Aplastic Anemia Treatment & Management

Updated: Dec 05, 2018
  • Author: Sameer Bakhshi, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Approach Considerations

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

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

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

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

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

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

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

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

Transfer considerations

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


Blood Transfusion

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

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

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

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

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


Treatment of Infections

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

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

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

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


Hematopoietic Cell Transplantation

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

HCT using an HLA-matched sibling donor

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

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

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

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

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

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

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

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

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

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

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

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


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

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

HCT using an unrelated donor

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

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


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

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

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

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

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

Graft failure

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

Pharmacotherapeutic regimens in HCT

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

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

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

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

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

Haploidentical HCT

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

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


Umbilical Cord Blood Transplantation

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


Immunosuppressive Therapy

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

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

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

ATG and cyclosporine

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

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

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

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

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

Time to response and relapse

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

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

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

Investigational immunosuppressive therapy

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

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

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

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



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

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

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

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

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


Diet and Activity

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

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

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