Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

non-severe acquired disease

1st line – monitoring ± immunosuppressive therapy

Back
ACUTE
|
non-severe acquired disease
1st line – 

monitoring ± immunosuppressive therapy

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 non-severe acquired AA (i.e., do not meet criteria for severe AA).[35]

Any potential aetiological agent (e.g., chloramphenicol, non-steroidal anti-inflammatory drugs) or exposure (e.g., benzene) should be withdrawn.[2][3]

Patients can be monitored conservatively with regular full blood count.

For transfusion-dependent patients, the current standard of care for immunosuppressive therapy is the combination of antithymocyte globulin (ATG) and a calcineurin inhibitor (preferably ciclosporin).[38][39][40][41][42][43][44]

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 centres 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). In Europe and other countries, horse-derived ATG availability is variable. The European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party and the British Society for Haematology recommend that it is reasonable to consider rabbit-derived ATG if horse-derived ATG is not available; even though response rates are lower, it is better than no treatment at all.[35][47]

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.

Response with immunosuppressive therapy occurs in 60% to 75% of patients.[35][53] Relapse may be reduced by prolonging the course of treatment with ciclosporin. Early tapering is often associated with relapse; therefore, dose should not be tapered earlier than 6 months, and it should be increased and maintained if there is relapse on taper. Between 15% and 30% of patients will need indefinite therapy with ciclosporin, albeit at lower doses than patients with severe or very severe disease.[39]

Primary options

lymphocyte immunoglobulin, anti-thymocyte globulin (equine): consult specialist for guidance on dose

or

antithymocyte immunoglobulin (rabbit): consult specialist for guidance on dose

-- AND --

methylprednisolone: consult specialist for guidance on dose

-- AND --

ciclosporin: consult specialist for guidance on dose

Secondary options

ciclosporin: consult specialist for guidance on dose

Consider – blood product transfusions

Back
ACUTE
|
non-severe acquired disease
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
non-severe acquired disease
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

severe/very severe acquired disease

1st line – matched related donor allogeneic stem cell transplantation

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
1st line – 

matched related donor allogeneic stem cell transplantation

Criteria for severe AA include: bone marrow cellularity <25% or cellularity <50% with <30% residual haematopoietic cells; and at least two among 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]

Any potential aetiological agent (e.g., chloramphenicol, non-steroidal anti-inflammatory drugs) or exposure (e.g., benzene) should be withdrawn.[2][3]

If a matched related donor is available for patients ≤50 years old, stem cell transplant is the first-line treatment option.

Typical conditioning consists of: for patients <30-35 years, high-dose cyclophosphamide with antithymocyte globulin (ATG) or alemtuzumab; for older patients, low-dose cyclophosphamide and fludarabine, with ATG or alemtuzumab.

Graft-versus-host disease (GVHD) prophylaxis: typically a combination of methotrexate with a calcineurin inhibitor (e.g., ciclosporin or tacrolimus), or a calcineurin inhibitor alone if alemtuzumab is used in the conditioning regimen.

Stem cell source: unmanipulated bone marrow; use of peripheral blood stem cells in younger patients is associated with an increased risk of chronic GVHD and poorer outcome than with bone marrow.

See local specialist protocol for regimens and dosing guidelines.

Consider – blood product transfusions

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65]

Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

Treatment with antibiotics and antifungal agents is required if an infection develops.

Neutropenic fever is treated with broad-spectrum intravenous antibiotics and early use of systemic antifungals if fever does not settle.

Local protocols should be followed.

2nd line – immunosuppressive therapy

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
2nd line – 

immunosuppressive therapy

If no matched related donor is available, immunosuppressive therapy is used.

The current standard of care for immunosuppressive therapy is the combination of antithymocyte globulin (ATG) and a calcineurin inhibitor (e..g., ciclosporin).[38][39][36][41][42][43][44] The addition of eltrombopag to ATG and ciclosporin in treatment-naïve patients with severe and very severe AA is associated with better responses, and this triple drug combination is approved for first-line therapy in the US.[46] This combination is associated with higher response rates and early haematological responses. Ciclosporin alone or in combination with eltrombopag may be used if ATG is not available.[47]

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 centres 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). In Europe and other countries, horse-derived ATG availability is variable. The European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party and the British Society for Haematology recommend that it is reasonable to consider rabbit-derived ATG if horse-derived ATG is not available; even though response rates are lower, it is better than no treatment at all.[35][47]

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.

