Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes

Guideline

GUIDELINES FOR THE DIAGNOSIS AND THERAPY OF ADULT MYELODYSPLASTIC SYNDROMES

The myelodysplastic syndromes (MDS) represent a hetero-geneous group of haematopoietic disorders affecting pre-dominantly elderly individuals (median age 69 years). Theoverall disease incidence is about 4 per 100 000 populationbut this rises to > 30 per 100 000 in the over 70 year agegroup. The pathological processes underlying the haemato-logical abnormalities seen in MDS are:1. augmented apoptosis, leading to ineffective haematopoi-

esis and peripheral cytopenias;2. transformation to acute myeloid leukaemia (AML).

The precise relationship between these pathologicalprocesses remains uncertain but has important implicationsfor the design of new therapeutic strategies targeting one orthe other or indeed both.

METHODS

The guideline group was selected to include UK-based medicalexperts in the clinical management of MDS and to include arepresentative from a District General Hospital. The draftinggroup met on six occasions. Each group member wasallocated responsibility for preparation of a selected compo-nent of the first draft. Medline ⁄Pubmed was systematicallysearched from 1982. The Cochrane database was searchedbut contained no references to MDS. Meeting abstracts werenot included in the systematic search strategy. The Chairmansynthesized the draft components, which were revised byconsensus through meetings 3–6. No recommendations areincluded for which full consensus was not achieved. The draftguideline was reviewed by the Sounding Board and by theCommittee of the British Committee for Standards in Hae-matology, and comments incorporated where appropriate.Following further helpful peer-review by the British Journal ofHaematology, a final revision is now presented. Criteria usedto quote Levels and Grades of Evidence are outlined in Table I.A full guideline revision is planned for May 2005.

DIAGNOSIS

The diagnosis and classification of MDS remain dependenton the morphological examination of blood and bonemarrow cells. Diagnostic criteria should ideally distinguishMDS from reactive conditions causing dysplastic haemato-poiesis and from other clonal myeloid disorders. Theminimum clinical assessment and laboratory investigationrequired for the definitive diagnosis of cases of suspected

MDS is shown in Table II. Practical issues regarding thediagnosis of MDS include the following:1. Should every patient have a bone marrow aspirate? A

bone marrow aspirate is usually necessary to make aconfident diagnosis and to provide important prognosticinformation. This may not, however, be necessary inelderly patients in whom a definitive diagnosis of MDSwould not alter management or whose poor generalhealth precludes active treatment.

2. Should every patient have a bone marrow trephine?Bone marrow histology complements the morphologicalinformation obtained from a marrow aspirate and hencea trephine biopsy should be performed in all cases ofsuspected MDS in whom bone marrow examination isindicated. Diagnostic certainty can be improved byfeatures such as the presence of megakaryocyte dyspla-sia, while disordered marrow architecture such ascentral clustering of immature myeloid cells (abnormallocalization of immature precursors or ALIPs) is anadverse prognostic marker (Tricot et al, 1984). Theassessment of cellularity and fibrosis define morphologi-cal variants, with the identification of hypocellular MDSof particular therapeutic importance (see below) (Mijovic& Mufti, 1998).

3. Should all patients have cytogenetic analysis? A chro-mosome abnormality confirms the presence of a clonaldisorder aiding the distinction between MDS and reactivecauses of dysplasia, and in addition has major prognosticvalue. Cytogenetic analysis should therefore be per-formed for all patients in whom a bone marrowexamination is indicated.

4. What are the minimal morphological diagnostic criteriafor MDS? Minimal diagnostic criteria are not clearlydefined in MDS. Difficulties arise because a variety ofreactive disorders are associated with dysplastic mor-phology and mild dysplastic features are frequently seenin the marrow of healthy people with normal bloodcounts (Bain, 1996; Ramos et al, 1999).

The following are recommended to increase the reliabilityof diagnosing MDS.a) At least 200 marrow cells and 20 megakaryocytes

should be evaluated where possible.b) Dysplastic features should be present in > 10% of

marrow cells (Kouides & Bennett, 1996).c) Particular attention should be given to the presence of

pseudo-pelger neutrophils, ring sideroblasts, micro-megakaryocytes and increased blasts as these abnormal-ities correlate most strongly with the presence of clonalmarkers in MDS and show least interobserver variation(Kuriyama et al, 1986; Ramos et al, 1999).

