Guidelines for the diagnosis and management of adult aplastic anaemia

The guideline group was selected to be representative of UK-based aplastic anaemia (AA) medical experts. Recommendations are based on review of the literature using MEDLINE and PUBMED up to December 2014 under the heading: 'aplastic anemia'. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are specified in the BCSH guidance pack http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html and the GRADE working group website http://www.gradeworkinggroup.org The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with AA. The guidance may not be appropriate to every patient and in all cases individual patient circumstances may dictate an alternative approach. Review of the manuscript was performed by the British Committee for Standards in Haematology (BCSH) Haemato-Oncology Task Force, BCSH Executive Committee and then reviewed by a sounding board of the British Society for Haematology (BSH). This compromises 50 or more members of the BSH who have reviewed this guidance and commented on its content and applicability in the UK setting. It has also been reviewed by the Aplastic Anaemia Trust patient group but they do not necessarily approve or endorse the contents. Aplastic anaemia is a rare and heterogeneous disorder. It is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis. To diagnose AA there must be at least two of the following (Camitta et al, 1975) haemoglobin concentration (Hb) <100 g/l, platelet count <50 × 109/l, neutrophil count <1·5 × 109/l. The majority (70-80%) of cases are idiopathic (Marsh et al, 2009). The remainder mainly consist of IBMFS. The incidence is 2-3 per million per year in Europe, but higher in East Asia (Montane et al, 2008). There is a biphasic distribution, with peaks at 10-25 years and over 60 years. AA not fulfilling the criteria for SAA or VSAA Patients commonly present with symptoms of anaemia and thrombocytopenia. Serious infection is not a frequent symptom early in the course of the disease. A preceding history of jaundice may suggest a post-hepatitic AA. Whilst the majority of cases are idiopathic, a careful drug, occupational exposure and family history should be obtained. Any putative drugs should be discontinued and the patient should not be re-challenged. If a possible drug association is suspected, this must be reported to the Medicines and MHRA using the Yellow Card Scheme (http://yellowcard.gov.uk). There is usually no hepatosplenomegaly or lymphadenopathy (except in infection). In young adults the presence of short stature, skin hyper/hypo pigmented areas and skeletal abnormalities, particularly affecting the thumb is suggestive of FA (Shimamura & Alter, 2010). The triad of nail dystrophy, reticular skin pigmentation and oral leucoplakia is characteristic of dyskeratosis congenita (DC) (Shimamura & Alter, 2010). The finding of peripheral lymphoedema may indicate a diagnosis of Emberger syndrome due to germline GATA2 mutation. See Table 1 for the summary of investigations for the diagnosis and further evaluation of AA; this table also summarizes the emerging diagnostics incorporating the latest molecular technologies that are likely to feature in the diagnosis and differential diagnosis within the next couple of years. Both a bone marrow aspirate and trephine biopsy are required for the diagnosis of AA, and the key bone marrow findings are summarized in Table 2. Karyotyping may fail in very hypocellular marrows with there being insufficient metaphases. In this situation perform FISH analysis for chromosomes 5, 7, 8 and 13 It was previously assumed that the presence of an abnormal cytogenetic clone indicated a diagnosis of MDS and not AA. However it is now evident that abnormal cytogenetic clones [such as del(13q), trisomy 8 and others], which may be transient, are present in up to 12% of patients with otherwise typical AA at diagnosis (Gupta et al, 2006; Afable et al, 2011b). Although monosomy 7 may indicate the likelihood of MDS in children, in adults monosomy 7 can also be seen in AA. Abnormal cytogenetic clones may arise during the course of the disease and the appearance of a new cytogenetic abnormality may provide evidence of clonal evolution (Maciejewski et al, 2002) The investigations in Table 1 should exclude non-AA causes of pancytopenia with a hypocellular bone marrow, which are listed in Table 3. A MDT meeting approach is recommended to collate relevant results and develop a treatment plan. Consideration should be given for seeking expert advice on the diagnosis and management of patients where there is uncertainty, or when an IBMFS is being considered. A number of inherited/genetic disorders are characterized by BMF/AA, usually in association with one or more somatic abnormality (Alter, 2007). The BMF typically presents in childhood but this can sometimes be in adulthood. The two syndromes frequently associated with generalized BMF/AA are FA and DC (Dokal, 2011; Soulier, 