Response with immunosuppressive therapy occurs in 60% to 75% of patients.[35][53] Relapse may be reduced by prolonging the course of treatment with ciclosporin. Early tapering is often associated with relapse; therefore, dose should not be tapered earlier than 6 months, and it should be increased and maintained if there is relapse on taper. Between 15% and 30% of patients will need indefinite therapy with ciclosporin.[39]

Primary options

lymphocyte immunoglobulin, anti-thymocyte globulin (equine): consult specialist for guidance on dose

or

antithymocyte immunoglobulin (rabbit): consult specialist for guidance on dose

-- AND --

methylprednisolone: consult specialist for guidance on dose

-- AND --

ciclosporin: consult specialist for guidance on dose

-- AND --

eltrombopag: consult specialist for guidance on dose

Secondary options

ciclosporin: consult specialist for guidance on dose

OR

ciclosporin: consult specialist for guidance on dose

and

eltrombopag: consult specialist for guidance on dose

Consider – blood product transfusions

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

Treatment with antibiotics and antifungal agents is required if an infection develops.

Neutropenic fever is treated with broad-spectrum intravenous antibiotics and early use of systemic antifungals if fever does not settle.

Local protocols should be followed.

3rd line – matched unrelated donor allogeneic stem cell transplantation

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
3rd line – 

matched unrelated donor allogeneic stem cell transplantation

Matched unrelated donor stem cell transplant (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]

Conditioning regimen (example): cyclophosphamide + fludarabine ± antithymocyte globulin or alemtuzumab.

Graft-versus-host disease prophylaxis: combination of methotrexate with a calcineurin inhibitor (ciclosporin or tacrolimus), or a calcineurin inhibitor alone if alemtuzumab is used in the conditioning regimen.

Stem cell source: unmanipulated bone marrow; peripheral blood stem cells may be an alternative to bone marrow if an alemtuzumab-based conditioning regimen is used. When possible, unrelated donors should be matched using allele-level typing for both major histocompatibility complex (MHC) I and MHC II loci.

Consult specialist for guidance on regimens and dose.

Consider – blood product transfusions

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

4th line – eltrombopag

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
4th line – 

eltrombopag

Eltrombopag, an oral thrombopoietin receptor agonist, can be considered for patients with severe acquired AA if a matched related or unrelated donor is not available and the patient is refractory to immunosuppressive therapy provided it has not been used as part of combination immunosuppressant therapy previously.[57] In Europe, eltrombopag can also be considered in patients with severe acquired AA who are heavily pretreated and are unsuitable for stem cell treatment.

In a 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 antithymocyte globulin.[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]

Primary options

eltrombopag: consult specialist for guidance on dose

Consider – blood product transfusions

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
severe/very severe acquired disease
|
age ≤50 years
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

1st line – immunosuppressive therapy

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
1st line – 

immunosuppressive therapy

Criteria for severe AA include: bone marrow cellularity <25% or cellularity <50% with <30% residual haematopoietic cells; and at least two among 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]

Any potential aetiological agent (e.g., chloramphenicol, non-steroidal anti-inflammatory drugs) or exposure (e.g., benzene) should be withdrawn.[2][3]

The current standard of care for immunosuppressive therapy is the combination of antithymocyte globulin (ATG) and a calcineurin inhibitor (e.g., ciclosporin).[38][39][36][41][42][43][44] The addition of eltrombopag to ATG and ciclosporin in treatment-naïve patients with severe and very severe AA is associated with better responses, and this triple drug combination is approved for first-line therapy in the US.[46] This combination is associated with higher response rates and early haematological responses. Ciclosporin alone or in combination with eltrombopag may be used if ATG is not available.[47]

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 centres 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). In Europe and other countries, horse-derived ATG availability is variable. The European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party and the British Society for Haematology recommend that it is reasonable to consider rabbit-derived ATG if horse-derived ATG is not available; even though response rates are lower, it is better than no treatment at all.[35][47]

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.

