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Treatment of aplastic anemia in adults

Treatment of aplastic anemia in adults
Literature review current through: Jan 2024.
This topic last updated: Dec 04, 2023.

INTRODUCTION — Acquired aplastic anemia (AA) is an immune-mediated hematopoietic disorder characterized by pancytopenia and hypocellular bone marrow. Affected patients typically present with infections due to neutropenia, bleeding due to thrombocytopenia, and/or fatigue due to anemia. Patients are at risk of life-threatening complications, especially when pancytopenia is severe. Almost all sporadic cases of AA, especially when severe and of sudden onset, are related to immune destruction of hematopoietic stem and/or progenitor cells.

This topic reviews the treatment and prognosis of AA in adults.

For adults, the evaluation of pancytopenia; pathogenesis, clinical manifestations, and diagnosis of AA; and hematopoietic cell transplantation for AA are discussed separately.

(See "Approach to the adult with pancytopenia".)

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

(See "Hematopoietic cell transplantation for aplastic anemia in adults".)

Management of acquired AA in children and adolescents is discussed separately. (See "Treatment of acquired aplastic anemia in children and adolescents".)

PRETREATMENT EVALUATION — Initial evaluation, diagnosis, and differential diagnosis of AA are discussed separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation'.)

Pretreatment evaluation requires exclusion of other causes, classification of disease severity, and assessment of medical fitness.

Exclude other causes — It is important to exclude other causes of pancytopenia prior to initiating treatment for acquired AA because of important differences in treatment. Exclusion of other causes includes history, physical examination, laboratory tests, bone marrow examination, cytogenetics, and molecular studies.

Inherited bone marrow failure syndromes (IBMFS) – Most cases of IBMFS present in childhood, but hematologic manifestations may not become apparent until adulthood in some patients. It is important to review the family history, prior blood counts (for cytopenias and/or macrocytosis), and examine the individual for possible syndromic findings.

In addition:

Age <40 years – We obtain chromosomal breakage analysis (to evaluate for Fanconi anemia) and telomere length analysis (to exclude telomere biology disorders [TBD]). (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Evaluation' and "Dyskeratosis congenita and other telomere biology disorders", section on 'Diagnosis'.)

Prior cytopenias, somatic findings, organ dysfunction, or myeloid malignancies – We obtain a next-generation sequencing panel for germline mutations in genes linked to IBMFS for patients with a personal or family history of unexplained cytopenias together with somatic findings that may be associated with IBMFS, liver or lung disease (associated with TBD), or myeloid leukemias (associated with GATA2 deficiency).

Examples of physical findings that may suggest an IBMFS include hyper- or hypo-pigmented patches of skin, oral leukoplakia, premature graying of hair, nail abnormalities, congenital limb anomalies, and deafness. Further evaluation for a familial hematologic disorder or IBMFS is provided separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Evaluation of patients with AL or MDS'.)

The differential diagnosis of AA in adults includes Fanconi anemia, dyskeratosis congenita and other TBDs, GATA2 deficiency, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. (See "Familial disorders of acute leukemia and myelodysplastic syndromes" and "Clinical manifestations and diagnosis of Fanconi anemia" and "Dyskeratosis congenita and other telomere biology disorders" and "Shwachman-Diamond syndrome".)

In one study of patients presenting with bone marrow failure and features suggesting an IBMFS, almost 40 percent were young adults [1]. Even with clear family histories, only half had mutations identified via current germline sequencing panels, suggesting that there remain undiscovered genes associated with IBMFS. In our experience, germline pathogenic mutations are more common in patients with blood counts in the moderate AA range, rather than the severe AA range.

Hypoplastic myelodysplastic syndromes (MDS) – It is important to exclude MDS prior to treatment for AA, especially in older adults [2]. Although most patients with MDS have increased bone marrow cellularity, a minority have a hypocellular bone marrow. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

The distinction between AA and hypocellular MDS can be challenging because both may be associated with some degree of dysplasia and/or certain cytogenetic or molecular findings. A finding of dysplasia in ≥10 percent of cells within a single lineage (particularly in myeloid or megakaryocytic lineages) or in two or more lineages provides strong evidence for MDS; by contrast, AA is more likely to be associated with dysplastic and/or megaloblastic erythroid precursors alone. MDS can also be unequivocally diagnosed based on certain clonal cytogenetic abnormalities alone (ie, without dysplastic changes); examples include loss of all or part of chromosomes 5, 7, or complex changes. Other chromosomal changes (eg, 6pCNLOH, trisomy 6, or loss of 13q) and somatic mutations in genes associated with clonal hematopoiesis of indeterminate potential (CHIP; eg, DNMT3A, TET2, ASXL1) may be seen with AA or MDS; detection of CHIP-associated mutations is not helpful for distinguishing between these conditions [3].

Diagnostic features of MDS and CHIP are described separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Other causes – Some transient causes of pancytopenia, such as a drug reaction or certain infections, can be difficult to distinguish from AA (table 1). These conditions generally cause moderate cytopenias but are unlikely to cause severe, persistent pancytopenia. (See 'Disease severity' below.)

For patients with moderate cytopenias, implicated drugs should be withdrawn, possible infections should be treated, and the patient can be observed for several weeks to exclude alternative causes, as described below. (See 'Moderate AA' below.)

There is a strong association between acquired AA and paroxysmal nocturnal hemoglobinuria (PNH). Detection of CD59/CD55-negative cells or other findings associated with PNH enhance the likelihood of acquired AA rather than an alternative cause of bone marrow failure. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Diagnosis and classification'.)

Disease severity — Severity of AA is classified as follows [4]:

Severe AA (SAA) – At least two of the following are present:

Absolute reticulocyte count (ARC) <60,000/microL (<60 x 109/L); some centers use a threshold of <50,000/microL

Platelet count <20,000/microL (<20 x 109/L)

Absolute neutrophil count (ANC) <500/microL (<0.5 x 109/L)

Very severe AA (vSAA) – Fulfills same criteria as SAA, but ANC <200/micro/L (<0.2 x 109/L)

Moderate (non-severe) AA – Not fulfilling criteria for SAA or vSAA

Distinguishing SAA and vSAA is important prognostically, but the two categories are considered together for treatment decisions. The presence of very severe neutropenia in vSAA increases the urgency for prompt initiation of treatment, as described below. (See 'Importance of prompt treatment' below.)

Although bone marrow hypocellularity is required to diagnose AA, it is not a component of severity grading. Bone marrow cellularity in SAA must be interpreted with caution because it may be heterogeneous (particularly early in the course of the disease), affected by clonal expansion of PNH-associated erythroid precursors in patients with co-existent PNH, and by infiltrating T lymphocytes [5,6].

Details of evaluation and diagnosis of AA are provided separately. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic criteria'.)

Medical fitness — We evaluate medical fitness for intensive therapies based on performance status (PS) and comorbid illnesses.

We assess PS with the Eastern Cooperative Oncology Group (ECOG) PS scale (table 2). Patients with ECOG PS >2 are generally unfit for hematopoietic cell transplantation (HCT) and may not tolerate intensive immunosuppressive therapy (IST). Patients who will receive intensive IST should have adequate renal function to tolerate cyclosporine (CsA) for many months and adequate cardiac function to tolerate antithymocyte globulin (ATG). Eligibility for allogeneic HCT is discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation", section on 'Impact of individual factors'.)

We use the following categories of medical fitness to select treatment of AA:

Medically fit patients can tolerate allogeneic HCT or intensive IST that includes ATG or CsA. (See 'Severe AA/very severe AA' below.)

Medically unfit patients have impaired PS or comorbid conditions that would not permit allogeneic HCT or intensive IST, they but can tolerate less intensive IST or eltrombopag. (See 'Lower-intensity treatments' below.)

When possible, we attempt to improve comorbid medical conditions to enable treatment with the most efficacious therapy, rather than treating with less effective treatments. As an example, for a patient with angina exacerbated by anemia, we might first pursue placement of a coronary stent, if that would enable treatment with intensive therapy.

Frail patients have extreme debility or severe comorbid medical conditions that cannot be reversed prior to initiating treatment. Such patients may benefit from supportive care, but some may select a lower-intensity treatment. (See 'Supportive care' below.)

Age, per se, does not exclude specific treatments nor determine the level of medical fitness. However, because of age-related comorbidities and increased risk of graft-versus-host disease (GVHD), caution should be applied when considering either HCT or intensive IST for patients ≥70 to 75 years old. We further evaluate patients ≥60 years of age with instruments such as the Charlson comorbidity index (CCI), HCT comorbidity index (HCT-CI), or Short Physical Performance Battery (SPPB) or consult with a geriatrician [7], as described separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults", section on 'Pretreatment evaluation'.)

Other pretreatment management

Evaluation for transplantation – For a patient who may be a candidate for HCT, we suggest prompt human leukocyte antigen (HLA) typing and consultation with a transplant team. In addition, the transfusion laboratory should be informed of the potential for transplantation to review transfusion requirements and restrictions.

Fertility and pregnancy – Fertility issues should be addressed with patients who might consider child-bearing, as discussed separately. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

SEVERE AA/VERY SEVERE AA

Importance of prompt treatment — Patients with severe AA (SAA) or very severe AA (vSAA) require prompt and judicious treatment decisions and ongoing supportive care until treatment is effective (algorithm 1). Treatment choices are similar for patients with SAA and vSAA, but the more severe neutropenia of vSAA further increases the urgency for initiation of treatment.

