cyclosporine A (CsA) without antithymocyte globulin (ATG). (See 'Initial immunosuppressive therapy' below.)

Individuals with severe neutropenia (eg, absolute neutrophil count [ANC] <200/microL) are at very high risk of infection and may derive a more rapid response from standard IST.

Individuals with an ANC >500/microL may be treated with eltrombopag alone or eltrombopag plus less toxic single agent IST such as CsA, especially if they have comorbidities that would increase the toxicity of IST. If they do not have a hematologic response, they may then be treated with standard IST.

We do not use androgens due to the limited benefit in our experience.

The increased risk of death from infection should be noted, with aggressive treatment of documented and suspected infections as appropriate.

Less intensive IST is associated with significant efficacy in older adults, although responses may be lower than those with standard IST. Addition of eltrombopag to less-intensive IST has not been evaluated in clinical studies. Examples of the findings from case series involving older adults include the following:

A series of 810 patients from the European Group for Blood and Marrow Transplantation (EBMT) Registry included 242 individuals over age 50 who were treated with IST [16]. Therapy was approximately equally divided between ATG alone, CsA alone, and ATG plus CsA. Findings included the following:

Older age correlated inversely with survival, with the following five-year overall survival rates:

-<50 years: 72 percent

-50 to 59 years: 57 percent

-≥60 years: 50 percent

Older age correlated with a lower probability of response in univariate analysis, but this correlation was not seen on multivariate analysis, suggesting that older patients had additional features such as more severe disease, greater risk of death from infection or bleeding, or use of less intensive therapy that correlated with lower response rate, but age by itself was not a risk factor for lower response.

IST using ATG plus CsA or ATG alone was associated with trend toward a better survival rate compared with CsA alone in patients over 50. In patients under 50 years in the same registry, there was a much stronger and statistically significant correlation between intensity of therapy and survival.

Responses were slow, with a median time to independence from transfusion of approximately six months.

A single institutional series described outcomes in 24 consecutive patients over the age of 60 years (range 61 to 78), 17 of whom treated with attenuated therapy that consisted of CsA alone (four patients), ATG alone (one patient), or CsA with 50 percent dose-reduced ATG (13 patients) [17]. The remaining six were treated with standard dose ATG and CsA. There were six early deaths from infection (25 percent, three in the attenuated therapy group and three in the standard therapy group). In the remaining patients, the cumulative response rate at two years was 42 percent, and the three-year overall survival was 49 percent. Of the group who received attenuated IST, 9 of 14 patients (64 percent) had a durable response to treatment.

Less commonly, a patient over 50 years may be in otherwise excellent health and may have a suitable donor (eg, HLA-matched related donor, syngeneic donor) available. In such cases, HCT may be appropriate. However, the risks of treatment toxicities and early mortality are greater in individuals over 50 years of age than they are in younger patients. (See "Hematopoietic cell transplantation for aplastic anemia in adults", section on 'Complications' and "Hematopoietic cell transplantation for aplastic anemia in adults", section on 'Survival and quality of life'.)

Moderate AA — Individuals with moderate disease may have persistent mild pancytopenia that does not require interventions or can be treated with occasional transfusions, or they may develop progressive disease. Thus, the approach is individualized to incorporate information about symptoms, disease severity, and changes in the degree of cytopenias over time. Close monitoring without initiating IST often is appropriate, especially when symptoms and transfusion requirements are minimal [3].

In contrast, those whose pancytopenia progresses to severe AA (or whose counts are showing a pattern of rapid decline) are treated for severe AA. (See 'Severe AA' above.)

Special populations — Hepatitis-associated AA and AA in the setting of paroxysmal nocturnal hemoglobinuria (PNH) generally is treated similarly to AA without these disorders; however, additional considerations may apply.

Hepatitis-associated AA — A preceding (or concurrent) history of hepatitis is seen in a small percentage of individuals with AA (2 to 5 percent in some series), almost always in adolescent boys or young men. In some cases, a known infectious (viral) cause is identified, but in many patients serologies are negative. A systematic review of hepatitis-associated AA reported potential associations with a number of hepatitis viruses including A, B, C, E, and G; as well as patients with negative viral serologies and fulminant hepatitis who have developed AA following liver transplantation [18]. A typical presentation is development of severe AA approximately two to three months following an episode of acute hepatitis in a boy or young man. Immune mechanisms appear to be involved. Additionally, some patients with autoimmune hepatitis are treated with azathioprine, which can cause AA if the patient has a variant in thiopurine methyltransferase (TPMT) that reduces enzymatic activity and leads to production of 6-thioguanine. (See "Autoimmune hepatitis: Treatment", section on 'Testing for TPMT enzyme activity and drug metabolite levels'.)

Management of AA associated with an episode of viral hepatitis may involve HCT or IST, with criteria similar to that used for individuals without hepatitis [19]. Since the affected individuals often are young, we move rapidly to HCT in most cases. The following additional considerations may apply:

For those with active hepatitis and an identified viral pathogen, antiviral therapy may be used, but pancytopenia is often so severe that immediate therapy for AA is needed.

Individuals with persistently elevated transaminases may be treated with hepatotoxic agents as part of the HCT conditioning regimen or IST [18]. In many cases, the hepatitis resolves upon administration of these agents. However, close monitoring is important, with decisions about continuing therapy made on a case-by-case basis.

In some patients, antiviral therapy may be administered following IST, if reactivation of a latent hepatitis infection occurs.

Interferon generally is avoided because it causes bone marrow suppression.

