Guidelines for the diagnosis and management of adult myelodysplastic syndromes

Abstract

The myelodysplastic syndromes (MDS) are a heterogeneous group of malignant haematopoietic disorders characterized by dysplastic changes in one or more cell lineages, ineffective haematopoiesis and a variable predilection to development of acute myeloid leukaemia (AML) (Swerdlow et al, 2008). The incidence of MDS is approximately 4/100 000 population/year, but it is predominantly a disease of the elderly with an incidence of > 30/100 000/year over the age of 70 years. Patients with suspected MDS should be assessed by a haematologist. As MDS is considered a rare or ‘orphan’ malignancy, patients should always be given the opportunity to be reviewed by a regional or national haematologist with a specific interest in MDS. All patients with a diagnosis of MDS must be discussed at a multi-disciplinary meeting (MDT), which should include allogeneic stem cell transplant representation. All patients diagnosed with MDS should be reported to the National Cancer Registry via the MDT, and to MDS-specific registries if appropriate. The diagnosis of MDS should be considered in patients with otherwise unexplained cytopenias(s). The minimum clinical assessment and laboratory investigation of a patient with possible MDS are shown in Table 1. Selected patients may require further investigations (Table 2). It is important to consider alternative diagnoses and reactive causes of marrow dysplasia. The initial assessment of a patient with unexplained cytopenias(s) may not confirm a diagnosis of MDS. In the absence of significant (>10%) marrow dysplasia or a clonal cytogenetic abnormality, a definitive diagnosis of MDS and distinction from other causes of cytopenia may be difficult. The term ‘idiopathic cytopenia of unknown origin’ may be used for patients with sustained (>6 months) cytopenia who do not fulfil the criteria for the diagnosis of MDS and where there is no other identifiable cause for the cytopenias (Valent et al, 2012). Such patients should be observed (with repeat marrow examination if necessary), as some may subsequently develop overt MDS. A blood film analysis and bone marrow examination for characteristic morphological features of dysplasia are both necessary for the diagnosis, classification and prognostic evaluation of MDS. This should be performed by a haematologist or haemato-pathologist. Blood film examination should include assessment of red cell, platelet and white cell morphology for features of dysplasia (Swerdlow et al, 2008; Bain et al, 2010). Bone marrow examination should include an assessment of May-Grünwald Giemsa (or equivalent) stained smears for myeloid, megakaryocyte and erythroid maturation, with identification of dysplasia if present. 500 nucleated cells and at least 30 megakaryocytes should, where possible, be evaluated and the percentage of blasts enumerated. Dysplastic features should be present in at least 10% of cells of the relevant lineage (myeloid, erythroid or megakaryocytic) (Swerdlow et al, 2008; Vardiman et al, 2009; Bain et al, 2010) (Evidence levels 2B,C). An iron stain (Prussian Blue/Perls stain) should be performed on all marrow aspirates to assess iron stores and to identify the presence and quantity of ring sideroblasts, which should be at least 15% of the total erythroblasts to be diagnostic of refractory anaemia with ring sideroblasts (RARS) or refractory anaemia with multilineage dysplasia + ring sideroblasts (RCMD-RS). A trephine biopsy (decalcified and paraffin-embedded or plastic embedded) including reticulin staining should be performed in all patients as it contributes significantly to the assessment of patients with MDS. It can provide information regarding cellularity and fibrosis, aiding the identification of hypocellular MDS and overlap myelodysplastic/myeloproliferative syndromes (Bennett & Orazi, 2009). If the aspirate is dilute, CD34+ staining of an adequate trephine biopsy specimen may allow assessment of bone marrow blast percentage. In patients with hypocellular marrows, the diagnosis of MDS requires dysplasia in the myeloid and/or megakaryocytic series, as erythroid dysplasia is common in aplastic anaemia. (Evidence levels 2B,C). Cytogenetic analysis should be performed on all patients with suspected MDS to confirm the diagnosis, inform management options and provide prognostic information. Cytogenetic analysis should be performed on at least 25 metaphases and should be reported in accordance with the International System for Human Cytogenetic Nomenclature Recommendations (Schaffer et al, 2009). Identification of clonal chromosomal abnormalities has become essential for the application of international prognostic scoring systems [such as the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R)]. A new comprehensive cytogenetic scoring system has been incorporated