Response with immunosuppressive therapy occurs in 60% to 75% of patients.[35][53] Relapse may be reduced by prolonging the course of treatment with ciclosporin. Early tapering is often associated with relapse; therefore, dose should not be tapered earlier than 6 months, and it should be increased and maintained if there is relapse on taper. Between 15% and 30% of patients will need indefinite therapy with ciclosporin.[39]

Primary options

lymphocyte immunoglobulin, anti-thymocyte globulin (equine): consult specialist for guidance on dose

or

antithymocyte immunoglobulin (rabbit): consult specialist for guidance on dose

-- AND --

methylprednisolone: consult specialist for guidance on dose

-- AND --

ciclosporin: consult specialist for guidance on dose

-- AND --

eltrombopag: consult specialist for guidance on dose

Secondary options

ciclosporin: consult specialist for guidance on dose

OR

ciclosporin: consult specialist for guidance on dose

and

eltrombopag: consult specialist for guidance on dose

Consider – blood product transfusions

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

2nd line – matched related donor allogeneic stem cell transplantation

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
2nd line – 

matched related donor allogeneic stem cell transplantation

Patients >50 years of age with unsuccessful immunosuppressive therapy or who relapse after initial treatment with immunosuppressive therapy may be offered stem cell transplant if a matched donor is available and the patient has good performance status and no other contraindications to transplant.

Conditioning regimen (example): fludarabine + cyclophosphamide + antithymocyte globulin + total body irradiation (200 cGy); or fludarabine + cyclophosphamide + alemtuzumab.

Graft-versus-host disease prophylaxis: combination of methotrexate with a calcineurin inhibitor (e.g., ciclosporin or tacrolimus), or a calcineurin inhibitor alone if alemtuzumab is used in the conditioning regimen.

Stem cell source: unmanipulated bone marrow; peripheral blood stem cells may be an alternative to bone marrow if an alemtuzumab-based conditioning regimen is used.

See local specialist protocol for regimens and dosing guidelines.

Consider – blood product transfusions

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

3rd line – matched unrelated donor allogeneic stem cell transplantation

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
3rd line – 

matched unrelated donor allogeneic stem cell transplantation

A matched unrelated donor stem cell transplant can be considered if a matched related donor is not available.

Conditioning regimen (example): fludarabine + cyclophosphamide + antithymocyte globulin + total body irradiation (200 cGy); or fludarabine + cyclophosphamide + alemtuzumab.

Graft-versus-host disease prophylaxis: combination of methotrexate with a calcineurin inhibitor (e.g., ciclosporin or tacrolimus), or a calcineurin inhibitor alone if alemtuzumab is used in the conditioning regimen.

Stem cell source: unmanipulated bone marrow; peripheral blood stem cells may be an alternative to bone marrow if an alemtuzumab-based conditioning regimen is used.

When possible, unrelated donors should be matched using allele-level typing for both major histocompatibility complex (MHC) I and MHC II loci.

See local specialist protocol for regimens and dosing guidelines.

Consider – blood product transfusions

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

4th line – eltrombopag

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
4th line – 

eltrombopag

Eltrombopag, an oral thrombopoietin receptor agonist, can be considered for patients with severe acquired AA if a matched related or unrelated donor is not available and the patient is refractory to immunosuppressive therapy provided it has not been used as part of combination immunosuppressant therapy previously.[57] In Europe, eltrombopag can also be considered in patients with severe acquired AA who are heavily pretreated and are unsuitable for stem cell treatment.

In a 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 longer than 4 months in patients with refractory AA and in patients unsuitable for first-line therapy with antithymocyte globulin.[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]

Primary options

eltrombopag: consult specialist for guidance on dose

Consider – blood product transfusions

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
severe/very severe acquired disease
|
age >50 years
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

inherited marrow failure syndrome

1st line – matched related donor allogeneic stem cell transplantation

Back
ACUTE
|
inherited marrow failure syndrome
1st line – 

matched related donor allogeneic stem cell transplantation

Matched related donor allogeneic stem cell transplantation is considered first-line therapy in patients with an inherited marrow failure syndrome. These patients will not respond to immunosuppressive therapy.