Prompt initiation of treatment is important to reduce the risk of life-threatening infections and limit complications from ongoing transfusions, antibiotics, and other medications. A short-term delay in initiating therapy of SAA/vSAA is acceptable to treat a serious bacterial infection or sepsis. However, we generally do not delay therapy to treat a fungal infection unless it can be managed by surgical resection (eg, mold infection of skin/sinuses/lungs); in general, resolution of a serious fungal infection requires adequate neutrophils, and prompt treatment of SAA is the most effective way to hasten the return of neutrophils in this setting.

Medically fit — For medically fit patients with SAA and vSAA, we stratify initial treatment according to age, fitness, and availability of a suitable allogeneic donor (algorithm 1). We consider 40 years a threshold for treatment decisions in this setting, but there is no consensus and practices vary among institutions. More importantly, age should be considered in the context of medical fitness and patient values and preferences. Eligibility for allogeneic hematopoietic cell transplantation (HCT) is discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

Patients <40 years — Our approach for fit patients <40 years follows:

For patients <40 years (some other experts advise <50 years) with SAA/vSAA and a rapidly-available matched related donor (MRD), we suggest proceeding directly to allogeneic HCT rather than immunosuppressive therapy (IST), because transplantation more rapidly normalizes blood counts and avoids possible clonal progression or disease relapse that can be associated with IST. (See 'Hematopoietic cell transplantation' below.)

For patients without a rapidly-available MRD, we initiate IST, because the search for an alternative donor typically requires at least six to eight weeks. The preferred regimen for IST-based therapy is discussed below. (See 'Triple IST (hATG, CsA, EPAG)' below.)

Patients ≥40 years — For patients ≥40 years (some other experts advise ≥50 years), we suggest triple IST (ie, horse antithymocyte globulin [hATG], cyclosporine [CsA], and eltrombopag) rather than IST with hATG plus CsA alone (without eltrombopag) or other regimens, based on superior outcomes with an acceptable safety profile.

Allogeneic HCT is associated with excessive morbidity and transplant-related mortality (TRM) in this setting; long-term survival is approximately 50 percent (inferior to that of younger patients) and has not changed significantly for several decades [8,9].

Triple IST is associated with a response in two-thirds and long-term survival in three-quarters of adults, but some patients are refractory to therapy, later relapse, or develop clonal progression.

A multicenter phase 3 trial reported that 197 patients (age ≥15 years) with SAA or vSAA who were randomly assigned to triple IST (hATG, CsA, eltrombopag) achieved earlier and higher rates of response with similar toxicity, compared with those who received hATG plus CsA (no eltrombopag) [10]. Triple therapy achieved superior complete response (CR) at three months (22 versus 10 percent, odds ratio 3.2 [95% CI 1.3-7.8]), six months (32 versus 20 percent), and 12 months (52 versus 33 percent) and better overall response rate (ORR) at three months (59 versus 31 percent) and six months (68 versus 41 percent). Triple therapy also achieved earlier first response (3 versus 9 months) and time to transfusion-independence for platelets (40 versus 68 days) and red blood cells (51 versus 140 days). However, there was no significant difference in two-year overall survival (OS; 90 versus 85 percent), the number of patients undergoing subsequent allogeneic HCT, or the degree of improvement in patient-reported outcomes. Acquisition of new mutations and incidence of adverse events (including infectious and hepatic complications) was similar in the two groups.

In a single-institution study, long-term follow-up of 178 patients treated with triple IST was compared with outcomes of historic controls treated with hATG plus CsA (without eltrombopag) [11,12]. There was no significant difference in four-year OS (93 percent with triple IST versus 85 percent for hATG plus CsA). Triple IST was associated with superior six-month ORR (81 versus 67 percent), but half of responding patients in each cohort maintained the response after one year. For patients treated with triple IST, the cumulative four-year incidence of relapse was 43 percent, high-risk clonal evolution developed in 6 percent, and low-risk clonal progression in 9 percent; these rates did not differ from those for the historic controls. However, patients treated with triple IST had earlier time to relapse (median 324 versus 774 days) and time to clonal evolution (median 186 versus 777 days).

There is no upper age limit for treatment with triple IST if kidney, heart, and lung function are sufficient to tolerate this treatment. Administration, toxicity, and outcomes with triple therapy are described below. (See 'Triple IST (hATG, CsA, EPAG)' below.)

Less fit or frail — For patients with SAA/vSAA who are not candidates for intensive IST or HCT, we individualize therapy, with a focus on relieving symptoms, improving quality of life, and prolonging survival, while limiting treatment-related adverse events (algorithm 1).

For patients with impaired heart or kidney function, we attempt to improve the patent's clinical condition to enable treatment with the most efficacious therapy and/or reduce adverse effects of treatment. Evaluation of medical fitness and examples of mitigation of comorbid conditions are described above. (See 'Medical fitness' above.)

Treatment for less-fit or frail patients is informed by the individual patient's values and preferences and is generally based on lower-intensity therapy or supportive care, as described below. (See 'Lower-intensity treatments' below and 'Supportive care' below.)

MODERATE AA — Moderate AA (MAA) is a heterogeneous category with a broad range of manifestations and clinical severity. The spectrum of MAA ranges from patients with ongoing transfusion needs and/or severe neutropenia or thrombocytopenia to those with persistent, mild cytopenias that do not require transfusions or substantially increase the risk for serious infections or bleeding.

When and whom to treat — Before initiating treatment for MAA, we generally follow the patient closely for several weeks to months to better define the trajectory and pace of the illness. Some patients will exhibit spontaneous remission of cytopenias, while others evolve to severe AA (SAA). We do not begin treatment for MAA until transient causes of cytopenias (eg, viral infection, medication) have been excluded. It is particularly important to exclude inherited bone marrow failure syndromes (IBMFS) in this setting because such patients often have cytopenias in the MAA range. (See 'Exclude other causes' above and 'Severe AA/very severe AA' above.)

We begin treatment for MAA when it is clear that ongoing transfusion support is required or the patient's lifestyle is impacted by cytopenias.

Red blood cell (RBC) transfusion-dependence – This is the most frequent indication for initiating treatment in MAA. We generally begin therapy when it is clear that the need for RBC transfusions is not remitting and/or when cumulative transfusions may soon cause iron overload. We typically begin treatment for MAA after transfusion of 6 to 10 units of RBCs.

Persistent, severe neutropenia or thrombocytopenia – In our experience, isolated severe neutropenia or thrombocytopenia are rarely indications for treatment of MAA. If one of these two lineages is severely impacted, at least one other lineage is usually also in the severe range (ie, the patient has SAA) or will soon progress to SAA; such patients require treatment for SAA. For a persistent absolute neutrophil count (ANC) <500/microL, the risk of life-threatening infections is substantial; we generally begin treatment for MAA with such severe neutropenia or in patients with platelet transfusion-dependence.

For patients who do not require ongoing RBC or platelet transfusions and have an ANC ≥500/microL, we continue close follow-up and provide supportive care as needed. (See 'Supportive care' below.)

Initial treatment for MAA — There is no optimal therapy for all patients with MAA who require treatment. Treatment choice is influenced by the ongoing needs for supportive care, degree of transfusion-dependence, severity of cytopenias, medical fitness, and the patient’s values and preferences (algorithm 1).

For most medically fit or less-fit patients with MAA, we suggest initial treatment with either lower-intensity immunosuppressive therapy (IST) or single-agent eltrombopag rather than intensive IST or allogeneic hematopoietic cell transplantation (HCT). We consider lower-intensity IST and eltrombopag equally acceptable based on the favorable balance of efficacy and adverse effects relative to HCT or intensive IST. Some experts avoid eltrombopag in patients with evidence of progression to a clonal disorder or substantial dysplasia with myelodysplastic syndrome (MDS)-defining cytogenetic abnormalities, because of unproven concerns that eltrombopag may enhance clonal proliferation. (See 'Eltrombopag alone' below and 'Lower-intensity IST' below and 'Clonal disorders' below.)

Some experts consider intensive IST to be acceptable for initial treatment of medically fit patients with MAA because they place more emphasis on higher rates of response than on the toxicity. HCT is rarely considered as first-line treatment for MAA, but some younger patients (eg, <40 years) and/or those with ongoing transfusion needs, substantial bleeding, or serious infections may choose HCT as offering a more favorable balance of risks and benefits. (See 'Hematopoietic cell transplantation' below.)

For frail patients, we generally provide supportive care with a focus on symptom relief, with the hope that this may improve the quality of life and/or prolong survival. Some frail patients may choose treatment options for less-fit patients. (See 'Supportive care' below.)

TREATMENTS

Triple IST (hATG, CsA, EPAG) — Triple immunosuppressive therapy (IST) for severe AA (SAA) comprises eltrombopag (EPAG; a bone marrow stimulating agent) plus two immunosuppressive agents (horse antithymocyte globulin [hATG] and cyclosporine [CsA]). As discussed above, triple IST is generally preferred over treatment with hATG plus CsA alone (no eltrombopag). (See 'Patients ≥40 years' above.)

There is no upper age limit for treatment with triple IST, if kidney, heart, and lung function are adequate to tolerate therapy. Evaluation of medical fitness for triple IST is discussed above. (See 'Medical fitness' above.)