into the IPSS-R (Schanz et al, 2012). In addition, identification of a specific cytogenetic abnormality may provide a marker for assessing response to therapy. In patients where conventional marrow cytogenetic analysis is not possible (‘dry tap’) or has failed, fluorescence in situ hybridization analysis of bone marrow or peripheral blood films for selected cytogenetic anomalies (for instance monosomy 7, deletion of 5q, trisomy 8) may help provide diagnostic and prognostic evaluation (Evidence levels 2B,C). Despite on-going advances in molecular genetics, the classification of MDS currently remains largely based upon morphological examination with incorporation of limited genetic information. The diagnosis and classification of MDS should be based on the World Health Organization Classification (WHO, 2008 revision) (Swerdlow et al, 2008), which has superseded the former French-American-British (FAB) Classification (Bennett et al, 1982). The specific WHO classification subtype should be identified for each patient and included in the marrow aspirate report (Table 3). Due consideration should be given to the MDS/Myeloproliferative Neoplasm (MPN) category, which now includes chronic myelomonocytic leukaemia (CMML), MDS/MPN neoplasms (unclassifiable), and the provisional entity RARS with thrombocytosis (RARS-T) (Swerdlow et al, 2008). Adult patients with >20% blasts are now classified as having AML, although those with between 20 and 30% blasts were included in the IPSS. MDS secondary to prior cytotoxic therapy is classified as a separate entity by the WHO Classification (therapy-related myeloid neoplasms). Refractory cytopenias with unilineage dysplasia (RCUD) Refractory anaemia (RA) Refractory neutropenia (RN) Refractory thrombocytopenia (RT) Unicytopenia or bicytopeniaa or rare blasts 10% of the cells of the lineage are dysplastic blasts of the erythroid are ring sideroblasts blasts dysplasia blasts of erythroid are ring sideroblasts or rare blasts in of cells in or more myeloid and/or erythroid and/or blasts ring sideroblasts or multilineage dysplasia dysplasia in 10% in myeloid cell but cytogenetic abnormality with blasts in peripheral blood with or platelet or rare blasts to megakaryocytes with blasts cytogenetic abnormality The of as analysis and has to the identification of in cells of patients with some of which may prognostic et al, 2009; et al, Identification by new of of cells with may help in clonal and disease et al, are with the ring et al, in other as and in analysis but prognostic in analysis has not been in et al, et al, analysis be incorporated into diagnostic or prognostic evaluation of patients with MDS but provide important information in the (Evidence levels 2B,C). is not for the diagnosis of MDS. is no specific diagnostic of MDS. anomalies may the diagnosis but should be in with morphological and cytogenetic (Evidence levels 2B,C). are on myeloid, and erythroid lineages, of et al, and CD34+ lineage Recommendations for of including for cell and been with of of for analysis et al, 2009; et al, et al, in the IPSS has been an important for assessing the of patients with MDS et al, prognostic been the important of which are cytogenetic (Table more prognostic information (Schanz et al, 2012). The IPSS has the of clinical with to by analysis of MDS patients not with the IPSS-R used the as the IPSS marrow and the IPSS-R has been to further by more cytogenetic of blast and of cytopenias (Table et al, 2012). This new scoring system has IPSS-R and has the prognostic to and in patients with MDS (Table A to the IPSS-R can be via the MDS This should be the scoring system for It should be the IPSS-R is not to be a scoring and can provide a at The WHO Prognostic Scoring System the WHO diagnosis, IPSS cytogenetic criteria and and the IPSS et al, allow an of at the disease for MDS largely the IPSS as are by the IPSS MDS includes patients with IPSS and MDS includes those with IPSS It remains IPSS-R patients should be into or As patients should be considered for management by clinical and and by patient and can be to response to therapy in to the which should be used to in all but not to therapy. all patients should be into clinical and/or Registry to information the and of MDS to National clinical are currently and MDS patients can be including and is to the management of MDS blood are a stem cell transplant or with cell is given to of et al, The for from patient to patient to as chronic disease and no for a can be red cell to including iron and the development of red cell should be given to red cell in patients who are and is for patients who are for a stem cell and for the management of including the assessment and management of possible are and are to In addition, the National for Health and for the and management of in patients are et al, 2012). The of may be considered in patients with who there