Correspondence: Dr David Bowen, Molecular and Cellular Pathol-

ogy, Ninewells Hospital, Dundee, DD1 9SY, UK. E-mail: d.t.bowen@

dundee.ac.uk

British Journal of Haematology, 2003, 120, 187–200

� 2003 Blackwell Publishing Ltd 187

d) The assessment of neutrophil granularity is criticallydependent on optimal staining and it is unwise to base adiagnosis of MDS solely on the presence of neutrophilhypogranularity in the absence of other dysplasticfeatures.

It is recognized that the definitive diagnosis of early refractoryanaemia may be difficult, for example in patients with a singleisolated cytopenia or isolated macrocytosis. If the morphological

diagnosis remains uncertain, it is recommended that the patientbe reviewed regularly in the haematology clinic with repeat bloodcount and morphological assessment at appropriate intervals.5. Overlap syndromes. At least three overlap syndromes are

recognized namely: fibrotic MDS (Mijovic & Mufti, 1998),MDS with thrombocytosis (Harris et al, 1999) andhypoplastic MDS (Tuzuner et al, 1994, 1995). Presently,only the latter requires a distinctive therapeuticapproach and as such is important to distinguish fromaplastic anaemia.

Hypocellular MDS versus aplastic anaemiaThe diagnosis of hypocellular MDS is of importance, aspreliminary data suggest that the response to immunosup-pressive therapy is higher than in cases of MDS with normo-or hypercellular marrows. A trephine may be consideredhypocellular if cellularity is < 30% in individuals youngerthan 60 years or < 20% in those over 60 years of age(Tuzuner et al, 1994, 1995). The diagnosis of myelodysplasiarequires the presence of dysplastic features in megakaryo-cytes and ⁄ or myeloid cells or an excess of blasts. Erythroiddysplasia is found in aplastic anaemia and cannot be usedalone to distinguish MDS from AA. The presence of anabnormal karyotype strongly favours the diagnosis of MDSbut cases of aplastic anaemia with an abnormal karyotypewithout morphological features of MDS and with a low risk oftransformation to MDS or AML have been described.

CLASSIFICATION OF MDS

The World Health Organization (WHO) recently publishedproposals for a new classification of MDS to supersede the

Table I.

(A) Levels of evidence.

Level Type of evidence

Ia Evidence obtained from meta-analysis of randomized controlled trials.

Ib Evidence obtained from at least one randomized controlled trial.

IIa Evidence obtained from at least one well-designed controlled study without randomization.

IIb Evidence obtained from at least one other type of well-designed quasi-experimental study.

III Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case

control studies.

IV Evidence obtained from expert committee reports or opinions and ⁄ or clinical experiences of respected authorities.

(B) Grades of recommendation.

Grade Evidence level Recommendation

A Ia, Ib Required – at least one randomized controlled trial as part of the body of literature of overall good quality and

consistency addressing specific recommendation.

B IIa, IIb, III Required – availability of well-conducted clinical studies but no randomized clinical trials on the topic of

recommendation.

C IV Required – evidence obtained from expert committee reports or opinions and ⁄ or clinical experiences of

respected authorities.

Indicates absence of directly applicable clinical studies of good quality.

Table II. Evaluation of suspected MDS.

History

Prior exposure to chemotherapy ⁄ radiation

Family history of MDS ⁄AML

Recurrent infections or bleeding ⁄ bruising

Examination

Pallor ⁄ infection ⁄ bruising

Splenomegaly

Full blood count

Macrocytosis, cytopenia(s), neutrophilia, monocytosis, thrombo-

cytosis

Blood film

Assay of serum ferritin, vitamin B12 and folate levels

Bone marrow aspirate

Bone marrow trephine biopsy

Bone marrow cytogenetic analysis

Exclusion of reactive causes of dysplasia

Megaloblastic anaemia

Human immunodeficiency virus infection

Alcoholism

Recent cytotoxic therapy

Severe intercurrent illness

188 Guideline

� 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200

French–American–British (FAB) classification (Bennett et al,1982). The new classification is based on a combination ofmorphology, karyotype and clinical features (Harris et al,1999), and potential problems with the adoption of the newclassification have recently been summarized (Greenberget al, 2000). The final classification has now been published(Jaffe et al, 2001) and is in the process of independentvalidation (Germing et al, 2000a; Nosslinger et al, 2001).Given the limited experience with the use of this newclassification to date, this guideline will use the more familiarFAB terminology (Bennett et al, 1982).