A decision to initiate triple IST must balance adverse effects (AEs) of therapy against the recognition that SAA/vSAA, particularly with profound neutropenia, is typically fatal within weeks to months, if untreated. Some experts avoid eltrombopag/triple therapy in patients with cytogenetic abnormalities because of concerns that eltrombopag might stimulate expansion of an abnormal hematopoietic clone; management of patients with clonal disorders is discussed below. (See 'Clonal disorders' below.)

Prior to beginning triple IST, patients generally require a central venous catheter for administration of medications, transfusions, and laboratory testing. IST requires attentive nursing and physician support, access to intensive monitoring for some patients, and knowledge of expected adverse effects and complications.

Medications included in triple IST are:

Horse antithymocyte globulin (hATG) – hATG is an equine polyclonal antithymocyte immune globulin preparation that is associated with a significant risk of infusion reactions and serum sickness [13]. Rabbit antithymocyte globulin (rATG) should not be substituted for hATG for initial treatment of AA, unless hATG is not available, because of a lower response rate in a randomized trial [14].

Pretreatment management – Patients who receive hATG are at risk for infusion reactions and serum sickness. We administer the following prior to treatment:

-Acetaminophen and diphenhydramine before each hATG dose to reduce infusion reactions.

-Prednisone (or methylprednisolone) 1 to 2 mg/kg daily to prevent serum sickness should begin with the first dose of hATG; the steroid should be continued at this dose for 10 days, followed by a rapid taper and discontinuation by day 21. If patients develop a rash or joint pain during the taper, the dose can be increased and/or the taper delayed, as described below.

-We discontinue beta blockers prior to hATG administration to allow more effective use of beta adrenergic agents to support blood pressure, in the event of a severe anaphylactic reaction to hATG.

We do not perform skin testing for hypersensitivity or use a desensitization regimen prior to treatment with hATG, because evidence for predictive value of skin testing is lacking and we do not want to delay initiation of IST.

Administration – hATG should be administered only by clinicians who are experienced with management of its severe and potentially life-threatening AEs.

hATG should be given daily for four consecutive days (beginning on day 1 of triple IST) at a dose of 40 mg/kg intravenously over four hours. If infusion reactions are severe, the duration of each daily infusion can be lengthened to 8 or even 24 hours. The entire course of hATG should be administered over four days; when it is given over longer periods (eg, 8 to 14 days) the incidence and severity of serum sickness is greater. hATG should be given through a central venous catheter, as it is sclerosing to peripheral veins [6].

Although there is no upper age limit for hATG, older patients with underlying cardiovascular and renal abnormalities must be managed very carefully. Frail patients may be unable to tolerate hATG-associated AEs and less intensive regimens should be considered. (See 'Lower-intensity IST' below.)

Adverse effects Infusion reactions and serum sickness are the most significant hATG-associated AEs, which can be mitigated by pretreatment management, as described above.

-Infusion reactions – Immediate infusion reactions to hATG are common and may include fevers to ≥40°C, chills, hypotension or hypertension, third space sequestration of fluid, and hypersensitivity rashes. Patients should be monitored closely and treated with meperidine for rigors, intravenous hydration and or vasopressors for hypotension, and supplemental oxygen for hypoxemia. Other aspects of management of infusion reactions are described separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)

-Serum sickness – Serum sickness is manifest later than acute infusion toxicities; it generally presents days to weeks after initiation of hATG with fever, rash, joint pain, malaise, or other constitutional symptoms [15,16]. If findings of serum sickness break through during the 10-day steroid taper, the taper can be stopped or the dose temporarily increased to 1 mg/kg/day prednisone (or methylprednisolone), along with adequate analgesia. Resolution usually takes several days, at which time the steroid taper should be resumed more slowly and extended for a longer period.

Other conditions may cause fever or other findings that resemble serum sickness. For a fever during or after hATG infusion, neutropenic patients must undergo a full evaluation for infectious causes. Empiric antibiotics should be initiated promptly and continued until the fever abates and microbial cultures are negative. (See "Serum sickness and serum sickness-like reactions", section on 'Differential diagnosis' and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

Cyclosporine (CsA) – CsA is a natural product derived from a fungus; CsA decreases lymphocyte function by inhibiting calcineurin phosphatase activity, thereby reducing T cell proliferation and production of inflammatory cytokines [17].

Administration – The initial dose of CsA is 6 mg/kg per day by mouth in two equal divided doses (ie, 3 mg/kg twice daily at 12-hour intervals), beginning on day 1 of IST. Patients who are concurrently receiving azole antifungal agents require significant reduction in initial dosing to avoid supratherapeutic CsA levels [18]. During initial CsA dose finding, blood pressure should be measured frequently, and serum creatinine and trough CsA levels should be monitored. Subsequent dosing should be titrated to achieve a trough level of 200 to 400 ng/mL; however, we target a trough level of 150 to 250 ng/mL for patients with pre-existent kidney disease or who develop renal dysfunction while receiving CsA [19]. Of note, different analytical techniques for measuring CsA levels can produce large variations in results [20]. (See "Pharmacology of cyclosporine and tacrolimus".)

There is no consensus regarding the optimal protocol and duration of CsA therapy. We generally treat with CsA for 12 months and initiate a slow taper (ie, <10 percent dose reduction at a time) over approximately one year. An alternative approach is treatment with full CsA dose for six months, followed by dose reduction to 2 mg/kg/day (or a trough level closer to 100 to 150 ng/mL) for a total duration of 24 months of CsA. If blood counts begin to drop during the CsA taper, the full dose should be reinstituted, followed by a slower taper after restoration of blood counts. Some patients may require chronic low to moderate dose CsA treatment to maintain blood counts (particularly platelet counts).

AEs – CsA may cause renal insufficiency, hypertension, and magnesium wasting. In our experience, many patients (even without a prior history of hypertension) require antihypertensive agents while taking CsA. Some patients require oral magnesium supplementation, but care must be taken to separate oral magnesium by ≥4 hours from eltrombopag. Neurologic symptoms should be evaluated promptly because CsA can rarely be associated with development of serious neurotoxicity, including posterior reversible encephalopathy syndrome (PRES) and progressive multifocal leukoencephalopathy (PML). 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".)

Eltrombopag in triple IST – For triple IST, eltrombopag should begin on day 1. Dosing, timing of eltrombopag administration, foods and medicines that may affect its absorption, and AEs are described below. While the phase 3 trial of triple IST initiated eltrombopag on day 14 [10], another study reported that eltrombopag AG beginning on day 1 was well-tolerated and appeared to result in a better hematologic complete response (CR) and overall response rate (ORR) [11]. (See 'Eltrombopag alone' below.)

Outcomes – Triple IST (hATG, CsA, and eltrombopag) offers the most favorable balance of outcomes and toxicity for IST in adults with SAA, based on a randomized trial and long-term follow-up of a single-institution study.

For adults with SAA, the single-institution study reported >80 percent six-month ORR, while the phase 3 trial (which used more stringent response criteria) reported 68 percent six-month ORR and 32 percent CR [10,12]. Resolution of severe neutropenia and transfusion-independence generally takes one to two months. The phase 3 trial reported that, compared with hATG plus CsA (no eltrombopag), triple IST achieved superior responses with equivalent toxicity [10]. Rates of CR at 3, 6, and 12 months with triple IST were 22, 32, and 52 percent, respectively; ORR were 59 and 68 percent at three and six months and two-year overall survival (OS) was 90 percent. The cumulative incidence of hemolytic paroxysmal nocturnal hemoglobinuria (PNH) at 24 months was 1 percent and the cumulative incidence of relapse at 18 months was 19 percent; somatic mutations were detected in 31 percent of patients at baseline, which increased to 55 percent at six months. (See 'Patients ≥40 years' above.)

Other studies have reported similar outcomes with triple therapy [11,19,20]. Addition of mycophenolate mofetil or sirolimus to ATG/CsA did not improve response rates [21-24].

Studies that evaluated individual components of triple IST include:

hATG – hATG achieved superior outcomes when compared with rATG in a randomized controlled trial [14]. hATG achieved superior ORR at six months (68 versus 37 percent, respectively) and three-year OS (96 versus 76 percent), while adverse effects and rates of clonal evolution were comparable between the treatment groups. A meta-analysis of 13 studies that compared hATG versus rATG for SAA reported that hATG was associated with higher ORR (risk ratio [RR] 1.33; 95% CI 0.69-2.57) and modestly lower early mortality [25]. No clinical trials have directly compared the efficacy of hATG versus rATG in the context of IST that includes eltrombopag.

Substitution of alemtuzumab for hATG in treatment-naïve patients was also associated with a lower response rate [22].

CsA – For triple IST, compared with six months of CsA, two-year CsA maintenance was associated with a reduced rate of relapse (14 versus 54 percent) [11]. Other studies also reported that two-year treatment with CsA also reduced and delayed relapses when compared to historical cohorts [26,27].

Eltrombopag – Response rates with triple IST are highest when eltrombopag is begun on day 1 of triple IST and continued for six months; OR rate at six months was 94 percent and CR at six months was 58 percent in this cohort [11].

Hematopoietic cell transplantation — Allogeneic hematopoietic cell transplantation (HCT) can cure AA, but transplantation is associated with substantial short- and long-term AEs. HCT both restores the supply of hematopoietic stem/progenitor cells and replaces the immune system that is responsible for depleting them.