is the of as in patients therapy for et al, there is no to should be given to all patients with The of platelet is to the management of in platelet may be of in patients but there is no to in thrombocytopenia patients not with platelet for in Blood The of as a in may be but should be shown in patients with disease or is some for the of in selected in of in the platelet et al, et al, The has been evaluated in a an et al, 2010). The of blast cell in patients It remains if into an in disease were and platelet in the currently be clinical The diagnosis of MDS is to the patient and It can be a diagnosis for the patient to and there are options and to All patients should be by the with in MDS. The MDS is a for all both at diagnosis and is patient information should be with at least on an et al, Patients by the IPSS as or and by the IPSS-R as and a The clinical in MDS patients to the of cytopenias and the to An for the management of MDS can be in 1. A chronic red cell for MDS patients in iron Patients with ineffective those with a of The to be and are for in in patients with predominantly erythroid disease RARS and et al, A may not iron is an of in stem cell et al, is by other iron for iron therapy are based upon The of red cell may be but it is is more relevant for total et al, et al, can be used to and iron but the with red cell has not been in MDS et al, et al, 2008; et al, is no to a for iron therapy in MDS and A of patients haematopoiesis on iron to for patients are all and limited et al, 2010). Despite there is in national and international for iron therapy in selected MDS patients et al, is the for iron therapy in MDS therapy is or The used for are MDS patients of of patients shown a in and iron over of therapy but remains et al, 2012). of all patients of to The and has a to the for for with and remains the therapy of as there is the of clinical it is and if although to is but not in patients et al, and therapy been used to the anaemia of MDS for over 20 and the et al, the of other has been Despite the in the of there are to the of in MDS to the in et al, 2010). are to at least there may be a for to therapy et al, 2008; et al, and in for et al, et al, not in the by et the to the of not been by include or not there is a significant in and for to to patients on red cell of in MDS are now The of patients who are to a of to are and not significantly the et al, et al, et al, The for response to should be used et al, et al, The and for with but is for with The is used as shown in Table therapy should be considered for MDS patients with an IPSS of or who fulfil the criteria for response and Patients with MDS in not to be considered for therapy with of and the of and stem cell which require red cell should with or The for is 30 000 for et al, If there is no response at the can be to or 30 000 for a further The for should be or et al, et al, 2008). The can be in to a of for a further of et al, are erythroid to the of to are et al, et al, et al, 2009). the of to is not as as used in of and is but there is of with to an response of in RARS et al, et al, 2009). It is the should be with from the in should be given as to approximately the white cell if or the white cell in the of clinical a of in to in is appropriate. of is a and of the has therapy of diagnosis response and the of to of et al, 2010). As a of therapy should be the of therapy to or the of et al, et al, the response criteria used were in other criteria for response used in the of response et al, are as of > and in and but remains Patients who a erythroid response been shown to a of response those who a erythroid response months) et al, patients who a erythroid response the of should be to the the If the response is at iron should be but common in MDS patients with in patients with anaemia. The of in MDS patients to has been at in one et al, and the of in significantly in patients with as or to therapy if the or if there is a in the can be with of the of to be a of in at least some patients with MDS. include a incidence of abnormalities cytotoxic et al, and of cells et al, is an overlap between MDS and aplastic anaemia. provide the for which are now an and for a of therapy should be considered in patients stem cell The response to in MDS patients is approximately et al, et al, In to aplastic a response to with age in MDS patients et al, 2008), although patient are The initial therapy be in patients with hypocellular bone marrow is and in patients with and been patients a response if et al, and presence of a has not been a for response et al, et al, 2008). with is with a in patients with aplastic anaemia et al, and in MDS should be to patients must be as an in with therapy. The of is as In aplastic anaemia there is for a and in patients with with et al, et al, for and in MDS is should be et al, and for at least to the Blood and must be of at of response