PROGNOSTIC SCORING SYSTEMS

All patients diagnosed with MDS have a reduced lifeexpectancy compared with age- and sex-matched normalcontrols, regardless of disease subtype. This difference isparticularly marked in younger patients (£ 60 years) andthose with �high-risk� disease. (Morel et al, 1996). While theFAB ⁄WHO classification systems are themselves of signifi-cant prognostic value, scoring systems employing objectiveparameters allow improved reproducibility for clinicaldecision-making but also for clinical trials and biologicalresearch in MDS patients. A series of different prognosticscoring systems have been developed since the originalBournemouth score (Mufti et al, 1985). The latest of theseis the International Prognostic Scoring System (IPSS)(Greenberg et al, 1997), which has improved prognosticpower compared with previous scoring systems, namely theSanz (Sanz et al, 1989) and Lille (Morel et al, 1993) scores.The IPSS is a multivariate analysis of patient characteristics

derived from a pool of 816 MDS patients who had beenincluded in the cohorts used to derive previous scoringsystems (Table III). A cautionary note is that the patientcohort analysed by the IPSS group were largely untreatedand may therefore include the MDS patients with poorestperformance status and therefore worst outlook. The IPSShas also excluded chronic myelomonocytic leukaemia(CMML) patients with a white blood cell count(WBC) > 12 · 109 ⁄ l, considering this group as myelopro-liferative rather than myelodysplastic. The IPSS score iscomputed from three parameters, namely bone marrowblast percentage, bone marrow cytogenetics and number oflineages with cytopenia, in decreasing order of prognosticpower. While this guideline advocates bone marrow cyto-genetic analysis for all MDS patients in whom a bonemarrow examination is deemed appropriate, we accept thatthis is not always technically successful. In this raresituation, an alternative scoring system most familiar tothe clinician will be required, such as the Sanz (Sanz et al,1989) or Bournemouth (Mufti et al, 1985) scores. Themethodology used to derive the Sanz score is more rigorousand provides greater prognostic discrimination than theBournemouth score, at least in patients with > 5% blasts.

While the use of prognostic scoring systems is advocated,it must be recognized that even within each prognosticgroup the emergence of distinct clinical entities, which havedifferent prognoses, is inevitable. Examples of these includepure sideroblastic anaemia (Germing et al, 2000b) andperhaps the �5q– syndrome�, both of which are associatedwith an excellent prognosis and a low rate of transforma-tion to acute leukaemia.

Table III.

(A) International Prognostic Scoring System: derivation of patient score.

Score value

0 0Æ5 1 1Æ5 2

BM blasts percentage < 5 5–10 11–20 21–30

Karyotype Good Intermediate Poor

Cytopenias 0 ⁄1 2 ⁄3

Score for risk groups are as follows: Low 0; INT-1 0Æ5–1Æ0; INT-2 1Æ5–2Æ0; High ‡ 2Æ5. Karyotype:

Good, normal, –Y, del(5q), del(20q); Poor, complex (‡ 3 abnormalities) or chromosome 7 anomalies;

Intermediate, other abnormalities. Cytopenias defined as haemoglobin concentration < 10 g ⁄ dl, neu-

trophils < 1Æ8 · 109 ⁄ l and platelets < 100 · 109 ⁄ l.

(B) Median survival: IPSS score.

Median survival (years)

£ 60 years

(n ¼ 205)

> 60 years

(n ¼ 611)

£ 70 years

(n ¼ 445)

> 70 years

(n ¼ 371)

Low (n ¼ 267) 11Æ8 4Æ8 9 3Æ9INT-1 (n ¼ 314) 5Æ2 2Æ7 4Æ4 2Æ4INT-2 (n ¼ 176) 1Æ8 1Æ1 1Æ3 1Æ2High (n ¼ 59) 0Æ3 0Æ5 0Æ4 0Æ4

