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




Guideline

GUIDELINES FOR THE DIAGNOSIS AND THERAPY OF ADULT MYELODYSPLASTIC SYNDROMES

The myelodysplastic syndromes (MDS) represent a hetero-            MDS is shown in Table II. Practical issues regarding the
geneous group of haematopoietic disorders affecting pre-           diagnosis of MDS include the following:
dominantly elderly individuals (median age 69 years). The          1. Should every patient have a bone marrow aspirate? A
overall disease incidence is about 4 per 100 000 population           bone marrow aspirate is usually necessary to make a
but this rises to > 30 per 100 000 in the over 70 year age            confident diagnosis and to provide important prognostic
group. The pathological processes underlying the haemato-             information. This may not, however, be necessary in
logical abnormalities seen in MDS are:                                elderly patients in whom a definitive diagnosis of MDS
1. augmented apoptosis, leading to ineffective haematopoi-            would not alter management or whose poor general
    esis and peripheral cytopenias;                                   health precludes active treatment.
2. transformation to acute myeloid leukaemia (AML).                2. Should every patient have a bone marrow trephine?
   The precise relationship between these pathological                Bone marrow histology complements the morphological
processes remains uncertain but has important implications            information obtained from a marrow aspirate and hence
for the design of new therapeutic strategies targeting one or         a trephine biopsy should be performed in all cases of
the other or indeed both.                                             suspected MDS in whom bone marrow examination is
                                                                      indicated. Diagnostic certainty can be improved by
                                                                      features such as the presence of megakaryocyte dyspla-
METHODS
                                                                      sia, while disordered marrow architecture such as
The guideline group was selected to include UK-based medical          central clustering of immature myeloid cells (abnormal
experts in the clinical management of MDS and to include a            localization of immature precursors or ALIPs) is an
representative from a District General Hospital. The drafting         adverse prognostic marker (Tricot et al, 1984). The
group met on six occasions. Each group member was                     assessment of cellularity and fibrosis define morphologi-
allocated responsibility for preparation of a selected compo-         cal variants, with the identification of hypocellular MDS
nent of the first draft. Medline ⁄ Pubmed was systematically           of particular therapeutic importance (see below) (Mijovic
searched from 1982. The Cochrane database was searched                & Mufti, 1998).
but contained no references to MDS. Meeting abstracts were         3. Should all patients have cytogenetic analysis? A chro-
not included in the systematic search strategy. The Chairman          mosome abnormality confirms the presence of a clonal
synthesized the draft components, which were revised by               disorder aiding the distinction between MDS and reactive
consensus through meetings 3–6. No recommendations are                causes of dysplasia, and in addition has major prognostic
included for which full consensus was not achieved. The draft         value. Cytogenetic analysis should therefore be per-
guideline was reviewed by the Sounding Board and by the               formed for all patients in whom a bone marrow
Committee of the British Committee for Standards in Hae-              examination is indicated.
matology, and comments incorporated where appropriate.             4. What are the minimal morphological diagnostic criteria
Following further helpful peer-review by the British Journal of       for MDS? Minimal diagnostic criteria are not clearly
Haematology, a final revision is now presented. Criteria used          defined in MDS. Difficulties arise because a variety of
to quote Levels and Grades of Evidence are outlined in Table I.       reactive disorders are associated with dysplastic mor-
A full guideline revision is planned for May 2005.                    phology and mild dysplastic features are frequently seen
                                                                      in the marrow of healthy people with normal blood
                                                                      counts (Bain, 1996; Ramos et al, 1999).
DIAGNOSIS
                                                                      The following are recommended to increase the reliability
The diagnosis and classification of MDS remain dependent            of diagnosing MDS.
on the morphological examination of blood and bone                 a) At least 200 marrow cells and 20 megakaryocytes
marrow cells. Diagnostic criteria should ideally distinguish          should be evaluated where possible.
MDS from reactive conditions causing dysplastic haemato-           b) Dysplastic features should be present in > 10% of
poiesis and from other clonal myeloid disorders. The                  marrow cells (Kouides & Bennett, 1996).
minimum clinical assessment and laboratory investigation           c) Particular attention should be given to the presence of
required for the definitive diagnosis of cases of suspected            pseudo-pelger neutrophils, ring sideroblasts, micro-
                                                                      megakaryocytes and increased blasts as these abnormal-
Correspondence: Dr David Bowen, Molecular and Cellular Pathol-        ities correlate most strongly with the presence of clonal
ogy, Ninewells Hospital, Dundee, DD1 9SY, UK. E-mail: d.t.bowen@      markers in MDS and show least interobserver variation
dundee.ac.uk                                                          (Kuriyama et al, 1986; Ramos et al, 1999).