Additional details of hepatitis therapy are presented in separate topic reviews. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis" and "Hepatitis B virus: Overview of management" and "Overview of the management of chronic hepatitis C virus infection".)

Underlying PNH — There is substantial overlap between AA and PNH. Patients with AA have an increased risk of developing PNH, and patients with PNH have an increased risk of developing AA. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'Aplastic anemia'.)

Therapy for AA in patients with a PNH clone is similar to that for patients without PNH. For those who undergo HCT, this may result in elimination of the PNH clone.

For those treated with IST, responses appear to be similar to individuals without a PNH clone [20,21]. Some patients with a small (clinically insignificant) PNH clone may develop expansion of the clone when treated with IST (see "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'Clonal selection and expansion'). In such patients, therapy for PNH should be pursued, as discussed separately. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)

INITIAL IMMUNOSUPPRESSIVE THERAPY — Immunosuppressive therapy (IST) is often used to treat severe AA, especially in patients for whom the risks of hematopoietic cell transplantation (HCT) are considered too great or for whom a suitable donor cannot be identified. The addition of eltrombopag to IST has been shown to improve cytopenias. (See 'Eltrombopag, horse ATG, CsA, and prednisone' below.)

Eltrombopag plus IST using horse antithymocyte globulin (ATG) and cyclosporin A (CsA) has been demonstrated to improve counts in a large proportion of patients, as described in the following sections. However, follow-up is relatively short (eg, two years). It is not known whether these responses are more durable than responses to IST alone, which are often incomplete and sometimes transient. Eltrombopag is a synthetic non-peptide agonist for the thrombopoietin (TPO) receptor (also referred to as a TPO mimetic). The mechanism by which it promotes disease response is likely to include activation of the TPO receptor (c-MPL) on hematopoietic stem and progenitor cells as well as megakaryocytes. (See "Biology and physiology of thrombopoietin", section on 'Effects on bone marrow precursor cells'.)

As noted below, eltrombopag also has demonstrated efficacy in the setting of refractory disease. (See 'Refractory disease' below.)

It appears that eltrombopag plus IST does not reduce the risks of subsequent development of clonal disorders. (See 'Disease relapse' below and 'Clonal disorders' below.)

As noted above, initial IST does not preclude later HCT for patients whose disease does not respond and for whom a donor is identified. (See 'Overview of approach: IST versus HCT' above.)

Eltrombopag, horse ATG, CsA, and prednisone — For patients with severe AA who do not undergo HCT, we suggest eltrombopag plus IST using horse ATG and CsA rather than ATG plus CsA alone. This practice is consistent with that of other experts, although the use of eltrombopag was only introduced in mid-2014 to 2015. Glucocorticoids are given with ATG to reduce the risk or severity of serum sickness; these may also have immunosuppressive properties but should not be used in isolation due to the increased risk of infection without demonstrated therapeutic benefit in AA. Exceptions to the standard doses of eltrombopag and IST may be a patient who cannot tolerate this therapy due to severe toxicities that cannot be managed (see 'Management of toxicities' below), or a patient enrolled in a clinical trial.

Evidence for efficacy — In a prospective, non-randomized study of 92 consecutive patients with severe AA (mostly adults), the addition of eltrombopag to standard IST was associated with higher rates of hematologic response at six months compared with historical controls (overall response rate [defined as no longer meeting criteria for severe AA] 87 versus 66 percent; and with higher rates of complete response [defined as absolute neutrophil count >1000/microL, hemoglobin >10 g/dL, and platelet count ≥100,000/microL] 39 versus 10 percent) [22]. Response rates were highest among patients treated with eltrombopag beginning on day 1 and continued for six months (overall response rate at six months, 94 percent, complete response rate at six months, 58 percent). Median survival at two years was 97 percent. Eltrombopag is a thrombopoietin receptor agonist that acts on megakaryocytes and hematopoietic stem cells. (See "Clinical applications of thrombopoietic growth factors".)

It is unknown whether different timing of therapy or different doses of eltrombopag (higher or lower) would result in better outcomes. Other trials using eltrombopag are ongoing. Additional unanswered questions include the duration of response, selection of patients for drug discontinuation, and safety of continuing (or initiating) therapy in individuals with clonal cytogenetic abnormalities or dysplasia [23]. As noted below, eltrombopag is our first choice therapy for refractory disease in transplant-ineligible patients. (See 'Refractory disease' below.)

Prior evidence that supported ATG plus CsA versus either treatment as a single agent came from a 1991 trial that randomly assigned 84 patients to receive ATG versus ATG plus CsA (all patients received glucocorticoids) [24]. Responses were superior in the CsA group (65 versus 39 percent), especially among patients with severe disease. Survival was greater in individuals with severe disease who received combination therapy; however, crossover and retreatment made direct comparisons difficult. A subsequent publication describing observation for over 11 years reported that among 43 patients whose disease responded to CsA, 11 (26 percent) required continued administration of CsA for more than six months [25]. Five were able to discontinue CsA after five to nine years, and six remained on the drug for 10 to 12 years. Actuarial survival at 11 years was similar for those who received ATG plus CsA versus ATG alone (58 versus 54 percent).