Age and medical fitness are important considerations in selecting allogeneic HCT as initial treatment of SAA and for relapsed or refractory AA. (See 'Severe AA/very severe AA' above and 'Refractory AA' below.)

Patients who may be candidates for HCT should have consultation with a multi-disciplinary transplantation team and undergo human leukocyte antigen (HLA) typing soon after being diagnosed with AA. (See 'Other pretreatment management' above.)

Outcomes and AEs with allogeneic HCT for AA are influenced by the age of the recipient. For patients >40 years old, long-term survival after transplantation is approximately 50 percent, which is inferior to survival in children and adolescents; survival after allogeneic HCT in adults has not changed significantly for decades [8,9]. No randomized studies have directly compared IST versus HCT for AA. Studies that have compared HCT with IST are generally small, retrospective, and poorly controlled [6,28-30]. Selection of a conditioning regimen, graft sources, and outcomes with allogeneic HCT for AA are discussed separately. (See "Hematopoietic cell transplantation for aplastic anemia in adults".)

Lower-intensity treatments

Eltrombopag alone — Eltrombopag is a non-peptide thrombopoietin receptor (TPO-R) agonist that can improve blood counts when administered as a single agent or as a component of triple IST. TPO-R is expressed by hematopoietic stem cells and multipotential bone marrow progenitor cells, as well as by maturing megakaryocytes, and eltrombopag acts as a broadly-acting bone marrow stimulating agent [21]. (See "Biology and physiology of thrombopoietin", section on 'Effects on bone marrow precursor cells'.)

Administration – Two different oral formulations of eltrombopag are available. These formulations are not interchangeable, as they are prepared as different salts (olamine versus choline), and they have different tablet strengths and recommended dosing. However, cautions about administration, drug interactions, and adverse effects are similar for both products.

Eltrombopag olamine 150 mg is taken once daily by mouth [31].

Eltrombopag choline 36 mg is taken once daily by mouth [32].

Eltrombopag should be taken on an empty stomach or with a meal low in calcium (eg, ≤50 mg). It should be taken ≥2 hours before or ≥4 hours after any medications or products containing polyvalent cations (eg, calcium, magnesium, aluminum, zinc, selenium, or iron), such as antacids, calcium-rich foods, and mineral supplements.

Individuals of East or Southeast Asian population should receive lower doses because of known population pharmacokinetics. For elevated levels of transaminases, the dose should be reduced and/or temporarily held as described in the package inserts.

Liver function should be monitored before and during treatment, and the dose should be adjusted or discontinued, if needed, as described in the package inserts.

Some experts avoid treatment with eltrombopag in patients with clonal cytogenetic abnormalities or clear evidence for myelodysplasia because of uncertain risks in these patients. Management of patients with AA that progress to clonal disorders is discussed below. (See 'Clonal disorders' below.)

Toxicity – Eltrombopag is generally well-tolerated, although AEs such as skin reactions or elevated hepatic transaminases may occur [11]. The most common AEs (≥20 percent) are nausea, fatigue, cough, diarrhea, and headache. A mild to moderate increase in indirect bilirubin is common, but without consequence to the patient [21]. Effects of long-term use of eltrombopag in AA have not been thoroughly evaluated. (See "Clinical applications of thrombopoietic growth factors", section on 'Side effects and risks'.)

Single-agent eltrombopag achieved a response rate of 50 percent in patients with moderate AA, including those who were not previously treated with IST or who failed prior lower- or higher-intensity IST [33]. Eltrombopag was well-tolerated, and no patients developed myelodysplastic syndrome (MDS) or monosomy 7.

Eltrombopag is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a single agent for SAA in patients with an inadequate response to initial immunosuppression; it is also approved as a component of triple IST in treatment-naïve SAA patients by the FDA, but not yet by the EMA [34]. Eltrombopag has not been shown to be beneficial for treatment of AA in children <15 years. (See "Treatment of acquired aplastic anemia in children and adolescents", section on 'Immune suppression therapy (IST)'.)

Avatrombopag, an oral TPO mimetic with less hepatotoxicity than eltrombopag, is approved by the FDA for treatment of thrombocytopenia associated with liver disease but has not yet been examined as an alternative to eltrombopag for initial treatment of SAA.

Lower-intensity IST — Lower-intensity IST with CsA alone or other immunosuppressive agents was associated with inferior responses when compared with ATG plus CsA. For patients with SAA who have limited heart or kidney function, we generally attempt to optimize the comorbid illness to permit triple IST rather than treating with lower-intensity IST. (See 'Medical fitness' above.)

For patients with moderate AA (MAA), single-agent CsA achieved overall response in 46 percent, transfusion-independence in 67 percent, and 93 percent OS at 180 days [35]. Studies of CsA plus eltrombopag (without hATG) for older or less-fit patients or those with MAA are ongoing. CsA plus levamisole achieved 100 percent response in 42 patients with newly diagnosed MAA and 87 percent response in 76 patients with MAA for >6 months [36]. Outcomes with CsA plus levamisole should be validated before this regimen is adopted.

Supportive care — Supportive care for cytopenias and their complications is important for all patients with AA, throughout the entire course of diagnosis and treatment.

Transfusions – Patients with severe anemia or thrombocytopenia may require transfusions of red blood cells (RBC) and/or platelets to improve anemia-related symptoms, reduce bleeding, and maintain the quality of life. We generally administer leukoreduced, irradiated blood products using a restrictive transfusion approach to reduce complications of transfusion.

All RBC units given to AA patients should be leukoreduced to minimize the risk of febrile nonhemolytic transfusion reactions and reduce transmission of cytomegalovirus (CMV) to CMV-negative patients; this is particularly important if the patient may later undergo allogeneic HCT. Irradiation depletes lymphocytes and reduces the risk of transfusion-associated graft-versus-host disease (ta-GVHD), especially during the first months of intensive IST. We generally transfuse with irradiated blood products, but irradiation may not be required for patients who receive supportive care alone (once an underlying immune deficiency condition has been excluded); patients who are not severely T cell immunodeficient are unlikely to develop ta-GVHD.

We apply a restrictive transfusion strategy and transfuse RBCs for symptomatic and/or severe anemia. Restrictive transfusion targets limit the number of transfusions and reduce the risk of alloimmunization and iron overload. The transfusion threshold should be individualized, based on symptoms, comorbid illnesses, and rate of decline of hemoglobin (Hb). Many centers seek to maintain Hb >7 g/dL, but there is no consensus threshold for transfusion. Blood products from a sibling or family donor should be avoided for potential HCT candidates to minimize the risk of graft failure caused by an immune reaction to donor antigens. Further discussion of RBC transfusions is presented separately. (See "Indications and hemoglobin thresholds for RBC transfusion in adults" and "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)

We generally administer prophylactic platelet transfusions for platelets <10,000/microL, but the transfusion threshold may need to be individualized. For patients with sepsis or recurrent severe bleeding complications, the platelet count should be kept >20,000/microL, especially if bleeding risks organ function. Thrombocytopenia may worsen during treatment with antithymocyte globulin (ATG), due to increased platelet consumption during high fevers and/or cross-reacting antibodies in the ATG preparation. We target >20,000 platelets/microL during and immediately following ATG administration. Platelets should be administered to severely thrombocytopenic patients prior to invasive procedures. Further discussion of platelet transfusion is provided separately. (See "Platelet transfusion: Indications, ordering, and associated risks".)

Transfusion of irradiated granulocytes can be considered in patients with life-threatening infections associated with severe neutropenia, while awaiting count recovery after HCT or definitive IST [37]. (See "Granulocyte transfusions", section on 'Aplastic anemia'.)

Iron management – Iron overload and associated organ toxicities may occur in individuals who receive multiple RBC transfusions. The risk for iron overload primarily affects patients with SAA refractory to initial IST and less-fit patients who choose supportive care alone. Evaluation and management of iron overload are discussed separately. (See "Iron chelators: Choice of agent, dosing, and adverse effects", section on 'Aplastic anemia'.)

Patients with a longer life expectancy who have iron overload may benefit from iron chelation therapy [38]. Deferasirox can be safely administered to patients with AA (ie, it does not cause drug-induced cytopenias). Deferasirox can reduce serum ferritin, but it may impair renal function and it should be used with caution in patients who are taking CsA. For patients who recover normal hematopoiesis after HCT or IST, phlebotomy can be used to reduce excess transfusional iron.

Patients with active hemolysis due to emergence of PNH may become iron depleted due to loss in the urine. Patients who are treated long-term with eltrombopag can become iron deficient due to the potent iron chelation properties of this drug [39].

Infection treatment and prevention – Infections are the major cause of death in AA. Fever with an absolute neutrophil count (ANC) <500/microL is a medical emergency. Evaluation and management of febrile neutropenia are discussed separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

Treatment with allogeneic HCT or intensive IST impairs T cell immunity and increases susceptibility to Pneumocystis jirovecii (formerly called P. carinii). Patients treated for AA should receive prophylaxis against P. jirovecii, but there is no consensus regarding who should receive prophylaxis for viruses, bacteria, or fungi. Our approach follows:

P. jirovecii – For prophylaxis against P. jirovecii, we favor prophylaxis with pentamidine rather than trimethoprim-sulfamethoxazole, because the latter can suppress bone marrow recovery and may increase levels of eltrombopag. We usually treat with monthly aerosolized pentamidine 300 mg beginning one month after beginning hATG and continuing for ≥3 months. (See "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Regimens for prophylaxis'.)