Ó 2003 Blackwell Publishing Ltd                                                                                          187
188          Guideline
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.                                          diagnosis remains uncertain, it is recommended that the patient
                                                                                be reviewed regularly in the haematology clinic with repeat blood
History                                                                         count and morphological assessment at appropriate intervals.
  Prior exposure to chemotherapy ⁄ radiation                                    5. Overlap syndromes. At least three overlap syndromes are
  Family history of MDS ⁄ AML                                                       recognized namely: fibrotic MDS (Mijovic & Mufti, 1998),
  Recurrent infections or bleeding ⁄ bruising                                       MDS with thrombocytosis (Harris et al, 1999) and
Examination                                                                         hypoplastic MDS (Tuzuner et al, 1994, 1995). Presently,
  Pallor ⁄ infection ⁄ bruising
                                                                                    only the latter requires a distinctive therapeutic
  Splenomegaly
                                                                                    approach and as such is important to distinguish from
Full blood count
  Macrocytosis, cytopenia(s), neutrophilia, monocytosis, thrombo-                   aplastic anaemia.
  cytosis
Blood film                                                                       Hypocellular MDS versus aplastic anaemia
Assay of serum ferritin, vitamin B12 and folate levels                          The diagnosis of hypocellular MDS is of importance, as
Bone marrow aspirate                                                            preliminary data suggest that the response to immunosup-
Bone marrow trephine biopsy                                                     pressive therapy is higher than in cases of MDS with normo-
Bone marrow cytogenetic analysis                                                or hypercellular marrows. A trephine may be considered
Exclusion of reactive causes of dysplasia                                       hypocellular if cellularity is < 30% in individuals younger
  Megaloblastic anaemia
                                                                                than 60 years or < 20% in those over 60 years of age
  Human immunodeficiency virus infection
                                                                                (Tuzuner et al, 1994, 1995). The diagnosis of myelodysplasia
  Alcoholism
  Recent cytotoxic therapy                                                      requires the presence of dysplastic features in megakaryo-
  Severe intercurrent illness                                                   cytes and ⁄ or myeloid cells or an excess of blasts. Erythroid
                                                                                dysplasia is found in aplastic anaemia and cannot be used
                                                                                alone to distinguish MDS from AA. The presence of an
                                                                                abnormal karyotype strongly favours the diagnosis of MDS
d) The assessment of neutrophil granularity is critically                       but cases of aplastic anaemia with an abnormal karyotype
    dependent on optimal staining and it is unwise to base a                    without morphological features of MDS and with a low risk of
    diagnosis of MDS solely on the presence of neutrophil                       transformation to MDS or AML have been described.
    hypogranularity in the absence of other dysplastic
    features.
                                                                                CLASSIFICATION OF MDS
   It is recognized that the definitive diagnosis of early refractory
anaemia may be difficult, for example in patients with a single                  The World Health Organization (WHO) recently published
isolated cytopenia or isolated macrocytosis. If the morphological               proposals for a new classification of MDS to supersede the