The greater efficacy of horse ATG versus rabbit ATG was demonstrated in a 2011 trial that randomly assigned 120 consecutive patients with severe AA (children and adults) to receive horse ATG (40 mg/kg daily for four days) versus rabbit ATG (3.5 mg/kg daily for five days) in addition to cyclosporin as first-line therapy [26]. Hematologic response at six months, which correlates strongly with survival, was greater with horse ATG (68 versus 37 percent). Most responses occurred within three months. Relapse rates at three years were similar between the two groups (28 versus 11 percent), and overall survival at three years was superior in the horse ATG group (96 versus 76 percent). Additional case series have also observed greater responses to horse versus rabbit ATG; some of these comparisons occurred when horse ATG became temporarily unavailable [27-29]. Rabbit ATG should be used only when horse ATG is not available [30].

A strong correlation between initial hematologic response to IST alone and overall survival was demonstrated in a 2003 cohort of 122 patients with severe AA (mostly adults, median age 35 years) treated with the standard regimen of horse ATG plus CsA (see 'Standard regimen' below) [31]. Actuarial survival at five years was 86 percent for individuals whose disease had response at three months, defined by transfusion independence and peripheral blood counts no longer indicative of severe disease, and there were no deaths after three years in this population despite relapses in 26 of 74 individuals (35 percent). In comparison, actuarial survival at five years was 40 percent for those whose disease did not respond to IST. (See 'Prognosis' below.)

Initial response to IST also appears to correlate with additional responses in patients whose disease relapses, as discussed below. (See 'Disease relapse' below.)

Standard regimen — Various approaches to administering eltrombopag, ATG, CsA, and glucocorticoids have been reported. We prefer to use a shorter, higher dose IST regimen because this reduces the length of hospitalization; however, other regimens have similar efficacy. Local institutional protocols should be established and followed to ensure that the therapy is given as desired with appropriate monitoring.

Eltrombopag – Eltrombopag is given at the doses used in the 2017 study demonstrating its efficacy in combination with standard IST [22]. The dose is 150 mg orally once per day in individuals over 12 years of age of non-Asian ancestry, starting on day 1 and continued for six months. Individuals of East or Southeast Asian ancestry are given half the normal dose (ie, 75 mg daily). The dose is reduced and/or temporarily held for high platelet counts or transaminase elevations, as done in the study. There are no dose range studies ongoing. Some individuals may not have access to eltrombopag due to the high cost and/or lack of insurance coverage.

ATG – Horse ATG is given at a dose of 40 mg/kg daily for four consecutive days. Each dose can be administered in 500 mL of saline over four to six hours.

Serum sickness is a significant concern with ATG products, which are polyclonal antibodies; however, this rarely precludes their administration. Skin testing for hypersensitivity to horse serum is performed prior to the first dose; glucocorticoids are administered concurrently with ATG, followed by a taper; and premedication with acetaminophen and diphenhydramine is administered before each dose of ATG. (See 'Management of toxicities' below.)

CsA – CsA is given at an initial dose of 10 to 12 mg/kg daily, administered orally in two equal divided doses (ie, 5 to 6 mg/kg orally twice a day). Subsequent dosing is titrated based on trough levels to a target trough level of approximately 200 to 400 ng/mL. Most experts measure trough levels in whole blood, although serum measurements can be used. CsA generally is continued for approximately six months, although we sometimes reduce the dose after the first month to a trough level of 200 to 250 ng/mL.

Data to guide the duration are extremely limited. For those with recovery of counts, we generally initiate a very slow taper after a total of six months of CsA administration, with close monitoring.

Of note, therapeutic CsA trough ranges have not been absolutely defined, and different analytical techniques for measuring CsA levels can produce large variations in results [32]. Local protocols may differ from these suggested trough levels. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Pharmacokinetics'.)

GlucocorticoidsPrednisone (or methylprednisolone) is administered at 1 mg/kg daily, starting with the first dose of ATG and continuing for two weeks, followed by a rapid taper and discontinuation by day 30.

Patients receiving this therapy generally have a double lumen central venous catheter to facilitate administration of these agents, transfusions, fluids, and laboratory testing. (See "Overview of central venous access".)

Management of toxicities — Eltrombopag is generally well-tolerated, although adverse effects such as skin reactions or elevations in hepatic transaminases may occur [22]. Some individuals can develop a high platelet count requiring dose reduction and/or temporary holding of the drug. The effect of long-term use in individuals with AA has not been thoroughly evaluated. (See "Clinical applications of thrombopoietic growth factors", section on 'Side effects and risks'.)

IST has several potential toxicities, the most concerning of which is a serum sickness reaction to ATG [3]. Both horse and rabbit ATG products (Atgam and Thymoglobulin, respectively) are polyclonal antibody preparations and have a significant risk of serum sickness, which may manifest as fever, rash, malaise, or other constitutional symptoms [33,34]. (See "Serum sickness and serum sickness-like reactions", section on 'Clinical manifestations'.)

Importantly, the possibility of other conditions that may be responsible for fever and rash (eg, infection) also should be evaluated, especially in individuals with severe neutropenia, because infectious complications of the disease are a major cause of morbidity and mortality. (See "Serum sickness and serum sickness-like reactions", section on 'Differential diagnosis'.)

We do the following to minimize toxicities from serum sickness:

A skin test for hypersensitivity to horse serum is performed before the first dose.