2011), which can sometimes present with AA alone as their initial manifestation. These syndromes are genetically heterogeneous; 16 FA genes and 10 DC genes have been identified. The FA genes are important in DNA repair, the DC genes in telomere maintenance. Based on the DNA repair defect a diagnostic test-'chromosomal breakage test' is available for FA. Patients with DC usually have very short telomeres and this measurement [using flow cytometric fluorescence in situ hybridization or multiplex quantitative polymerase chain reaction (PCR)] can be useful in the assessment of DC. Genetic testing for known DC genes (representing c. 60% of cases) is possible in specialized centres. In addition there are other genetic syndromes that are sometimes associated with AA/cytopenias. This includes Shwachman‒Diamond syndrome ‒ SDS (Dror et al, 2011) (mutations in SBDS), congenital amegakaryocytic thrombocytopenia ‒ CAMT (Ballmaier & Germeshausen, 2011) (mutations in MPL) and GATA2 deficiency (Emberger syndrome) (Horwitz, 2014) as well as genetically uncharacterized cases. Some cases of inherited AA first present in adulthood and it is important to recognize these as their management differs from that of idiopathic AA. Where there are sufficient characteristic abnormalities a diagnosis may be straightforward (e.g. mucocutaneous features in DC). Where the presentation is only with AA and with minimal non-haematological abnormalities, inherited BMF should be considered and testing for known BMF syndromes should be undertaken. Investigations for inherited forms of AA should be re-appraised in patients initially classified as "idiopathic AA" and who fail to respond to anti-thymocyte globulin (ATG). For most patients with AA, transfusion with red blood cells (RBC) is essential to maintain a safe blood count, improve symptoms of anaemia and maintain quality of life. The decision to transfuse RBC should be based on clinical symptoms (signs of anaemia), taking into consideration the patient's age and co-morbidities (cardiac, pulmonary or vascular). Although no specific pre-transfusion haemoglobin concentration (Hb) trigger can be recommended, it is important to maintain quality of life and avoid symptoms. A higher trigger may be needed for elderly patients and those with co-morbidities. Optimal use of RBC transfusion involves administration of enough red cells to maximize clinical outcome whilst avoiding unnecessary transfusions (Carson et al, 2012). Alloimmunization against red cell antigens and iron overload are the commonest risks associated with regular transfusion therapy. Provision of phenotype-matched blood (for Rh and Kell) should be considered to reduce the risk of alloimmunization. Regular platelet transfusion support may be required for AA patients. With the exception of one publication (Sagmeister et al, 1999), literature specific to platelet transfusion support in AA is lacking, and evidence is taken from studies addressing the need for platelet transfusion support in patients with reversible thrombocytopenia (Estcourt et al, 2012; Stanworth et al, 2013; Killick et al, 2014). It is recommended that prophylactic platelet transfusions should be given to stable AA patients on active therapy (where the treatment aims to reverse the severe thrombocytopenia) with a platelet count <10 × 109/l. For patients with sepsis, the platelet count should be kept >20 × 109/l. For thrombocytopenic patients requiring invasive procedures, platelet transfusions must be administered, aiming to achieve a platelet count in line with BCSH guidelines for the relevant procedures (British Committee for Standards in Haematology, 2003), and a pre-procedure platelet count should be checked. During treatment with ATG, worsening thrombocytopenia can occur. This is due to increased platelet consumption in the presence of cross-reacting antibodies in ATG binding to platelets. Although there are no studies to support the exact threshold for platelet transfusion support prior to ATG, most authors use a threshold of 20 × 109/l (Scheinberg et al, 2011; Scheinberg & Young, 2012). Regular support with RBC and platelet transfusions increases the risk of HLA and non-HLA (minor histocompatibility) alloimmunization, leading to poor platelet increments and increased risk of graft rejection after HSCT. Leucodepletion of cellular blood components may reduce, but not eliminate, alloimmunization (Killick et al, 1997; Desmarets et al, 2009). The possibility of HLA alloimmunization and provision of HLA-selected platelets should be considered for patients refractory to platelet transfusion, provided other causes of refractoriness have been excluded. In the absence of HLA antibodies and for patients failing to increment with HLA-matched platelets, investigation and matching for human platelet antigen antibodies should be considered. The use of irradiated granulocytes should be considered in patients with life-threatening infection related to severe neutropenia (Quillen