                                                                  Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
                                                                                                                    Guideline   189
French–American–British (FAB) classification (Bennett et al,              derived from a pool of 816 MDS patients who had been
1982). The new classification is based on a combination of                included in the cohorts used to derive previous scoring
morphology, karyotype and clinical features (Harris et al,               systems (Table III). A cautionary note is that the patient
1999), and potential problems with the adoption of the new               cohort analysed by the IPSS group were largely untreated
classification have recently been summarized (Greenberg                   and may therefore include the MDS patients with poorest
et al, 2000). The final classification has now been published              performance status and therefore worst outlook. The IPSS
(Jaffe et al, 2001) and is in the process of independent                 has also excluded chronic myelomonocytic leukaemia
validation (Germing et al, 2000a; Nosslinger et al, 2001).               (CMML) patients with a white blood cell count
Given the limited experience with the use of this new                    (WBC) > 12 · 109 ⁄ l, considering this group as myelopro-
classification to date, this guideline will use the more familiar         liferative rather than myelodysplastic. The IPSS score is
FAB terminology (Bennett et al, 1982).                                   computed from three parameters, namely bone marrow
                                                                         blast percentage, bone marrow cytogenetics and number of
                                                                         lineages with cytopenia, in decreasing order of prognostic
PROGNOSTIC SCORING SYSTEMS
                                                                         power. While this guideline advocates bone marrow cyto-
All patients diagnosed with MDS have a reduced life                      genetic analysis for all MDS patients in whom a bone
expectancy compared with age- and sex-matched normal                     marrow examination is deemed appropriate, we accept that
controls, regardless of disease subtype. This difference is              this is not always technically successful. In this rare
particularly marked in younger patients ( £ 60 years) and                situation, an alternative scoring system most familiar to
those with Ôhigh-riskÕ disease. (Morel et al, 1996). While the           the clinician will be required, such as the Sanz (Sanz et al,
FAB ⁄ WHO classification systems are themselves of signifi-                1989) or Bournemouth (Mufti et al, 1985) scores. The
cant prognostic value, scoring systems employing objective               methodology used to derive the Sanz score is more rigorous
parameters allow improved reproducibility for clinical                   and provides greater prognostic discrimination than the
decision-making but also for clinical trials and biological              Bournemouth score, at least in patients with > 5% blasts.
research in MDS patients. A series of different prognostic                   While the use of prognostic scoring systems is advocated,
scoring systems have been developed since the original                   it must be recognized that even within each prognostic
Bournemouth score (Mufti et al, 1985). The latest of these               group the emergence of distinct clinical entities, which have
is the International Prognostic Scoring System (IPSS)                    different prognoses, is inevitable. Examples of these include
(Greenberg et al, 1997), which has improved prognostic                   pure sideroblastic anaemia (Germing et al, 2000b) and
power compared with previous scoring systems, namely the                 perhaps the Ô5q– syndromeÕ, both of which are associated
Sanz (Sanz et al, 1989) and Lille (Morel et al, 1993) scores.            with an excellent prognosis and a low rate of transforma-
The IPSS is a multivariate analysis of patient characteristics           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             > 60 years          £ 70 years         > 70 years
                                            (n ¼ 205)              (n ¼ 611)           (n ¼ 445)          (n ¼ 371)

                 Low (n ¼ 267)              11Æ8                   4Æ8                 9                  3Æ9
                 INT-1 (n ¼ 314)             5Æ2                   2Æ7                 4Æ4                2Æ4
                 INT-2 (n ¼ 176)             1Æ8                   1Æ1                 1Æ3                1Æ2