Routine prophylaxis for serum sickness includes a two-week course of daily glucocorticoids (see 'Standard regimen' above)

Premedication with acetaminophen and diphenhydramine prior to each ATG dose

ATG may also cause infusion reactions, which generally occur more rapidly than serum sickness reactions (ie, at the time of infusion, rather than hours to days later), but otherwise may be difficult to distinguish from serum sickness. Patients should be monitored closely and treated with meperidine for rigors, intravenous hydration for hypotension, and/or supplemental oxygen for hypoxemia. Other aspects of management are similar to infusion reactions caused by monoclonal antibodies. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)

CsA may cause renal insufficiency and hypertension. In addition to following cyclosporin levels, we regularly monitor renal function with serum creatinine levels and frequent blood pressure measurement. Cyclosporin has also been associated with development of neurotoxicity, including posterior reversible encephalopathy syndrome (PRES) and progressive multifocal leukoencephalopathy (PML), and neurologic symptoms should be evaluated promptly. CsA also can cause hemolysis, tremor, vitiligo, gingival hyperplasia, and hypertrichosis, management of which is discussed in separate topic reviews. (See "Cyclosporine and tacrolimus nephrotoxicity" and "Pharmacology of cyclosporine and tacrolimus".)

IST may also lead to subclinical reactivation of latent viral infections such as cytomegalovirus (CMV) or Epstein-Barr virus (EBV), although symptomatic clinical disease is uncommon. As an example, in a study of 78 patients treated with IST who had monitoring for virus by polymerase chain reaction (PCR), laboratory evidence of CMV reactivation was seen in 19 of 57 CMV seropositive individuals (33 percent) and of EBV reactivation in 82 of 94 EBV seropositive individuals (87 percent) [35]. Despite this, there were no cases of symptomatic CMV or EBV infection. We check serologies for CMV and EBV prior to starting therapy, to help manage patients with suspected clinically important reactivation, but we do not alter initial therapy based on the results of this testing.

Monitoring of response — Patients treated with eltrombopag plus ATG and CsA are monitored regularly for hematologic response, which has been defined as independence from transfusion, no need for additional IST, and/or improvement of peripheral blood counts to the point that they no longer meet the criteria for severe AA [3]. Peripheral blood counts from the complete blood count (CBC) and reticulocyte count are more important than bone marrow cellularity, and improvement of counts to the point that the patient is no longer symptomatic or requiring of transfusions is more important than normalization of values, which is seen in a minority of patients.

The majority of responses occur within the first three months of therapy, with additional responses occurring between three and six months. The CBC, ANC, and reticulocyte count are monitored frequently during IST and in increasing intervals thereafter.

Return of frank pancytopenia suggests disease relapse, although the possibility of a new clonal disorder should also be evaluated. (See 'Disease relapse' below and 'Clonal disorders' below.)

For patients with less dramatic variations in the CBC, is important to observe trends and not alter therapy for an isolated measurement, which may reflect normal oscillations in counts or an intercurrent infection.

For those with recovery of counts, we continue the CsA for a total of six months and then initiate a very slow taper. (See 'Standard regimen' above.)

Bone marrow evaluation is not generally used to monitor response or guide additional IST; however, it may be important for detecting clonal evolution, especially in individuals with decreasing counts. (See 'Clonal disorders' below.)  

Modifications of the standard regimen — Various modifications of the standard therapy with ATG and CsA have been evaluated for the possibility of improving outcomes or reducing toxicity. Although these may be appropriate in selected patients, we do not use any of them routinely, with the possible exception of reduced intensity therapy for older patients.

Addition of G-CSF — We do not use granulocyte colony-stimulating factor (G-CSF) routinely in adult patients receiving IST. Our conclusion from the available data, which includes several small randomized trials and observational studies, is that G-CSF may reduce the incidence of infections, but it does not alter the course of the disease, response to IST, or survival [36-46]. In addition, concerns remain regarding a possible increased incidence of clonal disorders including myelodysplasia and/or acute leukemia. (See 'Role of growth factors' above.)

The largest randomized trial compared addition versus no addition of G-CSF to standard therapy with ATG and CsA in 192 patients [46]. There was no difference in overall survival (76 percent at approximately 3.5 years) or event-free survival (42 percent); additional subset analysis did not reveal a survival advantage based on disease severity or patient age. However, patients treated with G-CSF had fewer infections (24 versus 36 percent) and fewer hospitalization days (84 versus 87 percent of the initial 30 days of treatment spent in the hospital).

Addition of other immunosuppressive agents — Evidence for a role of adding additional immunosuppressive agents to standard IST is limited. As an example, a study in which 104 patients with severe AA were treated with standard IST plus additional mycophenolate mofetil (MMF) showed a similar response rate as that of historical and contemporaneous controls (response rate at six months, 62 percent) [47].

Reduced intensity therapy — For some individuals who are considered to be at especially high risk of treatment toxicity it may be appropriate to use eltrombopag alone, or single agent ATG or CsA. Alternatively, therapy with reduced doses of one or both of these agents could be tried. The best evidence regarding this practice is in patients over 50 years of age, for whom it is able to produce a good response rate, but not as good as standard therapy (see 'Over age 50' above). Such an approach might also be appropriate for younger patients with significant comorbidities.

High-dose cyclophosphamide — High-dose cyclophosphamide has been used to treat severe AA; however, we do not use this due to its high rate of toxicity without improved efficacy over standard therapy. The following illustrates the available findings:

Dosing based on HCT conditioning – Dosing regimens similar to that used as conditioning for HCT have been used, without subsequent infusion of stem cells. As an example, in one series 67 individuals with severe AA (44 without prior treatment and 23 with refractory disease) were treated with cyclophosphamide at 50 mg/kg daily for four consecutive days (total dose 200 mg/kg) [48]. All patients received bladder protection, growth factors, and prophylactic antibiotics. Despite this, toxicities were high. In the treatment-naïve group there were five deaths (11 percent), eight cases of severe fungal infection (18 percent), and two cases of hemorrhagic cystitis (5 percent); the median duration of hospitalization was 28 days. Actuarial probability of survival at 10 years was 88 percent in the treatment-naïve group and 62 percent for the patients with refractory disease. These impressive outcomes led to the initiation of a randomized trial designed to this dose of cyclophosphamide (plus CsA) versus ATG (plus CsA), but the trial was closed after accrual of 31 patients due to a high rate of invasive fungal infections and early deaths in the cyclophosphamide group [49]. It is considered unlikely that additional randomized trials of high-dose cyclophosphamide for initial therapy will be performed [50].