Fungal – For patients with an ANC that is persistently <200 cells/microL, we generally offer antifungal prophylaxis with either voriconazole or posaconazole; however, definitive evidence is lacking that fungal prophylaxis provides a benefit in this setting [38]. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Primary prophylaxis'.)

Viral – There is no consensus regarding viral prophylaxis. Some experts treat with valacyclovir 500 mg once or twice daily by mouth for at least one month following ATG to prevent herpes virus reactivation, but longer-term use must be balanced against a risk for nephrotoxicity that can exacerbate adverse effects of CsA. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)

IST may lead to subclinical reactivation of latent 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 were monitored by polymerase chain reaction (PCR) for virus reactivation, CMV reactivation was seen in 19 of 57 CMV seropositive individuals (33 percent) and EBV reactivation occurred in 82 of 94 EBV seropositive individuals (87 percent); nevertheless, there were no cases of symptomatic CMV or EBV infection [40]. EBV-related post-transplant lymphoproliferative disease has only very rarely been reported after ATG, most often after rabbit ATG [6].

Bacterial – For patients with severe neutropenia, we advise regular mouth care, including an antiseptic mouthwash (eg, chlorhexidine or saline) and food of low bacterial content [38]. We do not routinely administer antibiotic prophylaxis for bacteria, and there are no prospective clinical data regarding antibiotic prophylaxis in AA. We are concerned that prophylactic antibiotics can increase the risk of bacterial resistance, have deleterious effects on intestinal microflora, and some are myelosuppressive. Dietary precautions and other aspects of prevention of bacterial infections in neutropenic patients are discussed separately. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'Neutropenic diet'.)

Vaccinations – Whether and when to administer standard vaccinations (eg, influenza) after IST is controversial [6,41]. There are anecdotal reports of relapse of AA after vaccination but, conversely, active viral infections have been reported to precipitate relapse of AA. We avoid vaccinations within one year of beginning IST and while patients remain on CsA. Outside of these exclusions, decisions about vaccination should weigh the risk of serious complications from influenza or other infections, based on age, comorbidities, and the likelihood of environmental exposure. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

Cytokines – We do not routinely administer granulocyte colony-stimulating factor (G-CSF) and/or erythropoietin (EPO) for patients with AA. Use of eltrombopag in triple IST and as a single agent is discussed above. (See 'Eltrombopag alone' above and 'Triple IST (hATG, CsA, EPAG)' above.)

A trial that randomly assigned 192 patients to ATG plus CsA, with or without added G-CSF, reported that G-CSF was associated with a mild decrease in infections and reduced days in hospital, but there was no difference in OS or event-free survival [42]. Some clinicians treat patients who have profound neutropenia and a life-threatening infection with G-CSF for one to two weeks to assess a possible response [43]. (See "Management of the adult with non-chemotherapy-induced neutropenia", section on 'Myeloid growth factors to treat infection'.)

There is no evidence that G-CSF or EPO can correct the underlying hematopoietic stem/progenitor cell defect in AA or alter the course of disease, response to IST, or OS [42,44-53]. In addition, there are unproven concerns that G-CSF or EPO might increase the incidence of clonal disorders, such as MDS and/or acute leukemia.

RESPONSE MONITORING — Patients treated with immunosuppressive therapy (IST) for AA are monitored regularly for response, toxicities, and evidence of clonal progression.

Schedule and protocol — The schedule and protocol for response monitoring varies by institution, and there is no consensus regarding the optimal approach. Our approach follows:

First six months – During the first six months of IST we schedule outpatient visits every two to four weeks for patients with stable blood counts; for patients with severe cytopenias, closer monitoring may be needed for infection surveillance and transfusion support.

We generally obtain the following laboratory studies:

Complete blood count (CBC) and differential, reticulocyte count, electrolytes, blood urea nitrogen and creatinine, liver transaminases, and cyclosporine (CsA) levels are monitored at least every two to four weeks following hospital discharge. Patients with severe thrombocytopenia may require weekly or biweekly CBCs to assess a need for platelet transfusions.

Bone marrow examination should be performed at three and six months. For patients who have a partial response or if blood counts decline unexpectedly, we repeat a bone marrow examination to assess clonality or evidence of a hematologic malignancy.

Beyond six months – The interval between outpatient visits and laboratory studies can be increased after six months, as guided by the patient's clinical status. For patients still taking eltrombopag and/or CsA who are transfusion-independent and have an absolute neutrophil count (ANC) >500/microL, the interval between visits can be increased to monthly. Some experts repeat a bone marrow examination prior to beginning a taper of CsA.

Once a patient has discontinued all medications, the interval between visits can be increased to every three months, then every six months for the first two to three years, and then yearly.

Response assessment — Response to therapy is determined by trends in blood counts, rather than a single CBC. Therapy should not be altered based on an isolated value, because it may reflect normal oscillations in counts or an intercurrent infection.

Treatment responses are described as follows:

Hematologic response is defined as independence from transfusions and improvement of peripheral blood counts to the point that they no longer meet the criteria for severe AA (SAA) [15]. Most responses occur within the first three months of therapy, but some responses occur later in the first year of therapy.

Complete response has been defined variably in different clinical trials, but it requires transfusion-independence, along with hemoglobin >10/dL and platelet count >50,000 or >100,000/microL. It should be noted that a significant percentage of patients with SAA with otherwise excellent responses to IST never reach platelet counts >150,000/microL; there is no clear evidence that patients who have an otherwise robust hematologic response have increased rates of relapse or clonal progression.

Partial response is a clear improvement in blood counts and/or transfusion requirements that did not reach the thresholds that define a complete hematologic response.

Refractory disease refers to the lack of a significant improvement in blood counts and/or transfusion requirements; as discussed below, refractory disease should be distinguished from partial hematologic response. (See 'Refractory AA' below.)

Relapse describes a decline in blood counts after achieving a hematologic response.

Management of refractory and relapsed AA are described below. (See 'Refractory AA' below and 'Relapse' below.)

REFRACTORY AA — It is important to distinguish refractory disease, in which there was no meaningful response to treatment, from a partial hematologic response, in which the patient has clear clinical improvement with a stable pattern of modestly improved blood counts and/or transfusion-independence, as described above. (See 'Response assessment' above.)

In patients who are refractory to immunosuppressive therapy (IST), it is important to re-evaluate the underlying diagnosis. In some patients, refractoriness to IST may reflect a previously unrecognized underlying inherited bone marrow failure syndrome (IBMFS), while in others it may be due to progression to a myelodysplastic syndrome (MDS). (See 'Exclude other causes' above.)

Approximately 10 percent of patients with severe AA (SAA) are refractory to initial treatment with triple IST, while at least one-third of patients are refractory to other IST regimens. It is unclear whether refractory disease represents ongoing immune attack on hematopoietic cells (ie, inadequate immunosuppression) or a persistent deficiency of hematopoietic stem cells [54].

We favor participation in a clinical trial for these patients, when possible. Outside of a trial, the choice of treatment for refractory AA is influenced by the severity of cytopenias, medical fitness, and other factors, as described in the following sections.

Eligible for HCT – For patients with SAA that is refractory to triple IST, we relax the criteria for eligibility for allogeneic hematopoietic cell transplantation (HCT); especially when there is a suitable matched related donor (MRD), we generally consider medically fit patients ≤65 years of age to be eligible for transplantation.

For patients who are eligible for transplantation and have a suitable donor, we suggest allogeneic HCT rather than a second course of intensive IST or an alternative IST regimen. This suggestion is based on the balance of benefits and toxicities with HCT, in light of the high rate of mortality with prolonged, profound cytopenias.

For patients who do not have a suitable MRD, we initiate a search for a matched unrelated donor, haploidentical donor (eg, parent or child), or umbilical cord blood donor. The preferred alternative donor source varies by institution. Choices of conditioning regimen, graft source, management of complications, and outcomes of allogeneic HCT in this setting are discussed separately. (See "Hematopoietic cell transplantation for aplastic anemia in adults".)

Not eligible for HCT – There is no consensus regarding the optimal management for a patient with refractory SAA who is not a candidate for transplantation. The choice of treatment must be individualized and is informed by prior treatment. Examples include:

No prior eltrombopag (EPAG) – For patients who did not previously receive eltrombopag, we offer treatment with eltrombopag alone. However, we generally avoid treatment with eltrombopag for patients with a clonal cytogenetic abnormality. (See 'Triple IST (hATG, CsA, EPAG)' above and 'Clonal disorders' below.)

Eltrombopag monotherapy achieved 40 percent overall response at three to four months in 43 patients with refractory AA and persistent thrombocytopenia following IST [55,56]. Among 83 patients who received this regimen, evolution to an abnormal karyotype occurred in 19 percent, most seen within six months of beginning eltrombopag [57]. More than half of these cases involved complete or partial loss of chromosome 7, but only one patient had dysplasia; other karyotypic findings were often transient and not associated with disease progression. Compared with baseline, there was no change in the incidence or level of somatic mutations in myeloid cancer genes after six months of eltrombopag, or at longest follow-up in patients remaining on drug.

No prior horse antithymocyte globulin (hATG) – For patients who did not previously receive hATG, we treat with an hATG-including regimen. Responses to hATG were reported in 21 percent of 19 patients initially treated with CsA plus rabbit ATG (rATG) and in one of six patients who initially received cyclophosphamide plus CsA; three-year overall survival (OS) was 68 percent [58]. In a study of 30 patients with refractory disease following treatment with hATG and CsA, 77 percent had a disease response to a regimen that included rATG and CsA; with median follow-up of 2.5 years, OS was 93 percent, with no additional relapses [59].