Guideline 189


MANAGEMENT OF MYELODYSPLASTICSYNDROMES

It is recommended that, where possible, managementdecisions be based upon the patient’s IPSS score. It isimportant that the IPSS score is calculated during a stableclinical state and not, for example, during a florid infectiveinitial presentation. Management decisions should be takenwith the informed involvement of the patient and, to aidthis, information booklets are available from the LeukaemiaResearch Fund and the Myelodysplastic Syndromes Foun-dation. The guideline will critically review individual thera-peutic modalities designed to improve the clinical problemsspecific to an individual patient with MDS, and willconclude with recommendations for management strategiesdriven by the patient’s IPSS score and the overall clinicalpicture. It is, however, important to stress that mostrecommendations are made on the basis of a very limitedevidence base for the efficacy of interventional and non-interventional therapy in MDS. Most papers reportinginterventional therapy describe relatively small cohorts ofpatients and only one (small) placebo-controlled trial isavailable. Criteria for defining therapeutic response are alsohighly variable between studies. The recent publication ofstandardized response criteria for therapeutic studies inMDS patients (Cheson et al, 2000) may facilitate theinterpretation of how clinically meaningful new therapeuticinterventions in MDS really are.

Supportive care: principlesSupportive care remains the most important aspect ofmanagement for patients with good prognosis MDS andthose with poor prognosis disease whose age or performancestatus precludes them from receiving more intensive formsof therapy. The aim is to reduce morbidity and mortalitywhile at the same time providing an acceptable quality oflife. However, grade A and grade B evidence for the

effectiveness of supportive care in patients with myelodyspl-asia is absent and is unlikely to ever be obtainable. Forpatients with good prognosis MDS, it is often feasible toundertake a period of observation without needing tointroduce specific therapy. Where possible, this �wait andwatch� approach to management may also be useful forpatients with more advanced MDS, allowing one to appraisethe stability of the disease process and to assess the need tointroduce treatment.

Management of anaemiaAt presentation, up to 80% of cases of MDS will have ahaemoglobin concentration < 10 g ⁄ dl (Sanz et al, 1989).Anaemia in MDS is usually due to ineffective erythropoiesisbut other factors that may accentuate anaemia, e.g.nutritional deficiencies, haemorrhage, haemolysis andinfection, should be sought and treated as appropriate.Chronic anaemia is seldom life threatening but can lead tosignificant morbidity and is therefore important in relationto quality of life issues. Figure 1 outlines a flow chart for themanagement of the anaemic MDS patient.

Red cell transfusion and iron chelation therapy. The use ofred cell transfusion should be considered in any patient withsymptoms of anaemia. It is not possible to ascribe a singlehaemoglobin concentration as being the optimal level belowwhich red cell support should be dispensed and eachindividual case needs to be considered separately (Murphyet al, 2001). Studies in cancer patients have demonstrated apositive correlation between increases in the haemoglobinlevel (with recombinant Erythropoietin therapy) andimprovements in quality of life (QOL) (Glaspy et al, 1997;Demetri et al, 1998).

Recommendations for iron chelation treatment in mye-lodysplasia are based on limited data (evidence grade B,level III). Iron chelation should be considered once a patienthas received 5 g iron (approximately 25 units of red cells)but only in patients for whom long-term transfusion

Fig 1. Guidelines for the management of symptomatic anaemia in MDS patients.

190 Guideline


therapy is likely, such as those with pure sideroblasticanaemia or the �5q– syndrome�. Desferrioxamine20–40 mg ⁄ kg should be administered by 12 h subcuta-neous infusion 5–7 d per week. Audiometry and ophthal-mology review are essential prior to commencement ofdesferrioxamine. The target ferritin concentration should be< 1000 lg ⁄ l; if the ferritin concentration falls below< 2000 lg ⁄ l, the dose of desferrioxamine should be reducedand should not exceed 25 mg ⁄ kg. Vitamin C 100–200 mgdaily should be commenced after 1 month of desferriox-amine therapy. Vitamin C should be taken when theinfusion is set up. Repeat audiometry and ophthalmologyreview should be performed at least annually. The use oftwice daily subcutaneous bolus injections of desferrioxa-mine (Franchini et al, 2000) may be considered whereinfusions are not tolerated, but the common practice ofadding a single dose of desferrioxamine at each transfusionepisode has no basis and should be discouraged. At present,deferiprone (L1) cannot be recommended for routine use inthis group of patients, given the lack of published data inMDS patients and continuing concerns about both efficacyand safety (Pippard & Weatherall, 2000).