Modified high dose – A modified high-dose cyclophosphamide regimen in combination with CsA has been designed in an attempt to reduce the severe toxicity of the HCT conditioning dose regimen. Two small cohorts of patients have been treated with a more moderate dose of cyclophosphamide (30 mg/kg daily for four consecutive days, total dose 120 mg/kg) plus CsA. One of the studies was terminated early due to unacceptable toxicity (eg, prolonged neutropenia with average duration of two months) and high mortality (9 of 22 patients), with a response rate of only 41 percent [51]. The other study compared a cohort of 48 patients treated with this regimen to 73 controls treated with rabbit ATG plus CsA [52]. The early death rate with cyclophosphamide was 4 percent, and the response rate at 12 months was 73 percent, both of which were similar to the control group.

Investigational therapies

Anti-IL-2 receptor antibody — In a small study, patients with moderate AA were treated with daclizumab, a humanized monoclonal antibody directed at the interleukin 2 (IL-2) receptor [53]. There were six responses among the 16 evaluable patients (38 percent), two of whom reverted to completely normal blood counts that were sustained for more than two years following treatment. A later report from the same group indicated that 7 of 28 patients (25 percent) with moderate AA who were treated with this agent had long-term independence from red blood cell transfusion [54]. Toxicity was minimal. However, many patients with moderate AA would not be treated, and the role of this approach in moderate and/or severe AA remains unknown. Daclizumab has been withdrawn from the market worldwide for safety reasons.

Arsenic trioxide (ATO) plus CsA — Arsenic trioxide (ATO) is generally considered to have a role in cell differentiation rather than immunosuppression. In a small study, 10 patients with severe AA were treated with a combination of CsA (5 mg/kg orally per day, adjusted to achieve a whole blood trough level of 100 to 200 ng/mL) plus one or two courses of ATO (0.15 mg/kg intravenously daily for five days each week for eight weeks) [55]. Responses were seen in all 10 patients by eight weeks, and these persisted for at least 17 weeks. Toxicity of ATO was modest and did not compromise overall treatment. Further evidence is needed to justify the use of this therapy, especially given the unclear rationale for its efficacy in AA.

Pig ATG — ATG may be produced from the serum of other animals besides horse and rabbit. One study evaluated IST using porcine (pig) ATG (referred to as antilymphocyte globulin [ALG]) plus CsA in 69 patients (mostly adults) with severe AA [56]. The median age was 27 years (range 14 to 52). The overall response rate was 77 percent and two-year overall survival was 88 percent, with a median time to response of approximately 90 days. Transaminase elevations were seen in 28 percent, and fewer than one-third of the patients had serum sickness or an allergic reaction. Further experience with this product is needed.

Autologous HCT — In principle, autologous HCT could be a useful therapy for severe AA because it avoids the risks of allogeneic HCT. However, in a series of nine patients with severe AA who attempted peripheral blood stem cell mobilization using G-CSF, only two (22 percent) had sufficient mobilization of CD34+ cells to warrant collection [57].

CLONAL DISORDERS — Patients with AA have an appreciable risk of developing clonal mutations or cytogenetic abnormalities, and in some cases progressing to a clonal hematologic disorder such as a myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or paroxysmal nocturnal hemoglobinuria (PNH). This may occur before therapy is initiated, during therapy, or after treatment. The likelihood of MDS and AML increases over time in those treated with immunosuppressive therapy or myeloid growth factors, although it is not clear whether this is due to the therapy or the underlying disease. PNH may become more pronounced in individuals with an existing clone following IST. In contrast, the likelihood of developing these abnormalities is greatly reduced following hematopoietic cell transplantation (HCT). The risks of clonal disorders, and the concern regarding a possible contributory role of myeloid growth factors and/or immunosuppressive therapy (IST) to these risks, is discussed separately. (See "Introduction to recombinant hematopoietic growth factors", section on 'Possible stimulation of malignancy' and "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'PNH stem cell'.)

A number of questions remain unanswered regarding the appropriate screening, monitoring, and interventions for these disorders. Our approach is as follows:

Screening – For individuals with AA who were treated with IST or HCT and have had a good response, we monitor the complete blood count (CBC) and differential count monthly. If the findings are stable, we gradually extend the monitoring interval (eg, to two, then three, then six months). If the findings change, we repeat the bone marrow examination with cytogenetics.

PNH – For individuals with AA and subclinical PNH (eg, a small PNH clone not associated with hemolysis, thrombosis, or smooth muscle dystonia), we monitor the CBC every six to 12 months and the size of the PNH clone annually. For those who develop a clinically significant PNH clone (eg, with hemolytic anemia, thrombosis, or smooth muscle dystonia), interventions for PNH are indicated. These are discussed in detail separately. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)

Clonal genetic or cytogenetic changes – We do not routinely test for clonal gene mutations or cytogenetic changes because there are no data to support to use of additional therapy for such patients in the absence of frank MDS or AML. However, some individuals may have clonal changes identified on routine bone marrow evaluation or other testing. Monitoring for such individuals is discussed separately. (See "Idiopathic cytopenias of undetermined significance (ICUS), clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)'.)