                 High (n ¼ 59)               0Æ3                   0Æ5                 0Æ4                0Æ4



Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
190         Guideline
                                                                     effectiveness of supportive care in patients with myelodyspl-
MANAGEMENT OF MYELODYSPLASTIC
                                                                     asia is absent and is unlikely to ever be obtainable. For
SYNDROMES
                                                                     patients with good prognosis MDS, it is often feasible to
It is recommended that, where possible, management                   undertake a period of observation without needing to
decisions be based upon the patient’s IPSS score. It is              introduce specific therapy. Where possible, this Ôwait and
important that the IPSS score is calculated during a stable          watchÕ approach to management may also be useful for
clinical state and not, for example, during a florid infective        patients with more advanced MDS, allowing one to appraise
initial presentation. Management decisions should be taken           the stability of the disease process and to assess the need to
with the informed involvement of the patient and, to aid             introduce treatment.
this, information booklets are available from the Leukaemia
Research Fund and the Myelodysplastic Syndromes Foun-                Management of anaemia
dation. The guideline will critically review individual thera-       At presentation, up to 80% of cases of MDS will have a
peutic modalities designed to improve the clinical problems          haemoglobin concentration < 10 g ⁄ dl (Sanz et al, 1989).
specific to an individual patient with MDS, and will                  Anaemia in MDS is usually due to ineffective erythropoiesis
conclude with recommendations for management strategies              but other factors that may accentuate anaemia, e.g.
driven by the patient’s IPSS score and the overall clinical          nutritional deficiencies, haemorrhage, haemolysis and
picture. It is, however, important to stress that most               infection, should be sought and treated as appropriate.
recommendations are made on the basis of a very limited              Chronic anaemia is seldom life threatening but can lead to
evidence base for the efficacy of interventional and non-             significant morbidity and is therefore important in relation
interventional therapy in MDS. Most papers reporting                 to quality of life issues. Figure 1 outlines a flow chart for the
interventional therapy describe relatively small cohorts of          management of the anaemic MDS patient.
patients and only one (small) placebo-controlled trial is               Red cell transfusion and iron chelation therapy. The use of
available. Criteria for defining therapeutic response are also        red cell transfusion should be considered in any patient with
highly variable between studies. The recent publication of           symptoms of anaemia. It is not possible to ascribe a single
standardized response criteria for therapeutic studies in            haemoglobin concentration as being the optimal level below
MDS patients (Cheson et al, 2000) may facilitate the                 which red cell support should be dispensed and each
interpretation of how clinically meaningful new therapeutic          individual case needs to be considered separately (Murphy
interventions in MDS really are.                                     et al, 2001). Studies in cancer patients have demonstrated a
                                                                     positive correlation between increases in the haemoglobin
Supportive care: principles                                          level (with recombinant Erythropoietin therapy) and
Supportive care remains the most important aspect of                 improvements in quality of life (QOL) (Glaspy et al, 1997;
management for patients with good prognosis MDS and                  Demetri et al, 1998).
those with poor prognosis disease whose age or performance              Recommendations for iron chelation treatment in mye-
status precludes them from receiving more intensive forms            lodysplasia are based on limited data (evidence grade B,
of therapy. The aim is to reduce morbidity and mortality             level III). Iron chelation should be considered once a patient
while at the same time providing an acceptable quality of            has received 5 g iron (approximately 25 units of red cells)
life. However, grade A and grade B evidence for the                  but only in patients for whom long-term transfusion