et al, 2009), and anecdotally may be life saving. Data about the effectiveness of granulocyte concentrates are limited and usage is linked with a number of adverse events, such as transfusion-related acute lung injury, alloimmunization and febrile reactions. Irradiation of cellular blood components prevents transfusion-associated graft-versus-host disease (TA-GVHD). This is a rare complication of blood transfusion with 100% mortality. Irradiation may also reduce the risk of alloimmunization in AA, as reported from animal data (Bean et al, 1994). Following universal leucodepletion in the UK, the Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) no longer recommends the use of cytomegalovirus (CMV)-negative blood components (if they have been leucodepleted) for patients with immunodeficiency (unless pregnant) and those undergoing HSCT (SaBTO Annual Report, 2011/12), although PCR monitoring should be considered (https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/215126/dh_132966.pdf). To date, there has not been a statement from the British Society of Bone Marrow Transplantation regarding blood products and CMV status. CMV-negative granulocyte components should be provided for CMV-negative recipients. Aplastic anaemia patients on regular RBC transfusion support will develop tissue iron overload, but there remains debate on the clinical impact of transfusional iron overload. In the setting of HSCT, a raised serum ferritin is an adverse predictor of outcome in myeloablative stem cell transplantation (Armand et al, 2007). Although unreliable, serum ferritin remains the most widely quoted parameter for assessment of iron overload. Magnetic resonance imaging (T2* or R2) can quantitate cardiac and liver iron, and is a useful adjunct although its utility in AA has not been published. There are few published data regarding iron chelation therapy in AA. A large study was the 1-year Evaluation of Patients' Iron Chelation with Exjade study (Lee et al, 2010). This confirmed that chelation with deferasirox can be administered safely in patients with AA (no drug-induced cytopenias were noted), and can reduce the serum ferritin. However, dose adjustments are required to adequately chelate those who are heavily transfusion dependent. Impaired renal function is observed with deferasirox, and the drug should be used with caution in AA patients who are taking CSA. Deferasirox is licensed for use in transfusion-dependent anaemia, but only as second line therapy when desferrioxamine is inadequate or contra-indicated. Deferiprone is efficacious but not recommended in neutropenic patients (Cermak et al, 2011). For those responding to immunosuppression, or after a successful HSCT, venesection is recommended for iron overload. Infections remain the major cause of death in AA (Marsh & Kulasekararaj, 2013). In contrast to cancer patients undergoing chemotherapy, in SAA neutropenia is prolonged and persistent, resulting in a higher incidence of invasive fungal infection (IFI) and severe bacterial sepsis. Survival of non-responders to ATG in the last two decades has markedly improved and this has occurred in conjunction with decreased infection-related mortality and decreased frequency of IFIs (Valdez et al, 2011). Aplastic anaemia patients who are severely neutropenic should ideally be nursed in isolation when in hospital. In the UK it is common practice to give prophylactic antibiotics and antifungals, regular mouth care including an antiseptic mouthwash (such as chlorhexidine or saline) and food of low bacterial content (Hochsmann et al, 2013). Prophylactic antibiotics, either two non-absorbables (e.g. colistin and neomycin) or quinolones (e.g. ciprofloxacin), may be initiated but the preference should be according to local policy. A mould (aspergillus) active azole, preferably itraconazole or posaconazole, should be used as prophylaxis. In the UK, prophylaxis against Pneumocystis jirovecii is not routinely given. Anti-viral prophylaxis in untreated patients with AA is not routinely given. Antiviral prophylaxis with aciclovir or valaciclovir should be used during and after ATG therapy. During ATG therapy, sub-clinical reactivation of CMV and Epstein–Barr virus (EBV) is common but and not need disease has only very been reported after ATG, most after It is not UK practice to give Pneumocystis jirovecii prophylaxis with and guidelines for the management of febrile including the assessment and management of fungal are well and should local and for and guidance et al, 2012). therapy, as per local should be initiated early for patients with as these patients have transfusions may be life in severe sepsis, such as invasive fungal particularly for patients due to to HSCT (Quillen et al, 2009). such as and granulocyte are usually in blood in AA patients (Marsh et al, although results are reported with the et al, also on of AA in the first line is the of ATG and CSA. ATG is no longer available (Marsh et al, & Scheinberg & Young, 