Prior treatment included hATG – Patients who were previously treated with hATG may be treated with rATG, but they should not be treated again with hATG because of a high incidence of serum sickness [15,60-62]. Approximately one-third of patients with refractory AA respond to a second course of ATG, but failure-free survival may be as low as 10 percent [63].

Other agents

-Romiplostim is a parenteral thrombopoietin (TPO) agonist with substantial activity in refractory SAA. Romiplostim is a peptibody that comprises a TPO receptor (TPO-R) binding domain and an Fc module (to increase half-life). It enhances hematopoiesis by binding TPO-R, which is expressed by hematopoietic stem cells, multipotential bone marrow progenitor cells, and maturing megakaryocytes [64].

In a study of 31 patients (13 with either SAA or very severe AA [vSAA]), romiplostim was associated with 84 percent hematologic response at 27 weeks and 39 percent trilineage response at 53 weeks [65]. Although patients were judged refractory to immunotherapy, one-quarter had not previously received ATG. Patients initially received romiplostim 10 mcg/kg subcutaneously weekly, but the dose was titrated upward based on platelet count. Three patients had grade ≥3 hepatic toxicity, but all other adverse effects (eg, headache, muscle spasms) were mild or moderate. Other studies have also reported that romiplostim was effective and well-tolerated for refractory SAA and was not associated with clonal evolution [66].

-Alemtuzumab is a monoclonal antibody against CD52, which is expressed on lymphocytes and other hematopoietic cells. It may be given as a single agent or in combination with CsA. A consensus protocol for alemtuzumab administration has been published [67].

Alemtuzumab can be given to patients who are not tolerating additional CsA due to renal dysfunction. Alemtuzumab is associated with hypo- or hyper-thyroidism in some patients, but it is otherwise generally well-tolerated in patients with AA [22]. Neutrophil counts may drop after administration and can increase the risk for infections [68]. For patients treated with alemtuzumab, we suggest prophylaxis for P. jirovecii, because T cell counts can remain extremely low for months following treatment.

Autoimmune encephalitis (AIE) has been reported in association with alemtuzumab treatment [69]; patients with symptoms such as subacute onset of memory impairment, altered mental status, psychiatric symptoms, neurological findings, and/or seizures should be evaluated for AIE. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

A trial randomly assigned 54 patients with hATG/CsA-refractory disease to alemtuzumab monotherapy (10 mg/day for 10 days) versus rATG/CsA; similar response rates were reported for both arms (37 versus 33 percent) [22].

-High dose cyclophosphamide – We generally do not treat refractory AA with high dose cyclophosphamide because of its severe toxicity in this setting. Approximately half of 40 patients with refractory AA responded to cyclophosphamide (50 mg/kg/day for four days), but toxicity was appreciable and several died early due to severe infections [70,71].

RELAPSE — Relapses occur in up to one-third of patients who initially achieved a response to immunosuppressive therapy (IST). The actuarial rate of relapse among 719 patients treated with antithymocyte globulin (ATG; with or without cyclosporine [CsA], glucocorticoids, or other agents) was 35 percent at 14 years [47,72,73]. The likelihood of relapse is not predicted by age or disease severity, and relapse does not appear to be predictive of increased mortality [74-76]. Triple IST (ATG, CsA, plus eltrombopag), despite a higher response rate, does not appear to prevent relapse, with 39 percent cumulative relapse rate at four years [12].

When relapse is suspected, it is important to obtain serial blood counts over a period of at least several weeks, to be sure that the changes are not due to laboratory error or a transient worsening in response to a viral infection or other marrow stress. We perform a bone marrow examination to assess possible progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) for patients whose blood counts have declined.

For blood counts that decline during a taper of CsA, we reinstitute full dose CsA; this can generally halt the decline and/or improve cytopenias within weeks to two months. If blood counts do not respond to reinstitution of CsA, eltrombopag can be added. Approximately two-thirds of patients respond to reinstitution of one or both oral medications. However, for patients with rapidly worsening counts and/or severe neutropenia, we generally treat with triple IST, alemtuzumab, or allogeneic hematopoietic cell transplantation (HCT). Approximately 55 to 60 percent of patients with relapsed AA respond to a second course of IST [15,60,61].

SPECIAL CONSIDERATIONS

Clonal disorders — Patients with AA may develop clonal cytogenetic abnormalities that, in some cases, progress to myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or paroxysmal nocturnal hemoglobinuria (PNH). The presence of a clonal disorder influences decisions regarding monitoring and treatment of AA. Clonal progression may occur before, during, or after treatment for AA, and it is not clear whether this is due to therapy or the underlying disease.

Progression to PNH Patients with AA have an increased risk of developing PNH; conversely, patients with PNH have an increased risk of later developing AA. Clinical PNH can evolve following a response to immunosuppressive therapy (IST), due to emergence of endogenous PNH red blood cells (RBC); in contrast, clonal progression is rare following hematopoietic cell transplantation (HCT) [77].

Cells that have lost expression of glycosylphosphatidylinositol (GPI) proteins (a hallmark of PNH) may evade immune attack and thereby have a survival advantage in the setting of immune-mediated bone marrow failure. In one large study of 207 consecutive patients presenting with severe AA (SAA), 40 percent had a detectable population of PNH neutrophils (ie, lacking expression of GPI-linked proteins), with a median clone size of 9 percent [78]. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'Aplastic anemia'.)

Patients who become symptomatic with hemolytic anemia, thrombosis, or other clinical manifestations of PNH should be treated for PNH. In the rare patient who presents with concurrent hemolytic PNH and SAA, or in patients with PNH that is progressing to SAA, concurrent treatment with IST and eculizumab is feasible [79]. Response to IST is similar in individuals with and without a PNH clone [78,80,81]. Some PNH clones diminish in response to IST, while others show expansion. HCT can cure both SAA and PNH, but treatment with eculizumab prior to transplantation may lessen acute hemolytic events during HCT conditioning. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)

Monitoring patients with AA/PNH – Patients without active hemolysis and a stable-sized GPI-negative clone require no additional monitoring beyond annual flow cytometry for GPI-negative neutrophils and the standard AA follow-up. Additional surveillance bone marrow examinations and/or mutation analysis are not needed, unless there is a significant decrease in blood counts concerning for AA relapse and/or clonal replacement. (See 'Response monitoring' above.)

For patients with clinical manifestations of PNH or a clone that is increasing in size, monitoring and management should reflect that of de novo PNH, as discussed separately. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)

Cytogenetic or morphologic progression to MDS or AML For individuals who develop MDS, AML, monosomy 7, or complex cytogenetic abnormalities, treatment is similar to that for the corresponding de novo diseases. In our experience, patients with AA are unlikely to tolerate or respond to azacitidine, decitabine, or intensive induction chemotherapy, and we promptly refer them for evaluation of possible transplantation, if sufficiently fit. (See "Overview of the treatment of myelodysplastic syndromes" and "Acute myeloid leukemia in adults: Overview" and "Acute myeloid leukemia in younger adults: Post-remission therapy".)

We generally avoid treatment with eltrombopag in patients with progression to a clonal disorder other than PNH, because it may stimulate growth and/or survival of hematopoietic stem and progenitor cells with a clonal abnormality. Cells that harbor monosomy 7 have been reported to appear and progress rapidly in patients with refractory AA after beginning eltrombopag [57].

Monitoring for MDS/AML progression – For patients with declining blood counts or dysplasia, we perform a bone marrow examination with cytogenetics to evaluate for MDS or AML. In this setting, we repeat mutation analysis and compare the variant allele fraction to baseline; however, the relevance of such changes in the absence of additional evidence for clinical progression is presently unclear.

For patients who are being treated with eltrombopag, the US Food and Drug Administration (FDA) label suggests a bone marrow examination every six months to screen for emergence of cytogenetic abnormalities or morphologic changes [34].

Pregnancy and fertility — It is unclear if pregnancy increases the risk for AA, but AA can present during pregnancy and pregnancy appears to increase the risk of relapse of AA.

Management of a mother with AA and her fetus must be individualized:

Pregnancy – Supportive care is the mainstay of treatment of AA in pregnancy. We generally provide the mother with transfusions and delay definitive therapy with IST or transplantation until after delivery. The platelet count should be maintained >20,000/microL with platelet transfusions. Cyclosporine (CsA) can be given during pregnancy, if necessary, based on a larger experience of its safe administration following solid organ transplantation.

Pregnancy and a good obstetrical outcome are possible for women previously treated with IST. In a report of 36 women who had received IST and subsequently became pregnant, relapse of AA occurred in seven; relapse was more likely in women who initially had only a partial response to IST [82]. In this study, three women recovered spontaneously in the postpartum period, three responded to additional IST, a woman with AA and PNH had a fatal cerebral thrombosis after delivery, and one died of her disease [82]. There were two cases of preeclampsia and five required transfusions during delivery. There was minimal impact on the fetus, with only rare miscarriage or neonatal complications.

Fertility – Given the frequent presentation of patients before or during the child-bearing years, fertility is a concern of many patients and may influence the choice of transplantation versus IST. Pregnancy is possible following HCT, although transplantation is more likely to affect fertility than IST. Most reported pregnancies have occurred in patients receiving only cyclophosphamide and antithymocyte globulin (ATG) conditioning, with rarer reports in those receiving more intensive conditioning with busulfan and/or total lymphoid irradiation [83].