Erythropoietin (EPO) + ⁄ – granulocyte colony-stimulatingfactor (G-CSF). Many studies have clearly demonstratedthat EPO ± G-CSF can increase haemoglobin concentra-tion and reduce ⁄ eliminate red cell transfusion in selectedMDS patients, and a summary outline of these is providedin Tables IVA and B. These studies were small cohortstudies (< 120 patients in each) and only one (small)placebo-controlled randomized study (of EPO therapyalone) has been reported (Italian Cooperative StudyGroup, 1998). Given the small size of this placebo-controlled trial of EPO therapy alone (87 patients), thegrade of recommendation for EPO therapy alone shouldbe considered as grade A ⁄B (level Ib ⁄ IIa). The evidencefor efficacy of the combination of EPO + G-CSF therapy isgrade B (level IIa ⁄ IIb).

These studies suggest that patients with refractoryanaemia with ringed sideroblasts (RARS) are more likelyto respond to the combination of EPO + G-CSF (HellstromLindberg et al, 1997, 1998). Patients with refractoryanaemia (RA) or RA with excess blasts (RAEB) mayrespond well to EPO alone, though a proportion will benefitfrom the addition of G-CSF (Hellstrom Lindberg, 1995,Hellstrom-Lindberg et al, 1998; Italian Cooperative StudyGroup, 1998; Mantovani et al, 2000). Overall there issufficient evidence for the efficacy of EPO ± G-CSF therapyin appropriately selected patients. It is recommended thatthose patients with RA and RAEB [not eligible forchemotherapy ⁄ stem cell transplantation (SCT): see later]who are symptomatic of anaemia, with no ⁄ low transfusionrequirement (< 2 units ⁄month) and a basal EPO level ofless than 200 U ⁄ l (measured at the haemoglobin nadir intransfusion-dependent patients) be considered for a trial ofEPO alone at a dose of 10 000 units daily for 6 weeks(Hellstrom Lindberg, 1995). For non-responders, consid-eration should be given to either the addition of dailyG-CSF, doubling the dose of EPO, or both for a further6 weeks. The dose of G-CSF should be escalated weekly

from 75 lg, to 150 lg to 300 lg (multiple sampling fromsingle vials kept at 4�C) to maintain the WBC between 6and 10 · 109 ⁄ l. In responding patients, once the maxi-mum response has been reached, the G-CSF can bereduced to thrice weekly and the EPO to 5 d then 4 d to3 d per week at 4 weekly intervals to the lowest dose thatretains response.

For patients with RARS, symptomatic anaemia, basalEPO levels of < 500 U ⁄ l and a transfusion requirement ofless than 2 units per month, it is recommended thatcombined therapy with EPO and G-CSF is used from theoutset (Hellstrom Lindberg et al, 1997). Dosing recommen-dations are as for RA ⁄RAEB with consideration given todose escalation of EPO at 6 weeks in non-responders for afurther 6 weeks.

While there are no published data demonstrating thatgrowth factor therapy improves QOL, extrapolation fromcancer patients treated with EPO suggests that this is likelyto be the case and that maintenance of a stable augmentedhaemoglobin concentration may be preferable to the cyc-lical fluctuations of red cell transfusion programmes (Bowen& Hellstrom-Lindberg, 2001). It should also be noted thatthere are a lack of survival data and of quality pharmaco-economic data to support the use of haematopoietic growthfactor therapy. We would, therefore, encourage continuingrandomized-controlled trials of EPO ± G-CSF, which addressthe issues of QOL, survival advantage and pharmaco-economics.

Immunosuppression. Two groups have demonstrated theefficacy of horse anti-lymphocyte globulin (ALG) in raisingthe blood counts in a proportion of patients with MDS,although each cohort reported is small, namely n ¼ 25(Molldrem et al, 1997) [updated in abstract form to n ¼ 60(Barrett et al, 1998)] and n ¼ 12 (Killick et al, 1999)patients respectively. ALG seems to be more effective inhypoplastic MDS and in patients with a paroxysmalnocturnal haemoglobinuria (PNH) clone (Dunn et al,1999), but also induces significant improvements innormo- and hypercellular patients with low-risk MDS(IPSS £ INT-1). Preliminary data suggest that responses,when achieved, are durable and prolonged (Barrett et al,1998). Most clinically meaningful responses are in theerythroid lineage but bi- and trilineage responses are seen.Similar responses have been observed with cyclosporin A(Jonasova et al, 1998), with higher response rates also inhypocellular MDS. Anecdotal reports of corticosteroid-responsive MDS exist but this therapy cannot at presentbe recommended. The data support a recommendation for atrial of immunosuppressive therapy with ALG at least forpatients with hypoplastic MDS (evidence grade B, level IIb).