2012). A study from the of and a study at and and with ATG to ATG for first line (Scheinberg et al, 2011; et al, 2012). There is no for use of with ATG et al, 2011). is used with ATG for the of of of There is no age for ATG, but there is increased mortality in patients years with ATG et al, 2011) on of AA in the A second course of ATG may be indicated for to respond or after a first course or the patient is for HSCT (Marsh et al, & Scheinberg & Young, For a second ATG may be given. A second course of ATG is an alternative but this may be associated with more and (Marsh et al, 2012). to ATG, ATG more and prolonged in more It is important to that patients prophylactic support when using The dose of ATG is for It is given as an over to the risk of a dose must be given. practice is to use an dose of the SAA data the first of the first is given over 1 ATG should be given a or other as it is to peripheral and also for of administration of other drugs and blood dose of ATG should be with 1 and platelet transfusions aiming to the platelet count × 109/l (Marsh et al, Scheinberg & Young, 2012). antibiotics according to local should be given for febrile of the neutrophil commonly during ATG in careful to is is on the after ATG is at a dose of 1 for by over the should be as the dose is at a dose of to achieve blood levels of should be whilst the blood count to A of the drug every can be after at least a further of therapy, to reduce the risk of et al, 2013). of ATG are early including acute pulmonary syndrome and and serum from the of ATG, most commonly with and is with a and it usually a few of platelet transfusions are needed during the of serum due to platelet There is no for using with ATG as studies have that given for after ATG not improve or et al, 2011). to ATG defined in Table is after an of The to a first course of ATG is is 100% for age for for years and for years et al, 2011). In the to a first course of ATG is only with (Scheinberg et al, 2011; et al, 2012; Scheinberg & Young, 2012). For ATG results in higher to alone (Marsh et al, after ATG in up to of the risk of clonal evolution to is and in et al, Scheinberg & Young, 2012). (if previously or or of at least one cell line or of to a second course of ATG from most studies is for refractory AA and for AA (Marsh et al, & Scheinberg & Young, 2012). for are summarized in Table It is recommended that expert advice be when the use of other and are not recommended in the treatment of AA Table There is a risk of AA following in those patients who have to The evidence is limited and based on as well as an that a is likely to be an important trigger in the of AA et al, et al, including should be following HSCT, when AA patients should be routinely as recommended for all bone marrow transplantation HSCT The for HSCT are based on the guidelines et al, Patients should be in Society for and centres. HSCT from a is indicated for SAA in young and patients who have a data for patients to those years et al, However, co-morbidities should be to for transplantation of for patients years. HSCT is indicated for SAA after to respond to one course of There is no age but this should be on an individual patient and according to co-morbidities at the The should be or based on HLA for and HSCT using either a family or a may be other treatment after to respond to and in the absence of a and a et al, 2012; & 2013). should be for HLA the presence of which is associated with a very risk of graft There is clear guidance on the exact for alternative HSCT as this is successful or HSCT, but new to alternative HSCT are being using In the rare situation where there is a HSCT should be considered in all patients of age as (Marsh & Kulasekararaj, 2013). For all AA patients who may be HLA tissue should be performed at of that HSCT can as as and ideally the patient not only to HLA but also to and the of is that there is no to a course of ATG and the patient can then to HSCT the patient's is of with severe for to is usually at MDT approach is essential for the The aims of the up are to the diagnosis and clonal evolution assess co-morbidities the stem cell dose and and the transfusion of the and review of transfusion The of to use on patient age of preference for of ATG et al, et al, 2011) or (Marsh et al, 2011; et al, 2012). See Table For HSCT, the is but is the of and 50 years. A analysis has that after HSCT are no longer to HSCT, in that is not a predictor of et al, 2013; et al, 2014). to AA HSCT regarding early management and management of are summarized in Table The treatment of elderly patients with AA is more in patients. In the outcome is due to of the patients should be for co-morbidities and their specific should be as quality of life is an important outcome in this With to it is important to exclude as MDS is more common AA in this age group diagnostic age per is not a to treatment in the very is considered the treatment of There is no for HSCT as first line therapy in patients although HSCT can be considered in selected patients with a the least and most treatment should be given. However, consideration is a is such that those with life cytopenias count × or a severe infection requiring should be more those with severe disease. with ATG and results in a more and alone in patients with (Marsh et al, However, patients and have a higher risk of acute and the risks and of treatment should be up for individual Patients must be as the risk of and with ATG is higher in the patients have an after ATG to patients et al, or Although the of alone is to the of ATG and in is not as patients may respond to second line therapy with ATG and (Marsh et al, alone has the of being but patients must be for and may be used as a in AA, but medical very careful assessment in patients prior to this as a possible (Scheinberg et al, 2012). or can be considered in or to et al, et al, 2011). has may be a alternative for monitoring of is required as it can cause cardiac and raised blood Patients who are or who should be is a oral In an of an study at patients with refractory SAA were with et al, 2014). including were observed in of patients. The drug was well in most patients. levels may and there are about clonal including monosomy 7, which further has been by the and in the for treatment of SAA refractory to It has as of been licensed by the for SAA refractory to or patients who are heavily and for HSCT. It should be used with monitoring for clonal or following a clinical It is that a bone marrow is performed prior to treatment to exclude an abnormal cytogenetic clone typical of particularly monosomy Although the either or AA and is it remains a to and with a clinical AA can be for the first during in early or during but the disease may after or or after et al, is common during in AA patients who have previously to ATG, those with et al, not trigger of the disease in patients who successful HSCT. et in previously with for AA. reported a complication in the two cases of and of AA occurred in and a further needed transfusion during blood not from of AA during care in particularly in of blood has to in and outcome et al, However, it is important to with the patient and family the risks to the and et al, It is essential that the patient be frequently initially but more frequently and according to disease and with very with the and of a clone should with a The of should be on care is the of treatment of AA in and the platelet count be 20 × 109/l with platelet The risk of alloimmunization and platelet refractoriness to be considered. is safe during & and is recommended for those ATG, HSCT or for AA during are not should be by flow et al, et al, 2010). of is a and quantitative for the of clones which in up to of AA the on the of the flow cytometric analysis used et al, et al, clones are most in the neutrophil and in AA and will be by flow If the patient has a blood transfusion, a of red cells may be by flow in the granulocyte and However, the clinical of a clone in AA as by flow remains clones can remain in or the need for monitoring the is important is the presence of a clone associated with clinical or evidence of should be for as this is a feature of when the patient not have of associated with should be with the count, serum serum and Patients should be for at the diagnosis of AA. If for years and then to testing If the or for the first years and only reduce the frequency the of the cells has The presence of a clone in the setting of AA not the of therapy for the There is evidence that the finding of a clone a to but this is not universal in all published Patients with a clone ATG, should be for of AA may in patients in the presence of patients should be to one of the two specialized and to be for and for consideration for therapy, following MDT Patients will be seen in either of the two or in one of 10 Data from the to the that stem cell has an outcome in and to care including when indicated et al, 2012). the finding of a clone not or on the decision to the advice and in these guidelines is to be and at the of to the the British Committee for Standards in Haematology (BCSH) the for the content of these These guidelines are only to patients with AA. to and for their review of this The authors to the BCSH and the BSH sounding BCSH and the Aplastic Trust for their support in these the guidelines was the authors were in and of the authors the of the authors have a of to the BCSH and Task which may be reviewed on In summary the following authors have the following of has from for at and from for at and has from has from for has from for at has from and has from has from and and have from for The of the authors have no of of the group will the group new evidence available that the strength of the in this or it The will be and from the BCSH guidelines website it If new are an will be published on the BCSH guidelines website at If are required due to in of evidence or evidence a new of the guidance will be on the BCSH