is years. In the absence of it is to therapy response is A of should be but may in a of in which the should be in an to a further may a response although red cell is the may a for patients with of or a hypocellular bone is for and a response et al, not been The is characterized by a refractory in with characteristic megakaryocytes and erythroid It has a with a of at least but patients are and the at is approximately patients with MDS can the features or with as blasts and cytogenetic for in MDS with include thrombocytopenia and cytogenetic of are bone marrow blast and et al, 2012). of MDS to in the to in patients International criteria et al, et al, 2008). et the response of MDS with to the a of in a in patients with MDS to et al, Patients with the characteristic deletion an response to in patients with and patients with other cytogenetic This to a et al, and patients with deletion were with given for or in a of of patients were with a to response of although some patients to to a The were neutropenia and of et reported the of the in and MDS with which of for in a or for with The in in of patients with with in the group and in the with a of to Cytogenetic were in and of the In a platelet to response to patients with thrombocytopenia on in the for the of with IPSS or but it to in based on a of to This reviewed in a by the MDS who patients with for in a et al, 2012). patients to the of the The to a group of patients with who for the of with and not are in a some the of in patients with et al, reported an of secondary with in et al, 2012). This to limited to and chronic leukaemia from the of in MDS is not reported in The for for Human has now a for for the of patients with anaemia to or MDS with an deletion cytogenetic abnormality other options are or This is the which includes all patients with and IPSS of the of cytogenetic Patients with and/or bone marrow cells by a and largely to to This may be an to consider in the to et al, can be considered where on an Selected patients with and IPSS may be for allogeneic stem cell include patients who to those or patients with not considered for et al, 2010). is the with for MDS. all patients with diagnosed MDS should be discussed at a and the of allogeneic should be patient for is an important of and the to transplant patients with disease the of disease the of a transplant and the of As of the of should the disease In of an transplant are the patients with MDS a those with disease et al, et al, et al, 2010). for disease is to be if patients are at a with disease of and prior to the of et al, et al, et al, 2009). are the from et which the of disease for patients with IPSS and analysis not include patients with or patients with and not into In prognostic as red cell bone marrow and molecular abnormalities which were not included in the IPSS and a more for a given IPSS are currently for the of patients allogeneic are not considered in the or in the IPSS is some red cell can transplant et al, 2010). age not a on transplant but the are with age should be into assessing MDS patients for The et al, and the for Blood and et al, both been for MDS and shown to and et al, et al, 2009; et al, 2010). is not of assessed by has been with a and of allogeneic and et al, et al, 2008). the the prognostic of may be to of iron has been et al, and it remains to iron in patients who allogeneic This is a largely to the patient age and the of to The is 20 et al, and is at diagnosis, as patients and/or patients with disease may be considered for an allogeneic stem cell transplant at the As not incorporated in the incorporated in the alternative prognostic may be as the et al, and cytogenetic abnormalities should be into et al, A prognostic has been which a cytogenetic white blood cell for with a and This has been on of and to be in clinical patients a of for et al, include for and of or clinical are no specific to to in the performed in et al, is to alternative as specific in are is now by the for on the of patients included in the et al, 2009). in et al, et al, et al, 2012). a by the for Health Cancer MDS limited but with a of et al, 2012). has reported in but remains by the et al, et al, et al, 2008; et al, 2008; et al, A a response in a including 10% response and bone marrow response et al, patients on were to a to in the of et al, 2012). The of has not been in all patients and can be for the or in clinical may be considered for selected patients et al, if et al, 2008). transplant can in term for selected patients et al, although reported term significantly and are Patients with MDS IPSS or IPSS-R a to of to and a of et al, the for patients for therapy should be at the of the disease to Patients should be given the opportunity to in clinical given allogeneic is the therapy with should a patient is a possible transplant at diagnosis and the disease with the transplant is to and An