Approach

The major treatment modalities for adult patients with AA are:[35]

  • Withdrawal of any potential etiologic agent (e.g., chloramphenicol, nonsteroidal anti-inflammatory drugs) or exposure (e.g., benzene)

  • Immunosuppressive therapy

  • Allogeneic stem cell transplantation (SCT)

  • Eltrombopag (an oral thrombopoietin receptor agonist)

  • Supportive care with blood transfusions (red cell and platelet) and antibiotics/antifungals as needed.

The first and most important step when treating an adult patient with newly diagnosed AA is to confirm if they have acquired AA or an inherited marrow failure syndrome.

Treatment of patients with acquired AA is based on severity of illness. In practice, patients are stratified as having either non-severe, severe, or very severe disease. Criteria for severe AA include: bone marrow cellularity <25% or cellularity <50% with <30% residual hematopoietic cells; and at least two of the following: absolute reticulocyte count <20 × 10⁹/L (<60 × 10⁹/L using an automated analysis); platelet count <20 × 10⁹/L; absolute neutrophil count (ANC) <0.5 × 10⁹/L. In very severe AA the ANC is <0.2 × 10⁹/L.[36][37]​ Patients who do not meet the criteria for severe or very severe AA are classified as having non-severe AA.

Patients with an inherited marrow failure syndrome should be considered for early SCT or androgen therapy with danazol.[2][10]

Acquired non-severe AA

It is important to confirm a diagnosis of acquired AA before initiating treatment because patients with congenital AA commonly present with non-severe disease without any peripheral stigmata related to the underlying bone marrow failure, and are often misdiagnosed as having acquired AA.

There are no clear guidelines on the management of patients with acquired non-severe AA (i.e., do not meet criteria for severe AA). Patients can be monitored conservatively with regular complete blood count. For transfusion-dependent patients, the current standard of care is immunosuppressive therapy with antithymocyte globulin (ATG) combined with a calcineurin inhibitor (preferably cyclosporine).[38][39][40][41][42][43][44] Cyclosporine alone is also an option, but it has a lower response rate and failure-free survival rate compared with combined therapy with ATG.[38][39]  

Allergic reactions (e.g., rash, fever, serum sickness) are the main toxicities of ATG treatment. The risk and severity of allergic reactions to ATG may be reduced with high-dose corticosteroids (e.g., methylprednisolone) given concurrently with ATG treatment, followed by a taper over 14 days.

Acquired severe or very severe AA

For patients with acquired severe or very severe AA, the choice of treatment depends on the age of the patient and the availability of a matched related donor for SCT.

  • In general, patients ≤50 years of age with a matched related donor should be treated with upfront SCT. For patients ages 40 to 50 years, comorbidities should be carefully assessed to determine fitness for SCT. The typical conditioning regimen consists of high-dose cyclophosphamide with ATG or alemtuzumab for patients ages <30 to 35 years, or low-dose cyclophosphamide and fludarabine with ATG or alemtuzumab for older patients. If required, graft versus host disease prophylaxis can be instituted with methotrexate combined with a calcineurin inhibitor (e.g., cyclosporine or tacrolimus), or a calcineurin inhibitor alone if alemtuzumab is used in the conditioning regimen.

  • For patients ≤50 years without a matched related donor, or those >50 years, immunosuppressive therapy in the form of ATG and a calcineurin inhibitor (e.g., cyclosporine) is currently considered first-line therapy.[38][39][40][41][42][43][44] The addition of eltrombopag (an oral thrombopoietin receptor agonist) to ATG and cyclosporine in treatment-naïve patients with severe and very severe AA is associated with better responses; one open-label, multicenter, randomized, phase 3 trial has compared eltrombopag and standard immunosuppression (ATG + cyclosporine) versus standard immunosuppression alone (ATG + cyclosporine) for patients with severe AA.[45] Eltrombopag was shown to improve the rate, rapidity, and strength of hematologic response among treatment-naïve patients, without additional toxic effects. This triple drug combination of eltrombopag, ATG, and cyclosporine is approved as used in first-line therapy in the US.[46] Cyclosporine alone or in combination with eltrombopag may be used if ATG is not available.[47]