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

                                                        Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
                                                                                                            Guideline        191
therapy is likely, such as those with pure sideroblastic              from 75 lg, to 150 lg to 300 lg (multiple sampling from
anaemia or the Ô5q– syndromeÕ. Desferrioxamine                        single vials kept at 4°C) to maintain the WBC between 6
20–40 mg ⁄ kg should be administered by 12 h subcuta-                 and 10 · 109 ⁄ l. In responding patients, once the maxi-
neous infusion 5–7 d per week. Audiometry and ophthal-                mum response has been reached, the G-CSF can be
mology review are essential prior to commencement of                  reduced to thrice weekly and the EPO to 5 d then 4 d to
desferrioxamine. The target ferritin concentration should be          3 d per week at 4 weekly intervals to the lowest dose that
< 1000 lg ⁄ l; if the ferritin concentration falls below              retains response.
< 2000 lg ⁄ l, the dose of desferrioxamine should be reduced             For patients with RARS, symptomatic anaemia, basal
and should not exceed 25 mg ⁄ kg. Vitamin C 100–200 mg                EPO levels of < 500 U ⁄ l and a transfusion requirement of
daily should be commenced after 1 month of desferriox-                less than 2 units per month, it is recommended that
amine therapy. Vitamin C should be taken when the                     combined therapy with EPO and G-CSF is used from the
infusion is set up. Repeat audiometry and ophthalmology               outset (Hellstrom Lindberg et al, 1997). Dosing recommen-
review should be performed at least annually. The use of              dations are as for RA ⁄ RAEB with consideration given to
twice daily subcutaneous bolus injections of desferrioxa-             dose escalation of EPO at 6 weeks in non-responders for a
mine (Franchini et al, 2000) may be considered where                  further 6 weeks.
infusions are not tolerated, but the common practice of                  While there are no published data demonstrating that
adding a single dose of desferrioxamine at each transfusion           growth factor therapy improves QOL, extrapolation from
episode has no basis and should be discouraged. At present,           cancer patients treated with EPO suggests that this is likely
deferiprone (L1) cannot be recommended for routine use in             to be the case and that maintenance of a stable augmented
this group of patients, given the lack of published data in           haemoglobin concentration may be preferable to the cyc-
MDS patients and continuing concerns about both efficacy               lical fluctuations of red cell transfusion programmes (Bowen
and safety (Pippard & Weatherall, 2000).                              & Hellstrom-Lindberg, 2001). It should also be noted that
   Erythropoietin (EPO) + ⁄ – granulocyte colony-stimulating          there are a lack of survival data and of quality pharmaco-
factor (G-CSF). Many studies have clearly demonstrated                economic data to support the use of haematopoietic growth
that EPO ± G-CSF can increase haemoglobin concentra-                  factor therapy. We would, therefore, encourage continuing
tion and reduce ⁄ eliminate red cell transfusion in selected          randomized-controlled trials of EPO ± G-CSF, which address
MDS patients, and a summary outline of these is provided              the issues of QOL, survival advantage and pharmaco-
in Tables IVA and B. These studies were small cohort                  economics.
studies (< 120 patients in each) and only one (small)                    Immunosuppression. Two groups have demonstrated the
placebo-controlled randomized study (of EPO therapy                   efficacy of horse anti-lymphocyte globulin (ALG) in raising
alone) has been reported (Italian Cooperative Study                   the blood counts in a proportion of patients with MDS,
Group, 1998). Given the small size of this placebo-                   although each cohort reported is small, namely n ¼ 25
controlled trial of EPO therapy alone (87 patients), the              (Molldrem et al, 1997) [updated in abstract form to n ¼ 60
grade of recommendation for EPO therapy alone should                  (Barrett et al, 1998)] and n ¼ 12 (Killick et al, 1999)
be considered as grade A ⁄ B (level Ib ⁄ IIa). The evidence           patients respectively. ALG seems to be more effective in
for efficacy of the combination of EPO + G-CSF therapy is              hypoplastic MDS and in patients with a paroxysmal
grade B (level IIa ⁄ IIb).                                            nocturnal haemoglobinuria (PNH) clone (Dunn et al,
   These studies suggest that patients with refractory                1999), but also induces significant improvements in
anaemia with ringed sideroblasts (RARS) are more likely               normo- and hypercellular patients with low-risk MDS
to respond to the combination of EPO + G-CSF (Hellstrom               (IPSS £ INT-1). Preliminary data suggest that responses,
Lindberg et al, 1997, 1998). Patients with refractory                 when achieved, are durable and prolonged (Barrett et al,
anaemia (RA) or RA with excess blasts (RAEB) may                      1998). Most clinically meaningful responses are in the
respond well to EPO alone, though a proportion will benefit            erythroid lineage but bi- and trilineage responses are seen.
from the addition of G-CSF (Hellstrom Lindberg, 1995,                 Similar responses have been observed with cyclosporin A
Hellstrom-Lindberg et al, 1998; Italian Cooperative Study                  ´
                                                                      (Jonasova et al, 1998), with higher response rates also in
Group, 1998; Mantovani et al, 2000). Overall there is                 hypocellular MDS. Anecdotal reports of corticosteroid-
sufficient evidence for the efficacy of EPO ± G-CSF therapy             responsive MDS exist but this therapy cannot at present
in appropriately selected patients. It is recommended that            be recommended. The data support a recommendation for a
those patients with RA and RAEB [not eligible for                     trial of immunosuppressive therapy with ALG at least for
chemotherapy ⁄ stem cell transplantation (SCT): see later]            patients with hypoplastic MDS (evidence grade B, level IIb).
who are symptomatic of anaemia, with no ⁄ low transfusion                Other agents. Therapeutic agents with limited therapeutic
requirement (< 2 units ⁄ month) and a basal EPO level of              value that are not routinely recommended are outlined in
less than 200 U ⁄ l (measured at the haemoglobin nadir in             Table V.
transfusion-dependent patients) be considered for a trial of
EPO alone at a dose of 10 000 units daily for 6 weeks                 Management of thrombocytopenia
(Hellstrom Lindberg, 1995). For non-responders, consid-               Bleeding is a common and potentially serious complication
eration should be given to either the addition of daily               of MDS. Both the degrees of thrombocytopenia and platelet
G-CSF, doubling the dose of EPO, or both for a further                functional abnormalities may contribute to this. The role of
6 weeks. The dose of G-CSF should be escalated weekly                 platelet transfusions in MDS patients should be based on the

Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
                                                                                                                                                                                                                                                                                 192



                                                                               Table IV.
                                                                               (A) Trials of erythropoietin alone in MDS.


                                                                                                                                       Number of patients                          Results                         Comments

                                                                               Meta analyses
                                                                                                                                                                                                                                                                                 Guideline