Storing sperm prior to HCT for male patients is appropriate, but delaying HCT for egg retrieval in women with severe AA/very severe AA may not be advisable in patients at diagnosis (to avoid delays in initiating definitive therapy) and in patients with severe neutropenia. Ovarian tissue procurement and cryopreservation may be limited by risks of invasive surgery in patients with thrombocytopenia and neutropenia.

Older patients — There is no clear evidence to guide therapy for older patients with AA. We select a course of therapy based on medical fitness rather than a particular age threshold. (See 'Medical fitness' above and 'Severe AA/very severe AA' above.)

We have successfully treated patients into their eighties with intensive IST. Age influences decisions regarding eligibility for HCT, as discussed above. For older patients who are medically unfit or frail, acceptable options for treatment include single-agent CsA or eltrombopag, alemtuzumab, or anabolic steroids (eg, danazol).

PROGNOSIS — The overall prognosis of patients with severe AA (SAA) has improved with advances in supportive care, immunosuppressive therapy (IST) and triple IST, and hematopoietic cell transplantation (HCT). Current 5- or 10-year survival rates are as high as 80 to 90 percent, compared with 10 to 20 percent in the 1960s [38,84]. Untreated, SAA has a one-year mortality >70 percent [85].

Certain clinical and laboratory features of AA are associated with prognosis. Younger age and less severe disease are associated with more favorable outcomes [86]. Conversely, inferior outcomes have been associated with lower absolute reticulocyte count (ARC; ie, <25,000/microL) or lower absolute lymphocyte count (ALC; ie, <1000/microL) [87]. In some studies, trisomy 8 or del(13q) in the context of AA predicts for good response to antithymocyte globulin (ATG), and longer telomeres identify a subgroup of patients who show excellent overall survival after IST [88-90].

Examples of informative studies include:

A retrospective analysis of 316 patients with SAA treated with IST reported higher response rates and improved survival in younger patients and those with higher ARC and ALC [87]. 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.

A registry study of 1176 children and adults who underwent HCT for AA between 1995 and 2006 reported five-year survival was 76 percent overall [83]. The five-year cumulative incidence of chronic graft-versus-host disease was 22 percent in matched sibling transplants and 37 percent in unrelated donor transplants.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

Acquired aplastic anemia (AA) – AA is an immune-mediated hematopoietic disorder characterized by hypocellular bone marrow and possible life-threatening cytopenias.

Pretreatment evaluation

Exclude other conditions – Other inherited bone marrow failure syndromes (IBMFS), hypoplastic myelodysplastic syndrome, and other conditions (table 1) should be excluded. (See 'Exclude other causes' above.)

Severity – AA is categorized according to the severity of cytopenias (defined above) (see 'Disease severity' above) as:

-Severe AA (SAA)

-Very severe AA (vSAA)

-Moderate AA (MAA)

Fitness – We determine medical fitness based on performance status (PS) (table 2) and comorbid illnesses. (See 'Medical fitness' above.)

Transplant evaluation – Eligibility for hematopoietic cell transplantation (HCT) and human leukocyte antigen (HLA) typing should be performed soon after diagnosis of AA. (See 'Other pretreatment management' above.)

SAA/vSAA

Prompt treatment – Prompt evaluation and treatment (algorithm 1) is important to lessen severe infections and other complications. (See 'Severe AA/very severe AA' above.)

Medically fit

-Age <40 years – For patients <40 years with a suitable HLA-matched related donor (MRD), we suggest allogeneic HCT rather than immunosuppressive therapy (IST) (Grade 2C). (See 'Patients <40 years' above.)

For patients without a rapidly-available MRD, we initiate triple IST, but begin a search for an alternative donor in the event that IST is not successful.

-Age ≥40 years – For patients ≥40 years, we suggest triple IST therapy (ie, horse antithymocyte globulin [hATG], cyclosporine [CsA], and eltrombopag), rather than IST with hATG plus CsA alone (without eltrombopag) or other regimens (Grade 2B). (See 'Patients ≥40 years' above.)

Less fit or frail – For patients who are not candidates for intensive IST or HCT, we focus on relieving symptoms, improving quality of life, and prolonging survival, while limiting treatment-related adverse events. (See 'Less fit or frail' above.)

MAA – MAA is a heterogeneous category with a broad range of manifestations and clinical severity. We monitor patients with MAA for weeks or months to define the trajectory and pace of the illness. (See 'Moderate AA' above.)

Management of MAA – For most medically fit or less-fit patients with MAA, we suggest initial treatment with either lower-intensity IST or single-agent eltrombopag, rather than intensive IST or allogeneic HCT (Grade 2C). (See 'Lower-intensity treatments' above.)

Treatments

Triple IST – Administration, cautions, and outcomes with triple IST are discussed above. (See 'Triple IST (hATG, CsA, EPAG)' above.)

Transplantation – Use of HCT for AA is discussed separately. (See "Hematopoietic cell transplantation for aplastic anemia in adults".)

Lower-intensity treatments – Treatment with eltrombopag alone or other lower-intensity approaches are discussed above. (See 'Lower-intensity treatments' above.)

Supportive care – All patients with AA may require transfusions, management of iron overload, and infection prevention/management. (See 'Supportive care' above.)

ACKNOWLEDGMENT — Contributions provided by Cynthia Dunbar, MD to UpToDate were written in a personal capacity and do not necessarily reflect the opinions or endorsement of the National Institutes of Health (NIH), Department of Human Health Services (HHS), or the Federal Government.