  • Matched unrelated donor SCT can be considered in patients without a matched related donor who do not respond to one course of immunosuppressive therapy. It is currently not chosen as first-line therapy in adults except under special circumstances (e.g., young adults with life-threatening or recurrent severe infection who cannot wait for a response to a course of immunosuppressive therapy, which usually takes 3 months).[35][48][49][50] Several studies report reduced transplant-related complications with matched unrelated donor SCT, leading some physicians to consider early upfront matched unrelated donor transplantation for young adults with severe or very severe AA.[51][52]

Use of ATG

ATG is available in horse-derived and rabbit-derived formulations. Horse-derived ATG has been found to be superior to rabbit-derived ATG for the treatment of AA.[53][54][55]

Rabbit-derived ATG is more immunosuppressive than horse-derived ATG and is more likely to lead to infections. Therefore, it should only be used in centers with appropriate experience and adequate prophylactic antimicrobial support.[35]

In the US, horse-derived ATG is approved for AA and is the preferred formulation (although rabbit-derived ATG has been used off-label).

Relapsed or refractory acquired AA

The following options can be considered for patients who are unresponsive or relapse following first-line treatment with immunosuppressive therapy:

  • SCT

  • Eltrombopag (provided it has not been used as part of combination immunosuppressant therapy previously)

  • Attempt another course of immunosuppressive therapy

  • Consider investigational treatment as part of a clinical trial.

In general, SCT should be considered if a matched related donor exists and if the patient has good performance status and no other contraindications to transplant.[56] A matched unrelated donor can be considered if a matched related donor does not exist.[56]

Alternatively, patients may be treated with eltrombopag. Eltrombopag is approved for use in patients with acquired severe AA who are refractory to immunosuppressive therapy. In a small phase 2 study of 43 patients with refractory AA, eltrombopag resulted in improvement in blood counts and decreased transfusion requirement in 40% of patients.[57][58] A retrospective study reported high response rates with use of eltrombopag for 4 months in patients with refractory AA and in patients unsuitable for first-line therapy with ATG.[59] Although eltrombopag is generally well tolerated, there have been reports of clonal evolution with development of new cytogenetic abnormalities in around 19% of patients.[57][58]

A second course of immunosuppressive therapy may be attempted, but the response rate with a second course following failure of a first course is around 35%.[35]

Investigational therapies in clinical trials may be considered for patients not eligible for SCT who have had unsuccessful courses of immunosuppressive therapy or are refractory to eltrombopag treatment.

Inherited marrow failure syndrome

If an inherited marrow failure syndrome is diagnosed, the treatment options are allogeneic SCT or androgen therapy (e.g., danazol or oxymetholone), as such patients will not respond to immunosuppressive therapy.

Matched related donor SCT is considered first-line therapy. Matched unrelated donor SCT can be considered if a matched related donor is not available.

Androgen therapy can be used if SCT is not an option. Danazol is usually preferred to oxymetholone because it has good efficacy and is better tolerated.[60][61] Danazol is particularly effective in patients with an inherited telomeropathy (response rate is up to 80%).[61] It is thought that danazol binds to an estrogen-sensitive element of the TERT gene resulting in increased telomerase expression.

Hepatotoxicity (e.g., liver dysfunction, hepatomas, and peliosis hepatis) and virilization (in women) are complications associated with androgen therapy, although less so with danazol than with oxymetholone. Androgens must be used with caution, with regular liver monitoring (e.g., liver function, liver computed tomography/ultrasound, and alpha fetoprotein). Hematopoietic growth factors, granulocyte colony-stimulating factor and erythropoietin, may sometimes improve the neutrophil count and hemoglobin levels.[62]

Supportive care

Red cell and platelet transfusion can be given to maintain stable blood counts and improve symptoms and quality of life.[35] Human leukocyte antigen alloimmunisation may be reduced by leukocyte depletion of blood products, but it still remains an issue for 13% to 28% of patients with AA.[63][64] Using blood products donated from family members should be avoided to reduce the risk of the patient being sensitized to antigens from a future stem cell donor.

Patients receiving regular red cell transfusions should be monitored for iron overload. Use of iron chelation therapy to manage iron overload should be individualized.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Treatment with antibiotics and antifungal agents is required if an infection develops. Severe and very severe AA may warrant prophylactic antibiotics and antifungal agents. Neutropenic fever is treated with broad-spectrum intravenous antibiotics and early use of systemic antifungals if fever does not settle.

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