                                                                               Hellstrom Lindberg (1995)                               205 from 17 trials                          16% overall response            Response parameters standardized for all included studies.
                                                                                                                                                                                                                   Response rates compared with Mann–Whitney U test
                                                                                                                                                                                                                   (serum EPO concentration between subgroups) or
                                                                                                                                                                                                                   Fisher’s exact test (categories).
                                                                                                                                                                                                                   Higher response rates if: serum EPO < 200 U ⁄ l, non-RARS
                                                                                                                                                                                                                   FAB type, non-transfusion dependent
                                                                               Rodriguez et al (1994) (abstract only; Spanish)         115 from 10 studies                         23Æ5% response                  Higher response for RAEB. No relationship to EPO level or
                                                                                                                                                                                                                   transfusion requirement.
                                                                               Post-meta analyses (studies with > 10 patients)
                                                                               Italian Cooperative Study Group (1998)                  87                                          14 ⁄ 38 vs 4 ⁄ 37 responders;   Randomized double-blind placebo-controlled study of EPO
                                                                                                                                                                                   (P ¼ 0Æ007)                     in low-risk MDS. Response assessed at 8 weeks.
                                                                                                                                                                                   in favour of EPO                FAB type ¼ RA, basal EPO level <200 U ⁄ l, non-transfused,
                                                                                                                                                                                                                   all predicted for response
                                                                               Stasi et al (1997a)                                     43                                          16Æ7% (CR + PR)                 6 patients responded to dose escalation from
                                                                                                                                                                                                                   150 l ⁄ kg 3 · per week to 300 l ⁄ kg 3 · per week.
                                                                                                                                                                                                                   Erythroid hyperplasia and circulating erythroid
                                                                                                                                                                                                                   burst-forming units best predictors of response
                                                                               Stasi et al (1997b)                                     25 (note ? same patients as above)          4 CR, 5 PR                      Responders had lower serum concentration
                                                                                                                                                                                                                   of tumour necrosis factor-a
                                                                               Di Raimondo et al (1996)                                12 with RA only, normal WBC and             7 (58Æ3%) CR, 2 PR              Highly selected, mild cases of RA
                                                                                                                                       platelets and short duration of disease
                                                                               Rose et al (1995)                                       116                                         28%                             Authors all from R.W. Johnson Pharmaceutical
                                                                                                                                                                                                                   Company. RA and RARS responded.
                                                                                                                                                                                                                   Serum EPO < 100 U ⁄ l predicted for response (54% of RA
                                                                                                                                                                                                                   with low EPO responded)


                                                                                 CR, complete response PR, partial response.
                                                                               (B) Trials of erythropoietin plus G-CSF in MDS.


                                                                                                                                 Number of Patients                      Results                                                 Comments

                                                                               Mantovani et al (2000)                        33                                          61% erythroid response at 12 weeks                       12 ⁄ 17 responders at 12 weeks and 14 ⁄ 20
                                                                                                                                                                         80% erythroid response at 36 weeks                       responders at 20 weeks had Ôgood
                                                                                                                                                                                                                                  erythroid responseÕ namely independent of
                                                                                                                                                                                                                                  red cell transfusion ⁄ sustained increase in
                                                                                                                                                                                                                                  Hb > 2 g ⁄ dl.
                                                                               Remacha et al (1999)                          32                                          Erythroid response in 50%                                13 responders maintained response on




Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
                                                                                                                                                                         (12 patients CR and 4 PR).                               treatment for 2 years.
                                                                               Hellstrom Lindberg et al (1997)   Development of predictive model   36% response.                                       In multivariate analysis, serum EPO levels and
                                                                                                                 from Hellstrom-Lindberg et al     Median duration of response ¼ 11–24 months          initial transfusion need were significant predictors
                                                                                                                 (1998) and Negrin et al (1996)                                                        of response. Predictive score for response developed
                                                                                                                                                                                                       by log-likelihood and logistic regression analyses.
                                                                                                                                                                                                       Group 1 ¼ 74% probability of response, Group
                                                                                                                                                                                                       2 ¼ 23% probability of response, Group 3 ¼ 7%
                                                                                                                                                                                                       probability of response
                                                                               Hellstrom-Lindberg et al (1998)   50 in randomized study            Overall response rate was 38%.                      In randomized study:
                                                                                                                                                   Response rates in the two arms was identical.       Arm A ¼ G-CSF for 4 weeks followed
                                                                                                                                                   Median survival ¼ 26 months, leukaemic              by combination for 10 weeks.
                                                                                                                                                   transformation 28%. Median duration                 Arm B ¼ EPO for 8 weeks followed by the
                                                                                                                                                   of response in 20 long-term maintenance             combination for 10 weeks. Response rates for RA,
                                                                                                                                                   patients ¼ 24 months.                               RARS, RAEB were 20%, 46%, 37% respectively.
                                                                               Negrin et al (1996)               55                                53 (96%) had a neutrophil response.                 Response predicted by low serum EPO level,
                                                                                                                                                   44 patients evaluated for an erythroid response     higher absolute basal
                                                                                                                                                   and 21(48%) had a response.                         reticulocyte counts and normal cytogenetics
                                                                                                                                                   81% of these responders maintained their response   at study entry
                                                                                                                                                   during an 8-week maintenance phase.
                                                                               Imamura et al (1994)              10                                No responses in erythroid or platelets following    1 delayed erythroid response following cessation
                                                                                                                                                   10 weeks of treatment.                              of treatment.
                                                                                                                                                   80% had a neutrophil response                       Considerably higher doses of G-CSF
                                                                                                                                                                                                       (intravenous) than in other studies.
                                                                               Hellstrom Lindberg et al (1993)   22                                8 (38%) showed a significant response in Hb          Less advanced pancytopenia, lower levels of serum
                                                                                                                                                                                                       EPO and ring sideroblasts predicted for response.
                                                                               Negrin et al (1993)               24                                10 (42%) had an erythroid response                  Low pretreatment EPO levels only predictor for response.




Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
                                                                                                                                                                                                                                                                  Guideline
                                                                                                                                                                                                                                                                  193
194           Guideline
Table V. Therapeutic agents of limited value for the treatment of anaemia in MDS.


                                   Level of     Grade of
Agent                              evidence     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                IIb          B               Not recommended     Many small cohort studies with variable response
Retinoids + low-dose                                                                rates but none comparing combinations with single
Cytosine arabinoside                                                                agent in randomized trials; comprehensively
                                                                                    reviewed in Santini & Ferrini (1998).
Pentoxyfilline ⁄ Ciprofloxacin ±     IIb          B               CRP                 Small cohort study showed no response
Dexamethasone ± Amifostine                                                          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.




Royal College of Physicians of Edinburgh Consensus Con-                 Management of infection
ference Statement (Ancliff & Machin, 1998). Antifibrinolytic               Prophylactic. There are no published data to support the
agents (grade C, level IV) and Danazol (grade B, level IIb)             routine use of antibacterial or antifungal prophylaxis in
are occasionally useful but cannot be routinely recom-                  neutropenic MDS patients. Consideration may be given to
mended.                                                                 the use of prophylactic low-dose G-CSF therapy in severely

                                                            Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
                                                                                                               Guideline          195
neutropenic patients to maintain the neutrophil count                  Early indications are that autologous SCT may also prolong
> 1 · 109 ⁄ l (grade B, level IIb) (Negrin et al, 1996).               survival though stem cell mobilization is problematic in
   Therapeutic. Neutropenic sepsis in MDS patients should be           many cases (de Witte et al, 1997). A small group of patients
treated with intravenous antibiotics as for other patients             who may benefit from intensive chemotherapy alone can also
with neutropenia (e.g. post chemotherapy).                             be identified.
                                                                          IPSS Low. Neither intensive chemotherapy nor stem cell
Non-intensive chemotherapy                                             transplantation can currently be recommended for this
There is insufficient evidence to recommend routine use of              group whose median survival without treatment is
low-dose chemotherapy. Many relatively small studies are               4Æ8 (> 60 years))11Æ8 years (< 60 years) (Greenberg et al,
reported but none have demonstrated clear benefit in terms              1997).
of survival or improved quality of life (Table VI). Of these              IPSS Int-1. All patients < 65 years should be assessed for
agents, 5-aza-2-deoxycytidine (and the parent compound                 fitness ⁄ eligibility for allogeneic SCT as soon as possible after
5-azacytidine) shows perhaps the greatest promise.                     diagnosis, as SCT outcome is improved if performed early
                                                                       (Anderson et al, 1996). If eligible and a sibling donor is
Chronic myelomonocytic leukaemia                                       available, it is recommended that patients < 50 years are
CMML often has a myeloproliferative component, and                     offered ablative allogeneic SCT (evidence grade B, level IIb)
cytoreductive chemotherapy is frequently indicated.                    and patients > 50 < 65 years are considered for non-
Hydroxyurea is considered the standard treatment for                   ablative allogeneic SCT, within clinical trials where avail-
CMML, in preference to oral etoposide (evidence grade A,               able (evidence grade C, level IV). Patients with no sibling
level Ib) (Wattel et al, 1996).                                        donor, but with an unrelated donor should also be
                                                                       considered for ablative unrelated-donor SCT (< 40 years,
Intensive chemotherapy ⁄ stem cell transplantation                     evidence grade B, level III) or non-ablative unrelated-donor
For the small number of eligible patients, allogeneic stem cell        SCT within clinical trials (> 40 years, evidence grade C,
transplantation results in long-term event-free survival (EFS)         level IV), though the TRM from these procedures remains
in 32–54%. It is recommended that clinicians discuss all               high. Intensive cytoreductive chemotherapy prior to SCT is
patients eligible for stem cell transplantation with their local       not recommended for this group (evidence grade B, level
transplant unit. Factors associated with improved outcome              IIb).
following transplantation include younger age, shorter                    Patients > 65 years or < 65 years and not suitable for
disease      duration,    human      leucocyte     antigen-com         SCT should be offered supportive care and ⁄ or considered for
patibility, primary MDS, < 10% blasts, good-risk cytogenetics          growth factor therapy (e.g. EPO). Recommendations for the
(Anderson et al, 1993, 1996; Sutton et al, 1996; Deeg et al,           management of IPSS INT-1 MDS patients £ 65 years are
2000). IPSS score is also a strong predictor of outcome, with          outlined in Fig 2.
5-year EFS of 60%, 36% and 28% in Low ⁄ INT-1, INT-2 and
high-risk categories (Appelbaum & Anderson, 1998). Trans-              IPSS INT-2 ⁄ High
plant-related mortality (TRM) for ablative allogeneic trans-              Chemotherapy plus SCT. All patients < 65 years should
plant is 40% in most studies, although the probable evolution          again be considered as to fitness ⁄ eligibility for stem cell
towards non-ablative transplant approaches will reduce this.           transplantation early after diagnosis. In this group of