Other agents. Therapeutic agents with limited therapeuticvalue that are not routinely recommended are outlined inTable V.

Management of thrombocytopeniaBleeding is a common and potentially serious complicationof MDS. Both the degrees of thrombocytopenia and plateletfunctional abnormalities may contribute to this. The role ofplatelet transfusions in MDS patients should be based on the

Guideline 191


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192 Guideline


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Guideline 193


Royal College of Physicians of Edinburgh Consensus Con-ference Statement (Ancliff & Machin, 1998). Antifibrinolyticagents (grade C, level IV) and Danazol (grade B, level IIb)are occasionally useful but cannot be routinely recom-mended.

Management of infectionProphylactic. There are no published data to support the

routine use of antibacterial or antifungal prophylaxis inneutropenic MDS patients. Consideration may be given tothe use of prophylactic low-dose G-CSF therapy in severely

Table V. Therapeutic agents of limited value for the treatment of anaemia in MDS.

Agent

Level of

evidence

Grade of

evidence Recommendation Comments

Single agent

13 cis retinoic acid (13 CRA) Ib A Not recommended Although an early study suggested improved

survival with 13 CRA compared with

supportive care (Clark et al, 1987), a subsequent

randomized placebo-controlled trial in 68 patients

had only three minor responders (2 placebo vs 1 13

CRA) (Koeffler et al, 1988). Several non-randomized

studies have also showed low (< 20%) short-term

response rates (Picozzi et al, 1986; Kerndrup et al,

1987; Bourantas et al, 1995).

All-trans retinoic acid IIb B Not recommended Small non-randomized studies report low frequency

and only transient response (Visani et al, 1995).

9-cis retinoic acid IIb B Not recommended A small multicentre study showed 17% responses

(5 of 30; 1 complete and 4 minor) with poor

tolerability at the doses used (Hofmann et al 2000).

Vitamin D3 IIb B Not recommended Small cohort studies only (all < 20 patients)

with variable doses and responses. Occasional

patients achieved transfusion independence

(< 20%) (Mellibovsky et al, 1998). Higher doses

limited by hypercalcaemia (Koeffler et al, 1985).

Interferons IIb B Not recommended Small cohort studies only (mostly < 20 patients)

of either a-interferon (Elias et al, 1987; Galvani et al,

1988; Gisslinger et al, 1990; Aul et al, 1991; Nand

et al, 1992; Petti et al, 1996) or c interferon

(Stone et al, 1993). Low response rates

and generally high toxicity.

Amifostine IIb B CRP Haematopoietic stimulatory activity demonstrated

in cohort studies of intermittent dosing (List et al,

1997; Grossi et al 2000) but not continuous

schedule (Bowen et al, 1998). Responses are

transient and high side-effect profile ⁄ cost.

Pyridoxine III C Not recommended No trials reported; anecdotal responses in patients

with RARS but these most likely represent

late-onset congenital sideroblastic anaemia

rather than MDS (Cotter et al, 1995).

Combination therapy

Retinoids + low-dose

Cytosine arabinoside

IIb B Not recommended Many small cohort studies with variable response

rates but none comparing combinations with single

agent in randomized trials; comprehensively

reviewed in Santini & Ferrini (1998).

Pentoxyfilline ⁄Ciprofloxacin ±

Dexamethasone ± Amifostine

IIb B CRP Small cohort study showed no response

to Pentoxyfilline + Ciprofloxacin combination in

high-risk patients (Nemunaitis et al, 1995). Two

small cohort studies (12 and 29 patients) treated

with Pentoxyfilline + Ciprofloxacin + Dexamethasone

(PCD) (Novitzky et al, 2000) and PCD + Amifostine

(Raza et al, 2000) respectively. Clinically meaningful

erythroid responses in up to 30% patients.

Unclear which drugs were active.

CRP, to be used in defined clinical research protocols only.

194 Guideline


neutropenic patients to maintain the neutrophil count> 1 · 109 ⁄ l (grade B, level IIb) (Negrin et al, 1996).

Therapeutic. Neutropenic sepsis in MDS patients should betreated with intravenous antibiotics as for other patientswith neutropenia (e.g. post chemotherapy).