Typical conditioning consists of low-dose cyclophosphamide + fludarabine + antithymocyte globulin or alemtuzumab.

Low-dose total body irradiation is still sometimes considered for conditioning in these patients; however, it should be avoided if possible to minimise the risk of malignancies.

Graft-versus-host disease prophylaxis: combination of methotrexate with a calcineurin inhibitor (ciclosporin or tacrolimus), or a calcineurin inhibitor alone if alemtuzumab is used in the conditioning regimen.

Stem cell source: usually unmanipulated bone marrow, but T-cell-depleted bone marrow or umbilical cord blood may also be used. Peripheral blood stem cells may be an alternative to bone marrow if an alemtuzumab-based conditioning regimen is used.

See local specialist protocol for regimens and dosing guidelines.

Consider – blood product transfusions

Back
ACUTE
|
inherited marrow failure syndrome
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Haematopoietic growth factors, granulocyte colony-stimulating factor and erythropoietin, may sometimes improve the neutrophil count and haemoglobin levels.[62]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
inherited marrow failure syndrome
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

2nd line – matched unrelated donor allogeneic stem cell transplantation

Back
ACUTE
|
inherited marrow failure syndrome
2nd line – 

matched unrelated donor allogeneic stem cell transplantation

Matched unrelated donor allogeneic stem cell transplantation can be considered if a matched related donor is not available.

Typical conditioning consists of low-dose cyclophosphamide + fludarabine + antithymocyte globulin or alemtuzumab.

Low-dose total body irradiation is still sometimes considered for conditioning in these patients; however, it should be avoided if possible to minimise the risk of malignancies.

Graft-versus-host disease prophylaxis: combination of methotrexate with a calcineurin inhibitor (ciclosporin or tacrolimus), or a calcineurin inhibitor alone if alemtuzumab is used in the conditioning regimen.

Stem cell source: usually unmanipulated bone marrow, but T-cell-depleted bone marrow or umbilical cord blood may also be used. Peripheral blood stem cells may be an alternative to bone marrow if an alemtuzumab-based conditioning regimen is used.

When possible, unrelated donors should be matched using allele-level typing for both major histocompatibility complex (MHC) I and MHC II loci.

See local specialist protocol for regimens and dosing guidelines.

Consider – blood product transfusions

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ACUTE
|
inherited marrow failure syndrome
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Haematopoietic growth factors, granulocyte colony-stimulating factor and erythropoietin, may sometimes improve the neutrophil count and haemoglobin levels.[62]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
inherited marrow failure syndrome
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

3rd line – androgen therapy

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ACUTE
|
inherited marrow failure syndrome
3rd line – 

androgen therapy

Androgen therapy can be considered if allogeneic stem cell transplantation 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 oestrogen-sensitive element of the TERT gene resulting in increased telomerase expression.

Hepatotoxicity (e.g., liver dysfunction, hepatomas, and peliosis hepatis) and virilisation (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).

Primary options

danazol: consult specialist for guidance on dose

Secondary options

oxymetholone: consult specialist for guidance on dose

Consider – blood product transfusions

Back
ACUTE
|
inherited marrow failure syndrome
Consider – 

blood product transfusions

Additional treatment recommended for SOME patients in selected patient group

Red cell and platelet transfusion are 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 sensitised 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 individualised.[35][65] Patients with iron overload after successful SCT may undergo venesection.[35]

Haematopoietic growth factors, granulocyte colony-stimulating factor and erythropoietin, may sometimes improve the neutrophil count and haemoglobin levels.[62]

Consider – antibiotics and antifungal agents

Back
ACUTE
|
inherited marrow failure syndrome
Consider – 

antibiotics and antifungal agents

Additional treatment recommended for SOME patients in selected patient group

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.

Local protocols should be followed.

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