Table VI. Non-intensive chemotherapeutic agents.


                          Level of     Grade of
Agent                     evidence     evidence      Recommendation      Comments

Low-dose cytosine         Ib           A             Not recommended     Two large studies of predominantly high-risk MDS patients.
arabinoside (LDAC)                                                       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% ÔsignificantÕ
                                                                         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.

Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
196         Guideline




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




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



high-risk patients, stem cell transplantation should only be          ablative SCT is yet to be clearly defined. Nevertheless, TRM
considered for those responding to remission induction                is lower for both modalities and preliminary evidence
chemotherapy (complete ⁄ good partial response) as the                suggests that both will have a future role (de Witte et al,
outcome for non-responding patients is very poor (evidence            1997; Slavin et al, 1998).
grade B, level IIb) (Sutton et al, 1996; Anderson et al, 1997;           Chemotherapy alone. Both patients > 65 years and those
Nevill et al, 1998). For patients < 65 years, eligible for SCT        < 65 years who are ineligible for stem cell transplanta-
and responding to chemotherapy, recommendations for SCT               tion should be considered for intensive chemotherapy
consolidation are outlined in Fig 3. Large cohort studies are         alone. There have been no prospective randomized,
available for the assessment of ablative sibling and unrelat-         controlled trials evaluating outcome following intensive
ed allogeneic SCT but the role of autologous and non-                 chemotherapy compared with supportive care alone in

                                                          Ó 2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 187–200
                                                                                                                Guideline           197
                                                                      1                                                        1
MDS. Cohort studies suggest that of all high-risk MDS                  Molecular and Cellular Pathology,      David Bowen
patients (‡ INT-2), those with RAEB in transformation                 Ninewells Hospital, Dundee,             Dominic Culligan 2
                                                                      2
(RAEB-t, 20–30% marrow blasts) and lacking an                          Aberdeen Royal Infirmary,               Simon Jowitt 3
independent adverse risk factor [karyotype, age, perfor-              Aberdeen, 3Stepping Hill                Stephen Kelsey 4 *
mance status, length of antecedent haematological                     Hospital, Stockport,                    Ghulam Mufti 5
                                                                      4
disorder (Estey et al, 1997)] respond best to intensive                Department of Oncology, St.            David Oscier 6
ÔAML-typeÕ chemotherapy (evidence grade B, level IIb)                 Bartholomews and Royal London           Jane Parker 5
(Wattel et al, 1997). Thus, intensive chemotherapy alone              MDS, London, 5Department of             of the UK MDS
is recommended for consideration in these patients. No                Haematological Medicine, King’s         Guidelines Group
chemotherapy combination is clearly superior, but most                College of Medicine and Dentistry,
commonly used regimens contain cytosine arabinoside                   London, and 6Royal Bournemouth
with any of an anthracycline, etoposide and ⁄ or fludara-              Hospital, Bournemouth, UK
bine. The median number of chemotherapy courses in                    *Present address: Genetech, Inc.,
most studies is two (one induction and one consolidation)             South San Francisco, CA, USA
and patients rarely tolerate more than this. In all other
high-risk MDS patients (namely those for whom intensive
chemotherapy alone is not recommended), intensive
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   tumour necrosis factor-alpha predict response to recombinant




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