Non-intensive chemotherapyThere is insufficient evidence to recommend routine use oflow-dose chemotherapy. Many relatively small studies arereported but none have demonstrated clear benefit in termsof survival or improved quality of life (Table VI). Of theseagents, 5-aza-2-deoxycytidine (and the parent compound5-azacytidine) shows perhaps the greatest promise.

Chronic myelomonocytic leukaemiaCMML often has a myeloproliferative component, andcytoreductive chemotherapy is frequently indicated.Hydroxyurea is considered the standard treatment forCMML, in preference to oral etoposide (evidence grade A,level Ib) (Wattel et al, 1996).

Intensive chemotherapy ⁄ stem cell transplantationFor the small number of eligible patients, allogeneic stem celltransplantation results in long-term event-free survival (EFS)in 32–54%. It is recommended that clinicians discuss allpatients eligible for stem cell transplantation with their localtransplant unit. Factors associated with improved outcomefollowing transplantation include younger age, shorterdisease duration, human leucocyte antigen-compatibility, primary MDS, < 10% blasts, good-risk cytogenetics(Anderson et al, 1993, 1996; Sutton et al, 1996; Deeg et al,2000). IPSS score is also a strong predictor of outcome, with5-year EFS of 60%, 36% and 28% in Low ⁄ INT-1, INT-2 andhigh-risk categories (Appelbaum & Anderson, 1998). Trans-plant-related mortality (TRM) for ablative allogeneic trans-plant is 40% in most studies, although the probable evolutiontowards non-ablative transplant approaches will reduce this.

Early indications are that autologous SCT may also prolongsurvival though stem cell mobilization is problematic inmany cases (de Witte et al, 1997). A small group of patientswho may benefit from intensive chemotherapy alone can alsobe identified.

IPSS Low. Neither intensive chemotherapy nor stem celltransplantation can currently be recommended for thisgroup whose median survival without treatment is4Æ8 (> 60 years))11Æ8 years (< 60 years) (Greenberg et al,1997).

IPSS Int-1. All patients < 65 years should be assessed forfitness ⁄ eligibility for allogeneic SCT as soon as possible afterdiagnosis, as SCT outcome is improved if performed early(Anderson et al, 1996). If eligible and a sibling donor isavailable, it is recommended that patients < 50 years areoffered ablative allogeneic SCT (evidence grade B, level IIb)and patients > 50 < 65 years are considered for non-ablative allogeneic SCT, within clinical trials where avail-able (evidence grade C, level IV). Patients with no siblingdonor, but with an unrelated donor should also beconsidered for ablative unrelated-donor SCT (< 40 years,evidence grade B, level III) or non-ablative unrelated-donorSCT within clinical trials (> 40 years, evidence grade C,level IV), though the TRM from these procedures remainshigh. Intensive cytoreductive chemotherapy prior to SCT isnot recommended for this group (evidence grade B, levelIIb).

Patients > 65 years or < 65 years and not suitable forSCT should be offered supportive care and ⁄ or considered forgrowth factor therapy (e.g. EPO). Recommendations for themanagement of IPSS INT-1 MDS patients £ 65 years areoutlined in Fig 2.

IPSS INT-2 ⁄HighChemotherapy plus SCT. All patients < 65 years should

again be considered as to fitness ⁄ eligibility for stem celltransplantation early after diagnosis. In this group of

Table VI. Non-intensive chemotherapeutic agents.

Agent

Level of

evidence

Grade of

evidence Recommendation Comments

Low-dose cytosine

arabinoside (LDAC)

Ib A Not recommended Two large studies of predominantly high-risk MDS patients.

Randomized study versus supportive care (141 patients)

showed no survival advantage and higher toxicity for

LDAC (Miller et al, 1992). Cohort study (n ¼ 102)

(Hellstrom Lindberg et al, 1992) demonstrated 29% �significant�and clinically meaningful responses. These and most smaller

studies showed responses usually of short duration.

5-aza-2-deoxycytidine IIb B CRP One moderate sized cohort study (n ¼ 66) of IPSS INT I ⁄ II and

High-score patients reported a 49% response rate of 31 weeks

median duration (Wijermans et al, 2000).

Melphalan IIb B CRP Two small cohort studies [n ¼ 21 (Omoto et al, 1996) and

n ¼ 14 (Denzlinger et al, 2000)] reported clinically meaningful

responses in selected patients; hypocellular RAEB ⁄ t with a

normal karyotype.