The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

  1. Bluteau O, Sebert M, Leblanc T, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood 2018; 131:717.
  2. Tichelli A, Marsh JC. Treatment of aplastic anaemia in elderly patients aged >60 years. Bone Marrow Transplant 2013; 48:180.
  3. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med 2015; 373:35.
  4. Rovó A, Tichelli A, Dufour C, SAA-WP EBMT. Diagnosis of acquired aplastic anemia. Bone Marrow Transplant 2013; 48:162.
  5. Guinan EC. Diagnosis and management of aplastic anemia. Hematology Am Soc Hematol Educ Program 2011; 2011:76.
  6. Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol 2016; 172:187.
  7. Derman BA, Kordas K, Ridgeway J, et al. Results from a multidisciplinary clinic guided by geriatric assessment before stem cell transplantation in older adults. Blood Adv 2019; 3:3488.
  8. Giammarco S, Peffault de Latour R, Sica S, et al. Transplant outcome for patients with acquired aplastic anemia over the age of 40: has the outcome improved? Blood 2018; 131:1989.
  9. Gupta V, Eapen M, Brazauskas R, et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica 2010; 95:2119.
  10. Peffault de Latour R, Kulasekararaj A, Iacobelli S, et al. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med 2022; 386:11.
  11. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med 2017; 376:1540.
  12. Patel BA, Groarke EM, Lotter J, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood 2022; 139:34.
  13. https://www.fda.gov/media/78206/download (Accessed on April 09, 2020).
  14. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med 2011; 365:430.
  15. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012; 120:1185.
  16. Bielory L, Gascon P, Lawley TJ, et al. Human serum sickness: a prospective analysis of 35 patients treated with equine anti-thymocyte globulin for bone marrow failure. Medicine (Baltimore) 1988; 67:40.
  17. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/050715s035,050716s038lbl.pdf (Accessed on April 10, 2020).
  18. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050573s035,050574s043,050625s049lbl.pdf (Accessed on May 22, 2020).
  19. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050715s027,050716s028lbl.pdf (Accessed on April 20, 2020).
  20. Holt DW, Johnston A, Kahan BD, et al. New approaches to cyclosporine monitoring raise further concerns about analytical techniques. Clin Chem 2000; 46:872.
  21. Scheinberg P. Activity of eltrombopag in severe aplastic anemia. Blood Adv 2018; 2:3054.
  22. Scheinberg P, Nunez O, Weinstein B, et al. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood 2012; 119:345.
  23. Scheinberg P, Nunez O, Wu C, Young NS. Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil. Br J Haematol 2006; 133:606.
  24. Scheinberg P, Wu CO, Nunez O, et al. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study. Haematologica 2009; 94:348.
  25. Hayakawa J, Kanda J, Akahoshi Y, et al. Meta-analysis of treatment with rabbit and horse antithymocyte globulin for aplastic anemia. Int J Hematol 2017; 105:578.
  26. Frickhofen N, Heimpel H, Kaltwasser JP, et al. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood 2003; 101:1236.
  27. Scheinberg P, Rios O, Scheinberg P, et al. Prolonged cyclosporine administration after antithymocyte globulin delays but does not prevent relapse in severe aplastic anemia. Am J Hematol 2014; 89:571.
  28. Young NS. Aplastic Anemia. N Engl J Med 2018; 379:1643.
  29. Aljurf M, Al-Zahrani H, Van Lint MT, Passweg JR. Standard treatment of acquired SAA in adult patients 18-40 years old with an HLA-identical sibling donor. Bone Marrow Transplant 2013; 48:178.
  30. Bacigalupo A, Brand R, Oneto R, et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000; 37:69.
  31. Drug packaging information for PROMACTA eltrombopag olamine tablet and powder. DailyMed. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7714a0ed-34bb-46e6-a0a5-b363908b22c2 (Accessed on December 01, 2023).
  32. FDA drug prescription information for ALVAIZ eltrombopag tablets. US Food and Drug Administration. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216774s000lbl.pdf (Accessed on December 01, 2023).
  33. Fan X, Desmond R, Winkler T, et al. Eltrombopag for patients with moderate aplastic anemia or uni-lineage cytopenias. Blood Adv 2020; 4:1700.
  34. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207027s000lbl.pdf (Accessed on April 07, 2020).
  35. Marsh J, Schrezenmeier H, Marin P, et al. Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood 1999; 93:2191.
  36. Li X, Shao Y, Ge M, et al. A promising immunosuppressive strategy of cyclosporine alternately combined with levamisole is highly effective for moderate aplastic anemia. Ann Hematol 2013; 92:1239.
  37. Quillen K, Wong E, Scheinberg P, et al. Granulocyte transfusions in severe aplastic anemia: an eleven-year experience. Haematologica 2009; 94:1661.
  38. Höchsmann B, Moicean A, Risitano A, et al. Supportive care in severe and very severe aplastic anemia. Bone Marrow Transplant 2013; 48:168.
  39. Zhao Z, Sun Q, Sokoll LJ, et al. Eltrombopag mobilizes iron in patients with aplastic anemia. Blood 2018; 131:2399.
  40. Scheinberg P, Fischer SH, Li L, et al. Distinct EBV and CMV reactivation patterns following antibody-based immunosuppressive regimens in patients with severe aplastic anemia. Blood 2007; 109:3219.
  41. Hendry CL, Sivakumaran M, Marsh JC, Gordon-Smith EC. Relapse of severe aplastic anaemia after influenza immunization. Br J Haematol 2002; 119:283.
  42. Tichelli A, Schrezenmeier H, Socié G, et al. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood 2011; 117:4434.
  43. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015; 33:3199.
  44. Marsh JC, Socie G, Schrezenmeier H, et al. Haemopoietic growth factors in aplastic anaemia: a cautionary note. European Bone Marrow Transplant Working Party for Severe Aplastic Anaemia. Lancet 1994; 344:172.
  45. Deyell RJ, Shereck EB, Milner RA, Schultz KR. Immunosuppressive therapy without hematopoietic growth factor exposure in pediatric acquired aplastic anemia. Pediatr Hematol Oncol 2011; 28:469.
  46. Kadia TM, Borthakur G, Garcia-Manero G, et al. Final results of the phase II study of rabbit anti-thymocyte globulin, ciclosporin, methylprednisone, and granulocyte colony-stimulating factor in patients with aplastic anaemia and myelodysplastic syndrome. Br J Haematol 2012; 157:312.
  47. Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO). Blood 2000; 95:1931.
  48. Bacigalupo A, Broccia G, Corda G, et al. Antilymphocyte globulin, cyclosporin, and granulocyte colony-stimulating factor in patients with acquired severe aplastic anemia (SAA): a pilot study of the EBMT SAA Working Party. Blood 1995; 85:1348.
  49. Socie G, Mary JY, Schrezenmeier H, et al. Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT). Blood 2007; 109:2794.
  50. Locasciulli A, Bruno B, Rambaldi A, et al. Treatment of severe aplastic anemia with antilymphocyte globulin, cyclosporine and two different granulocyte colony-stimulating factor regimens: a GITMO prospective randomized study. Haematologica 2004; 89:1054.
  51. Kojima S, Hibi S, Kosaka Y, et al. Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood 2000; 96:2049.
  52. Gluckman E, Rokicka-Milewska R, Hann I, et al. Results and follow-up of a phase III randomized study of recombinant human-granulocyte stimulating factor as support for immunosuppressive therapy in patients with severe aplastic anaemia. Br J Haematol 2002; 119:1075.
  53. Teramura M, Kimura A, Iwase S, et al. Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan. Blood 2007; 110:1756.
  54. Desmond R, Townsley DM, Dunbar C, Young NS. Eltrombopag in aplastic anemia. Semin Hematol 2015; 52:31.
  55. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med 2012; 367:11.
  56. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood 2014; 123:1818.
  57. Winkler T, Fan X, Cooper J, et al. Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag. Blood 2019; 133:2575.
  58. Scheinberg P, Townsley D, Dumitriu B, et al. Horse antithymocyte globulin as salvage therapy after rabbit antithymocyte globulin for severe aplastic anemia. Am J Hematol 2014; 89:467.
  59. Di Bona E, Rodeghiero F, Bruno B, et al. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Br J Haematol 1999; 107:330.
  60. Marsh JC, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2009; 147:43.
  61. Passweg JR, Marsh JC. Aplastic anemia: first-line treatment by immunosuppression and sibling marrow transplantation. Hematology Am Soc Hematol Educ Program 2010; 2010:36.
  62. Marsh JC, Bacigalupo A, Schrezenmeier H, et al. Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party. Blood 2012; 119:5391.
  63. Kosaka Y, Yagasaki H, Sano K, et al. Prospective multicenter trial comparing repeated immunosuppressive therapy with stem-cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia. Blood 2008; 111:1054.
  64. Molineux G, Newland A. Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: from bench to bedside. Br J Haematol 2010; 150:9.
  65. Jang JH, Tomiyama Y, Miyazaki K, et al. Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study. Br J Haematol 2021; 192:190.
  66. Lee JW, Lee SE, Jung CW, et al. Romiplostim in patients with refractory aplastic anaemia previously treated with immunosuppressive therapy: a dose-finding and long-term treatment phase 2 trial. Lancet Haematol 2019; 6:e562.
  67. Risitano AM, Schrezenmeier H. Alternative immunosuppression in patients failing immunosuppression with ATG who are not transplant candidates: Campath (Alemtuzumab). Bone Marrow Transplant 2013; 48:186.
  68. http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/alemmil050701LB.htm (Accessed on September 15, 2015).
  69. Highlights of prescribing information: Lemtrada (alemtuzumab). US Food and Drug Administration. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/103948s5185lbl.pdf (Accessed on June 03, 2022).
  70. Brodsky RA, Chen AR, Dorr D, et al. High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. Blood 2010; 115:2136.
  71. Brodsky RA, Chen AR, Brodsky I, Jones RJ. High-dose cyclophosphamide as salvage therapy for severe aplastic anemia. Exp Hematol 2004; 32:435.
  72. Paquette RL, Tebyani N, Frane M, et al. Long-term outcome of aplastic anemia in adults treated with antithymocyte globulin: comparison with bone marrow transplantation. Blood 1995; 85:283.
  73. Schrezenmeier H, Marin P, Raghavachar A, et al. Relapse of aplastic anaemia after immunosuppressive treatment: a report from the European Bone Marrow Transplantation Group SAA Working Party. Br J Haematol 1993; 85:371.
  74. Rosenfeld SJ, Kimball J, Vining D, Young NS. Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia. Blood 1995; 85:3058.
  75. Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA 2003; 289:1130.
  76. Tichelli A, Passweg J, Nissen C, et al. Repeated treatment with horse antilymphocyte globulin for severe aplastic anaemia. Br J Haematol 1998; 100:393.
  77. Oved JH, Stanley N, Babushok DV, et al. Development of hemolytic paroxysmal nocturnal hemoglobinuria without graft loss following hematopoietic stem cell transplantation for acquired aplastic anemia. Pediatr Transplant 2019; 23:e13393.
  78. Scheinberg P, Marte M, Nunez O, Young NS. Paroxysmal nocturnal hemoglobinuria clones in severe aplastic anemia patients treated with horse anti-thymocyte globulin plus cyclosporine. Haematologica 2010; 95:1075.
  79. Griffin M, Kulasekararaj A, Gandhi S, et al. Concurrent treatment of aplastic anemia/paroxysmal nocturnal hemoglobinuria syndrome with immunosuppressive therapy and eculizumab: a UK experience. Haematologica 2018; 103:e345.
  80. Dunn DE, Tanawattanacharoen P, Boccuni P, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999; 131:401.
  81. Piaggio G, Podestà M, Pitto A, et al. Coexistence of normal and clonal haemopoiesis in aplastic anaemia patients treated with immunosuppressive therapy. Br J Haematol 1999; 107:505.
  82. Tichelli A, Socié G, Marsh J, et al. Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression. Ann Intern Med 2002; 137:164.
  83. Buchbinder D, Nugent DJ, Brazauskas R, et al. Late effects in hematopoietic cell transplant recipients with acquired severe aplastic anemia: a report from the late effects working committee of the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2012; 18:1776.
  84. Scheinberg P. Aplastic anemia: therapeutic updates in immunosuppression and transplantation. Hematology Am Soc Hematol Educ Program 2012; 2012:292.
  85. Young NS. Aplastic anaemia. Lancet 1995; 346:228.
  86. Tichelli A, Socié G, Henry-Amar M, et al. Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party. Ann Intern Med 1999; 130:193.
  87. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol 2009; 144:206.
  88. Maciejewski JP, Risitano A, Sloand EM, et al. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 2002; 99:3129.
  89. Holbro A, Jotterand M, Passweg JR, et al. Comment to "Favorable outcome of patients who have 13q deletion: a suggestion for revision of the WHO 'MDS-U' designation" Haematologica. 2012;97(12):1845-9. Haematologica 2013; 98:e46.
  90. Scheinberg P, Cooper JN, Sloand EM, et al. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA 2010; 304:1358.
Topic 7158 Version 80.0

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