MDS – For individuals with AA who develop MDS, therapy is similar to other patients with MDS, although outcomes are likely to be poor. (See "Overview of the treatment of myelodysplastic syndromes".)

AML – For individuals with AA who develop AML, therapy generally involves chemotherapy followed by HCT in first remission, due to unfavorable cytogenetics. (See "Overview of acute myeloid leukemia in adults" and "Post-remission therapy for acute myeloid leukemia in younger adults".)

IRON OVERLOAD — Individuals who receive multiple red blood cell transfusions are at risk for iron overload and associated organ toxicities, which can impact morbidity and mortality [8].

Patients who undergo HCT or IST followed by recovery of normal hematopoiesis can be treated with phlebotomy. There are no specific guidelines regarding phlebotomy after HCT in patients with AA, but an approach similar to that used for other conditions associated with transfusional iron overload would be reasonable.

In contrast, those with transfusional iron overload who remain anemic may benefit from iron chelation therapy. (See "Iron chelators: Choice of agent, dosing, and adverse effects", section on 'Aplastic anemia'.)

DISEASE RELAPSE — Relapses occur in approximately 10 percent of individuals with initial disease response to immunosuppressive therapy (IST). In the largest study, which included 719 patients, there were 74 relapses, with an actuarial relapse rate at 15 years of 35 percent [15,39,58]. The likelihood of relapse is not predicted by age or disease severity, and relapse in turn does not appear to be predictive of increased mortality [31,59,60].

Importantly, many patients whose disease responded to ATG and CsA initially (with or without eltrombopag) can be retreated with the same regimen; if horse ATG was used initially, we often switch to rabbit ATG. (See 'Horse (or rabbit) ATG if not used previously' below.)

In the large series that reported relapses in 74 patients, 39 had a second response to IST and an actuarial survival of 86 percent, which was similar to that of individuals who did not have a relapse [58]. Although serum sickness occurs earlier with repeated courses of horse ATG (6 versus 13 days in one study), such regimens are generally well tolerated [60].

As noted above, it is also important to evaluate the possibility of other causes of pancytopenia such as an inherited bone marrow failure syndrome (if not done previously) or hypoplastic myelodysplastic syndrome following initial disease response. (See 'Initial considerations' above and 'Clonal disorders' above and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)

REFRACTORY DISEASE — Immunosuppressive therapy (IST) fails to produce a hematologic response in approximately one-fourth of patients with severe AA. It is not known whether refractory disease represents ongoing immune attack on hematopoietic cells (ie, a failure of immunosuppression) or a persistent stem cell deficiency [9]. Therapies directed at either (or both) of these problems may be useful. Potential approaches include eltrombopag, alemtuzumab (alone or in combination with cyclosporin), or high-dose cyclophosphamide [61]. Data are lacking to guide the choice of therapy. In the absence of data, for those who had refractory disease with standard IST, we would use eltrombopag plus IST. For those who had refractory disease with eltrombopag plus IST, we would use agents discussed below such as alemtuzumab or high dose cyclophosphamide.

Eltrombopag — Eltrombopag is our first choice for the treatment of refractory disease.

The efficacy of single-agent eltrombopag in refractory AA was demonstrated in a 2014 prospective study of 25 adults with persistent thrombocytopenia (platelet count <30,000/microL) after one or more courses of IST, in which 11 (44 percent) had a clinically significant hematologic response [62]. Subsequently, long-term follow up on these plus an additional 18 patients was reported [63]. Responses, including bi-lineage and tri-lineage responses, were seen in 17 of 43 individuals (40 percent). Five individuals with robust near-normalization of peripheral blood counts were able to discontinue the drug, and counts remained stable at a median of 13 months after discontinuing eltrombopag. Eight patients (two with disease response and six without) developed new cytogenetic abnormalities, but none evolved to acute myeloid leukemia. The only major toxicities were reversible elevation in hepatic transaminases. There was no increased bone marrow reticulin and no thrombotic events attributed to therapy (one patient had a deep vein thrombosis 14 months after stopping the drug).

Further experience with eltrombopag in the refractory disease setting is awaited. Unanswered questions include the duration of response, selection of patients for drug discontinuation, and safety of continuing (or initiating) therapy in individuals with clonal cytogenetic abnormalities or dysplasia [23].

Alemtuzumab (refractory disease) — Alemtuzumab (Campath) is another good option for treating refractory disease that does not respond to eltrombopag plus IST, or for patients who do not have access to (or whose disease does not respond to) eltrombopag.

Alemtuzumab is an immunosuppressive humanized monoclonal antibody directed against CD52, which is present on lymphocytes and other hematopoietic cells. Alemtuzumab has shown efficacy in refractory disease and as initial therapy, either alone or in combination with cyclosporin A (CsA):

One trial that randomly assigned 54 patients with refractory disease following treatment with horse ATG and CsA to receive alemtuzumab versus rabbit antithymocyte globulin (ATG) plus CsA found similar response rates in both arms (37 versus 33 percent) [64]. The degree and duration of lymphopenia (over six months) and rate of relapse (3 of 27 patients in each group) was also similar in both arms. There was a trend towards a lower rate of clonal evolution and greater survival with alemtuzumab, but numbers were very small.

Several small studies have suggested response rates to initial therapy with alemtuzumab plus CsA in the range of 37 to 58 percent [65-67].

Single agent alemtuzumab was only minimally effective as initial treatment in a trial that randomly assigned patients with severe AA to horse ATG plus CsA, rabbit ATG plus CsA, or alemtuzumab alone [64]. The alemtuzumab arm was discontinued early due to responses in only three patients (19 percent) and early death in an additional three patients.

A consensus protocol for alemtuzumab administration has been published [68]; however, we encourage enrollment in a clinical trial.

Alemtuzumab is associated with thyroid abnormalities in some patients (hypo- or hyperthyroidism) but is otherwise generally well tolerated in patients with AA [64]. Hematologic toxicity, infusion reactions, and infections including bacterial fungal, viral, protozoal, and reactivation of latent cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV), are possible [69].  

Horse (or rabbit) ATG if not used previously — Patients with refractory disease who did not receive horse ATG as part of initial treatment may benefit from treatment that includes horse ATG, and those whose disease did not respond to horse ATG may benefit from a regimen using rabbit ATG.

Switching to horse ATG – The benefit of using horse ATG in patients who had not previously received it was demonstrated in a series of patients treated initially with CsA plus rabbit ATG (19 patients) or CsA plus cyclophosphamide (6 patients) [70]. Responses to horse ATG plus CsA were seen in 4 of 19 who initially received rabbit ATG and one of six who initially received cyclophosphamide (21 and 16 percent, respectively). Those whose disease responded to horse ATG did not experience a relapse during three years of additional observation, and the overall survival of the cohort at three years was 68 percent.

Switching to rabbit ATG – In a study of 30 patients with refractory disease following treatment with horse ATG and CsA, 23 (77 percent) had a disease response to a regimen including rabbit ATG and CsA [71]. Independence from transfusion occurred at a median of 95 days, and nine patients had a complete response. Overall survival at a median of 2.5 years was 93 percent, with no additional relapses.  

High-dose cyclophosphamide for refractory disease — As noted above, high-dose cyclophosphamide has efficacy in AA, but toxicities are greater than standard therapy and we do not favor its use as initial therapy. (See 'High-dose cyclophosphamide' above.)

However, high-dose cyclophosphamide also has shown efficacy in the setting of refractory disease and may be appropriate if other therapies are not effective or available. As examples:

In a series of 17 patients with refractory severe AA treated with high-dose cyclophosphamide (50 mg/kg daily for four days), nine individuals (53 percent) had a partial or complete response at a median of 29 months [72]. In those with a response, the median time to absolute neutrophil count (ANC) >500/microL was 54 days, the median time to the final platelet transfusion was 99 days, and the median time to the final red blood cell transfusion was 125 days.

In a series that included 23 patients with refractory severe AA who were treated with high-dose cyclophosphamide followed for 10 years, the overall actuarial survival was 62 percent, response rate was 48 percent, and event-free survival was 27 percent [48]. Toxicity was appreciable, with an early mortality of 17 percent secondary to bacterial or fungal sepsis.

Allogeneic HCT — It may be possible to perform allogeneic hematopoietic cell transplantation (HCT) in some patients with refractory disease, including those who did not initially have an available donor but subsequently found an HLA-matched unrelated donor or decided to use a mismatched or haploidentical donor. (See "Hematopoietic cell transplantation for aplastic anemia in adults".)

PROGNOSIS — The clinical course of AA is variable, with life-threatening complications of pancytopenia (eg, infection, bleeding) or evolution to a clonal disorder in some patients, and a milder symptoms and long life expectancy in others [1].

Survival — The overall prognosis of patients with severe AA has improved dramatically due to the increasing availability of hematopoietic cell transplantation (HCT) and more effective immunosuppressive therapy (IST) and supportive care, with survival rates as high as 80 to 90 percent compared with 10 to 20 percent in the 1960s [8,73]. Untreated, AA has a one-year mortality of over 70 percent [74].

The major factors that affect prognosis are the severity of pancytopenia, response to initial therapy, and patient age. This has been demonstrated the following series:

In a retrospective study of patients with severe AA who were treated with HCT (168 patients) or IST (227 patients), actuarial survival at 14 years was 69 percent for HCT and 38 percent for IST (figure 1) [13]. Improved survival was related to younger age, higher absolute neutrophil count (ANC), absence of transfusion prior to HCT, and use of HCT as primary therapy.

In a retrospective review of 810 patients in the European Group for Blood and Bone Marrow Transplantation (EBMT) Registry, five-year survival correlated inversely with age (72, 57, and 50 percent for ages <50, 50 to 59, and >60, respectively) and ANC [16]. In contrast, response to therapy, relapse rates, and risk of clonal complications was similar in all age groups. The increased mortality in the older patients was due largely to infection or bleeding.

A retrospective analysis of 316 patients with severe AA treated with IST reported higher response rates and greater survival in younger patients and those with higher absolute reticulocyte count (ARC) and absolute lymphocyte count (ALC) [75]. Five-year survival in those with an ARC ≥25,000/microL and ALC ≥1000/microL was 92 percent, versus 53 percent for those in the low ARC/ALC group.

Race may affect outcomes following HCT. In a case-control study that compared outcomes of HCT in individuals of African heritage compared with Caucasians, African ancestry was associated with a greater mortality (relative risk [RR] 1.73), which was attributed at least in part to a higher risk of high-grade acute graft-versus-host disease (GVHD; 29 verus 13 percent) and extensive chronic GVHD (72 versus 49 percent) [76].