CRP, to be used in defined clinical research protocols only.

Guideline 195


high-risk patients, stem cell transplantation should only beconsidered for those responding to remission inductionchemotherapy (complete ⁄ good partial response) as theoutcome for non-responding patients is very poor (evidencegrade B, level IIb) (Sutton et al, 1996; Anderson et al, 1997;Nevill et al, 1998). For patients < 65 years, eligible for SCTand responding to chemotherapy, recommendations for SCTconsolidation are outlined in Fig 3. Large cohort studies areavailable for the assessment of ablative sibling and unrelat-ed allogeneic SCT but the role of autologous and non-

ablative SCT is yet to be clearly defined. Nevertheless, TRMis lower for both modalities and preliminary evidencesuggests that both will have a future role (de Witte et al,1997; Slavin et al, 1998).

Chemotherapy alone. Both patients > 65 years and those< 65 years who are ineligible for stem cell transplanta-tion should be considered for intensive chemotherapyalone. There have been no prospective randomized,controlled trials evaluating outcome following intensivechemotherapy compared with supportive care alone in

Fig 3. Guidelines for SCT in the management of IPSS INT-2 ⁄high MDS patients aged £ 65 years.

Fig 2. Guidelines for the management of IPSS INT-1 MDS patients aged £ 65 years.

196 Guideline


MDS. Cohort studies suggest that of all high-risk MDSpatients (‡ INT-2), those with RAEB in transformation(RAEB-t, 20–30% marrow blasts) and lacking anindependent adverse risk factor [karyotype, age, perfor-mance status, length of antecedent haematologicaldisorder (Estey et al, 1997)] respond best to intensive�AML-type� chemotherapy (evidence grade B, level IIb)(Wattel et al, 1997). Thus, intensive chemotherapy aloneis recommended for consideration in these patients. Nochemotherapy combination is clearly superior, but mostcommonly used regimens contain cytosine arabinosidewith any of an anthracycline, etoposide and ⁄ or fludara-bine. The median number of chemotherapy courses inmost studies is two (one induction and one consolidation)and patients rarely tolerate more than this. In all otherhigh-risk MDS patients (namely those for whom intensivechemotherapy alone is not recommended), intensiveremission-induction chemotherapy (two courses) shouldbe offered only if stem cell transplantation is proposed asconsolidation (Fig 3).

Supportive care ⁄ investigational therapy. If patients do notfall into any category for which chemotherapy ± SCT isrecommended they should be offered supportive care orinvestigational therapies within clinical research protocols.

USEFUL WEB SITES

http://www.aamds.orghttp://www.mds-foundation.org/http://www.leukaemia-research.org.uk

USEFUL TELEPHONE NUMBERS

Leukaemia Research Fund +44 (0)207 12421488.

CONFLICTS OF INTEREST

Meeting expenses were covered by support from Janssen-Cilag. Dr Stephen Kelsey became an employee of Phar-macia Upjohn during the guideline preparation process.Dr Culligan and Professor Mufti are members of theROCHE Steering Group for the treatment of cancer-relatedanaemia.

DISCLAIMER

Whilst the advice and information contained in thisguideline are believed to be true and accurate at the timeof going to press, neither the authors nor the publisher canaccept any legal responsibility or liability for any errors oromissions that may be made.

NOTE ADDED IN PROOF

A randomized study of azacytidine versus supportive carehas demonstrated a probable survival advantage andreduced AML transformation for MDS patients randomizedto receive azacytidine (Silverman et al, Journal of ClinicalOncology, 2002, 20, 2429–2440).

David Bowen1

Dominic Culligan2

Simon Jowitt3

Stephen Kelsey4

*

Ghulam Mufti5

David Oscier6

Jane Parker5

of the UK MDS

Guidelines Group

1Molecular and Cellular Pathology,Ninewells Hospital, Dundee,2Aberdeen Royal Infirmary,Aberdeen, 3Stepping HillHospital, Stockport,4Department of Oncology, St.Bartholomews and Royal LondonMDS, London, 5Department ofHaematological Medicine, King’sCollege of Medicine and Dentistry,London, and 6Royal BournemouthHospital, Bournemouth, UK*Present address: Genetech, Inc.,South San Francisco, CA, USA

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Keywords: myelodysplastic syndrome, guidelines, manage-ment, diagnosis.

200 Guideline


Documents

Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes