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Cellular Therapy and Transplantation (CTT), Vol. 3, No. 9

Please cite this article as follows: Marsh J. Current aplastic anaemia guidelines and unresolved problems. Cell Ther Transplant. 2010;3:e.000085.01. doi:10.3205/ctt-2010-en-000085.01

© The Author. This article is provided under the following license: Creative Commons Attribution 3.0 Unported

Abstract accepted for "4th Raisa Gorbacheva Memorial Meeting on Hematopoietic Stem Cell Transplantation",
Saint Petersburg, Russia, September 18–20, 2010

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Current aplastic anaemia guidelines and unresolved problems

Judith Marsh

Department of Haematological Medicine, King’s College Hospital, London, UK

Correspondence: Professor Judith C.W. Marsh, Department of Haematological Medicine, King’s College Hospital, Denmark Hill, London SE59RS, UK, Tel: +44-203-299-1039, Email: judith.marsh@spam is badkch.nhs.uk


The rationale and objectives of two current guidelines on Aplastic Anemia (AA) as issued by the British Committee for Standards in Hematology (BCSH) and the European Group for Blood and Marrow Transplantation (EBMT) are introduced. Some details are given on the diagnosis of AA and on the standard treatment of severe AA, more particularly on human leukocyte antigen (HLA) identical sibling hemopoietic stem cell transplantation (HSCT), immunosuppressive therapy (IST), and unrelated donor (UD) HSCT. The treatment options for refractory patients, namely high dose cyclophosphamide (CY) without stem cell support, treatment with Alemtuzumab, and novel HSCT approaches are also summarized. It is highlighted that the EBMT seeks to encourage all centers to contribute to new advances in treatments and scientific developments in AA.

Keywords: aplastic anemia, AA, antithymocyte globulin, ATG, hemopoietic stem cell transplantation, HSCT

Introduction: Objectives of national and European guidelines

The main reasons for establishing guidelines on the diagnosis and management of aplastic anemia (AA) are (i) it is a rare disease (ii) different treatment options are available, and (iii) large clinical trials are of great importance, although becoming increasingly difficult to organize. Due to the rarity of AA, many guideline recommendations are based on review of the literature and expert or consensus opinion rather than on clinical trials. In Europe, two major guidelines exist currently, both supported by organizations without conflict of interest and/or where potential conflicts of interest of members are declared. The EBMT Severe AA Working Party (SAAWP) has recently established "The complete treatment algorithm (CTA) for SAA" [1] and the British Committee for Standards in Haematology (BCSH) has published "Guidelines for the Diagnosis and Management of Aplastic Anaemia" [2]. The guidelines aim to provide clear guidance with recommendations but not mandates. Individual patient circumstances and patient preference may dictate an alternative approach. The EBMT CTA encourages all centers to register patients, and participate and report outcomes, but a center is free to decide on treatment strategy. The guidelines require regular updating to take account of new advances in treatments and scientific developments in AA.

Diagnosis of AA

All new patients should be carefully assessed to (i) confirm the diagnosis and exclude other possible causes of pancytopenia with hypocellular bone marrow (ii) classify the disease severity using standard blood and bone marrow criteria (iii) document the presence of associated PNH (by flow cytometry) and cytogenetic clones, and (iv) exclude a possible late onset inherited bone marrow failure disorder. Peripheral blood lymphocytes should be tested for chromosomal breakage to identify or exclude Fanconi anemia. Dyskeratosis congenita may be excluded by identifying a known mutation but there are other mutations yet to be identified. Along with measuring telomere lengths, this is not currently available as a routine clinical service. A multi-disciplinary team approach to the diagnosis and clinical management is recommended. Referral for specialist advice and/or review of the blood and bone marrow morphology at a specialist centre is encouraged.

Standard treatment of severe AA 
1. HLA identical sibling HSCT

First line HLA identical sibling HSCT is indicated in patients with severe AA, and who are <40 years old. Patients 40–50 years old may also be considered, as recent data from EBMT indicates similar outcomes compared with patients aged 30–40 years. For young patients, the standard conditioning is cyclophosphamide (CY) 200 mg/kg with ATG (Thymoglobulin 3.75 mg/kgx2, and post graft immunosuppression with ciclosporin (CSA) and methotrexate (MTX). Older patients (>30–40 years) should receive a fludarabine-based regimen (Fludarabine 30 mg/m2x4) with low dose CY (300 mg/m2x4) and ATG, due to worse outcomes with higher GVHD using CY200+ATG. A low stem cell dose is associated with a high risk of graft rejection. The ideal target dose is >3.0x108 nucleated cells/kg or >2.0x106 CD34+ cells/kg [3]. Using these regimens, the preferred stem cell source is bone marrow, as the use of PBSC is associated with more chronic GVHD in young patients and worse survival [4]. The major unresolved issue is chronic GVHD in 30–40%. Graft rejection occurs in 5–15%. New approaches to chronic GVHD are needed. The replacement of ATG with Alemtuzumab is the first maneuver to show a major reduction in chronic GVHD in both MSD and UD HSCT for AA (see later). 

2. Immunosuppressive therapy (IST)

IST is recommended for (i) patients with non-severe AA who are transfusion dependent (ii) patients with severe or very severe disease who are >40–50 years old and (iii) younger patients with severe or very severe disease who do not have an HLA identical sibling donor. Standard IST is the combination of ATG and CSA. CSA should be continued for at least 12 months after achieving maximal hematological response, with later tapering up to 24 months according to response, to reduce the risk of relapse. G-CSF may be used on demand for neutropenic infection but is not recommended as a routine treatment with ATG and CSA, as prospective trials show no benefit in terms of improving response or survival, although it does reduce early infections and days of hospitalization after ATG [5]. Long term follow-up of patients is necessary to monitor for clonal evolution, MDS/AML in 15%, hemolytic PNH in 10% and solid tumors in 10%. Recent clinical trials from the National Institute of Health (NIH) indicate that adding either mycophenolate mofetil or sirolimus to ATG plus CSA do not increase the benefit of the standard treatment [6,7]. Following the withdrawal of Lymphoglobuline horse ATG from the market, a phase II pilot EBMT study using 3.75 mg/kg/day x 5 is in progress to evaluate efficacy and tolerability of rabbit ATG (Thymoglobulin) when given as the first course of IST. There is also a need for treatment modalities that improve event free survival after IST with ATG plus CSA, as there has been no further improvement in survival over the last two decades [8]. A second course of ATG (using rabbit after horse for the first course) results in response in around 60% if given for relapse after the first course, but only 30% when given for non-response to a first course of ATG [9].

3. Unrelated donor (UD) HSCT

There have been recent changes in the approach to UD HSCT as a result of significant improvements in outcome [10,11]. The upper age limit has been extended and UD HSCT should now be considered after failure of only one course of IST. UD BMT may be considered when a patient with SAA has a fully matched (or one antigen mis-matched) donor, and they are <50 years old (or 50–60 years old with good performance status). A future challenge will be to extend HSCT to even older patients. The optimal conditioning regimen for MUD BMT is uncertain, but currently a fludarabine, non-irradiation-based regimen is favored for younger patients (FCATG: Fludarabine 30 mg/m2x4, CY (300 mg/m2x4) and ATG (Thymoglobulin 3.75 mg/kgx2)) with CSA and MTX. For older patients, or when a one antigen mis-matched donor is used, low dose TBI 2Gy is often added to the conditioning regimen. Overall survival is currently 73–79%. The FCC regimen (where ATG is replaced by Alemtuzumab and which requires only CSA as post graft immunosuppression without the need for MTX), is associated with excellent outcomes (overall survival 95% for MSD, 83% for UD, graft rejection 10% MSD and 15% for UD, acute GVHD 14% (all grade I–II), and chronic GVHD 4% [3,12,13].

Treatment of refractory patients

This is a difficult area and represents one of the main unresolved issues in the management of AA. A proportion of non-responders to IST may be shown subsequently to have inherited AA associated with telomerase gene complex mutations. Androgens induce response in around 60% of such patients and the option of HSCT should also be explored, ensuring that similarly affected siblings are not used as donors. Options for refractory acquired AA include:

1. High dose CY without stem cell support

The use of high dose CY without stem cell support has been explored by the Johns Hopkins group. CY without CSA is associated with survival of 88%, response in 71% and event-free survival rate 58% in previously untreated patients. Patients with refractory severe AA fare less well with survival, response, and actuarial event-free survival rates of 62%, 48%, and 27%, respectively. CY leads to long-lasting cytopenias (median time to response of 5 months) and a high incidence of fungal infections [14]. High dose CY is not currently recommended in Europe, in the absence of prospective multi-centre studies comparing it to standard ATG with CSA.

2. Alemtuzumab 

Alemtuzumab is currently being evaluated in the treatment of AA. A small prospective study combined with a retrospective review of cases reported to EBMT on the use of a single course of Alemtuzumab and CSA in AA showed response in 9 out of 18 patients, although relapses were common [15]. At NIH, preliminary data from ongoing studies (but with larger number of patients) suggest that Alemtuzumab may be effective for patients refractory to ATG or who have relapsed after ATG.

3. Novel HSCT approaches

Umbilical cord blood transplantation (UCBT): The Japan Cord Blood Network reported 31 patients undergoing single UCBT, with a median age of 27.9 years (range 0.8–72.7). Most patients received fludarabine, TBI, and melphalan, with or without ATG. Sustained engraftment was seen in only 17 patients. Survival at 2 years was 41%; 20% for patients aged >40yrs [16]. The EBMT/EUROCORD group showed similar outcomes in a series of 68 adults with SAA or PNH. The major issue for SAA is that a higher stem cell dose is needed compared with patients transplanted for hematological malignancy in order to achieve engraftment. Haploidentical HSCT is being re-evaluated in AA. There are anecdotal reports during the last 5 years, most in children, using very immunosuppressive conditioning and CD34+ -selected stem cells, showing that some selected patients might benefit from this approach. An alternative approach using high dose CY in the immediate post graft period, as pioneered in hematological malignancies, has been reported anecdotally in PNH patients and warrants further exploration in AA [17].


[References with links indicate that an article is available Open Access]

1. EBMT Severe Aplastic Anaemia Working Party. The complete treatment algorithm for SAA. http://www.ebmt.org/Slidebank_2010.html. Algorithm document will shortly be available on the EBMT website.

3. Islam MS, Anoop P, Datta-Nemdharry P, Sage D, Gordon-Smith EC, Turner D, Wiltshire S, O'Regan L, Marsh JCW. Implications of CD34+ cell dose on clinical and haematological outcome of allo-SCT for acquired aplastic anaemia. Bone Marrow Transplantation (12 October 2009) doi:10.1038/bmt.2009.267 Original Article

11. Meyers G, Maziarz RT. Is it time for a change? The case for early application of unrelated allo-SCT for severe aplastic anemia. Bone marrow Transplant. 2010;1-10.

15. Risitano AM, Seneca E, Marando L, Serio B, Selleri C, Scalia G, Vecchio LD, Iori A, Kulagin A, Maury S, Halter J, Gupta V, Bacigalupo A, Socié G, Tichelli A, Marsh J, Schrezenmeier H, Passweg JR, Rotoli B. Subcutaneous Alemtuzumab is a safe and effective treatment for global or single-lineage immune-mediated marrow failures: a survey from the EBMT-WPSAA. Brit J. Haematol. 2009;148:791-796.

© The Author. This article is provided under the following license: Creative Commons Attribution 3.0 Unported

Please cite this article as follows: Marsh J. Current aplastic anaemia guidelines and unresolved problems. Cell Ther Transplant. 2010;3:e.000085.01. doi:10.3205/ctt-2010-en-000085.01

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