Pregnancy — Pregnancy (and a good obstetrical outcome) is possible following IST for AA. This was illustrated in a report of 36 women who had received IST and subsequently became pregnant [77]. The following outcomes were reported:

Neonatal – There were 34 live births (including one set of twins), two elective abortions, and one miscarriage. Five deliveries were preterm; there were no major neonatal complications.

Maternal – Relapse of AA occurred in seven pregnancies (19 percent), and an additional five patients required transfusions during delivery. Of the seven patients who had a relapse during pregnancy, three recovered spontaneously in the postpartum period, three had a response to treatment, and one died of her disease. Another woman with AA and paroxysmal nocturnal hemoglobinuria had a fatal cerebral thrombosis after delivery. There were two cases of preeclampsia.

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Basics topics (see "Patient education: Aplastic anemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Initial considerations in the treatment of adults with aplastic anemia (AA) include assessment of the underlying cause and severity of pancytopenia. Some individuals may benefit from a trial of drug discontinuation (table 1) or therapy for an infection. (See 'Initial considerations' above.)

Management of cytopenias with transfusions, antibiotics, and (rarely) growth factors is an integral component of therapy for patients with AA. Importantly, however, these interventions do not alter the course of disease and should not be considered substitutes for appropriate therapy. Transfusions should be used selectively for potential candidates for hematopoietic cell transplantation (HCT) but should not be withheld from individuals with symptomatic/severe anemia or bleeding/severe thrombocytopenia. We use leukoreduced products. (See 'Management of cytopenias' above.)

For patients with severe AA without an alternative underlying treatable cause of bone marrow failure, we stratify the initial treatment strategy according to patient age and the availability of a donor (algorithm 1). Testing for poor-prognosis mutations may be helpful in decision-making in some cases. (See 'Overview of approach: IST versus HCT' above.)

For patients with severe AA who are under the age of 20 years, and those ages 20 to 50 years who are otherwise in good health (ie, without other major comorbidities), we suggest allogeneic HCT rather than initial immunosuppressive therapy (IST) (Grade 2C). If a sibling donor is available, we proceed directly to HCT. For those who do not have an available sibling donor, we may use a course of eltrombopag or eltrombopag plus IST while aggressively searching for an unrelated donor. (See 'Under age 20' above and 'Ages 20 to 50' above.)

For patients over 50, the decision to use IST versus supportive care alone, and more intensive versus less intensive IST, is individualized based on the patient’s overall health, comorbidities, and preferences. If the patient can tolerate IST, we suggest eltrombopag for six months plus IST, rather than IST alone (Grade 2C). Limited data suggest the addition of eltrombopag to standard IST is associated with improvement in cytopenias over the short term. Clonal evolution appears to be similar with and without eltrombopag. Eltrombopag dosing and schedule are described above. IST uses horse anti-thymocyte globulin (ATG), cyclosporin A (CSA), and glucocorticoids; if horse ATG is not available, we use rabbit ATG. For patients who are elderly or may not tolerate this regimen, we may use less intensive therapy. (See 'Over age 50' above and 'Eltrombopag, horse ATG, CsA, and prednisone' above.)

Patients for whom HCT is appropriate but who lack a donor are treated with IST, but the donor search should continue, especially for younger patients with severe disease. Donor selection, the rationale for using bone marrow rather than peripheral blood stem cells, conditioning regimens, and graft-versus host disease (GVHD) prophylaxis are presented separately. (See "Hematopoietic cell transplantation for aplastic anemia in adults".)

Eltrombopag plus IST has a number of potential toxicities, the most concerning of which is a serum sickness reaction to ATG. Close monitoring is required. Measures to mitigate this and other toxicities are described above. (See 'Eltrombopag, horse ATG, CsA, and prednisone' above and 'Modifications of the standard regimen' above and 'Management of toxicities' above.)

Patients treated with IST are monitored regularly for hematologic response. Peripheral blood counts from the complete blood count (CBC) and reticulocyte count are more important than bone marrow cellularity. The majority of responses occur within three months. (See 'Monitoring of response' above.)

Iron overload may be treated with phlebotomy or chelation depending on the patient's response to therapy. (See 'Iron overload' above.)

Clonal evolution and development of myelodysplastic syndrome (MDS) acute leukemia, or paroxysmal nocturnal hemoglobinuria (PNH) are significant concerns. Our approach to monitoring and management of these conditions is discussed above. (See 'Clonal disorders' above.)

The actuarial rate of disease relapse is approximately 35 percent at 15 years. The likelihood of relapse is not predicted by age or disease severity, and relapse in turn does not appear to be predictive of increased mortality. For those whose disease initially responded to IST, we suggest retreatment. (See 'Disease relapse' above.)

Options for treating disease that does not respond to eltrombopag plus IST or IST alone (refractory disease) include alemtuzumab, an alternative source of ATG, high-dose cyclophosphamide, and alternative donor HCT. (See 'Refractory disease' above.)

Overall prognosis for patients with AA has improved dramatically, with survival rates as high as 80 to 90 percent. Successful pregnancy following treatment is also possible. (See 'Prognosis' above.)

The diagnostic evaluation for AA, specific inherited bone marrow failure syndromes, and HCT for pediatric AA are presented separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Inherited aplastic anemia in children and adolescents" and "Acquired aplastic anemia in children and adolescents" and "Clinical manifestations and diagnosis of Fanconi anemia" and "Management and prognosis of Fanconi anemia" and "Dyskeratosis congenita and other short telomere syndromes".)

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