for the management of MDS can be in patients with IPSS of age is and with an allogeneic transplant a for et al, In patients with has been to be for et al, of patients with MDS may to over with which for the presence of disease et al, The IPSS and the et al, The which from in to in et al, 2008). In age not disease or et al, et al, 2010). patient consideration include and the which in transplant et al, patients with disease and the of a transplant to be the possible from with significantly is is et al, of with for group of patients with a incidence of acute and at the of of which remains the for et al, et al, et al, et al, 2008; et al, et al, 2012). the from are to those with et al, from a is not or if there is a to bone marrow is an in et al, should be given to alternative from blood or clinical stem cell for MDS is not of clinical et al, 2010). disease at the of transplant significantly et al, 2009; et al, it to to prior to patients with bone marrow blasts or or where the of significant as are hypocellular marrow or reticulin a to to transplant should be patients with blasts and may from initial therapy to This can be by The is to a cytogenetic response and/or the blast percentage to The of in those patients an of but a abnormality is As the of marrow and is in MDS AML, it is to identify a prior to if An of therapy is to identify those patients with in the is Such patients should be considered for therapy or as et al, in MDS and both with and et al, et al, 2012). Such are of interest but As be as a to transplant in MDS of clinical those patients not for can be used in an to disease response and patients should be into clinical where The of are the if is and the of been reported of term in patients with MDS and an et al, patients are in AML, is months) and of marrow and more et al, et al, et al, et al, et al, 2010). of patients over the age of with MDS or an of 10% and an to in of the patients et al, to those with a who a of those with a abnormalities or a of The of for MDS et al, it is cytogenetic are to in patients with as there is no to in be et al, 2009). of as and an alternative to in MDS. do not a by the may a and are in the elderly and those with The of are the it is an based with a of with a response of and a with is to the of the et al, 2009). The of should be to clinical has been by et al, and the as a for patients not for with MDS or and with blasts and Patients should be for a minimum of The is which is for by a of The for the of in patient from the et al, 2009). This with significantly to conventional or et al, 2009). in with of patients to on the conventional In a analysis of the elderly patients the significantly to conventional 15% is the of in patients with and MDS et al, 2010). has been shown to be in all cytogenetic with conventional patients with a of with for conventional et al, 2009). patients with monosomy or 7, or as of a with to a over those with conventional et al, 2009). The of is unknown but therapy for as as a response is is patients a significant in with those having at least of the et al, of therapy for disease should be at the patient and It is patients a bone marrow assessment (for morphology and prior to the disease has not and at the of the should there be there is of disease for include given for no for further of given on a or a given for et al, 2009). been predominantly in but The is a alternative to the and is as the alternative to the for the of can be in the by et In selected patients who a with a and an in the of a should be of in MDS been et al, et al, used given for of patients and but to significant in patients has in MDS. may been by the a significant of patients or of The patients with 20 for as for a of et al, 2009). response + marrow response to criteria et al, of red cell and platelet to the response in the were of patients were the of the the has in both and the of over in the therapy in MDS. therapy be considered for a and rare group of those with an of blasts in a hypocellular marrow with a for no alternative therapy is and/or appropriate. The of patients with of et al, a but for a patients are Patients not for the and information in is to be and at the of to the the for the for the of The for in on an to it remains the at to if the has been or The the the The group selected to be of myelodysplastic (MDS) Recommendations are based on of the and to the The group the which subsequently revised with by of the of the for in The reviewed by a of approximately the and the for were incorporated where appropriate. of and of been assessed the of Recommendations and for assessing the of and of The of is to provide with on the management of patients with MDS. The may not be to patient and in all patient may an alternative All the to the of The to and been in of and/or from and/or In addition, has for for for & and for and and no of interest to of all can be by the