The levels of evidence (I–IV) and strength of recommendations (A–C) are defined at the end of the "Major Recommendations" field.
Diagnosis
The diagnosis and classification of myelodysplastic syndromes (MDS) remain dependent on the morphological examination of blood and bone marrow cells. Diagnostic criteria should ideally distinguish MDS from reactive conditions causing dysplastic haematopoiesis and from other clonal myeloid disorders. The minimum clinical assessment and laboratory investigation required for the definitive diagnosis of cases of suspected MDS is shown in the table below.
Evaluation of suspected MDS
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History
Prior exposure to chemotherapy/radiation
Family history of MDS/acute myeloid leukaemia (AML)
Recurrent infections or bleeding/bruising
Examination
Pallor/infection/bruising
Splenomegaly
Full blood count
Macrocytosis, cytopenia(s), neutrophilia, monocytosis, thrombocytosis
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
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Management of Myelodysplastic Syndromes
Where possible, management decisions be based upon the patient's International Prognostic Scoring System (IPSS) score. It is important that the IPSS score is calculated during a stable clinical state, and not, for example, during a florid infective initial presentation. Management decisions should be taken with the informed involvement of the patient and, to aid this, information booklets are available from the Leukaemia Research Fund and the Myelodysplastic Syndromes Foundation.
Supportive Care: Principles
For patients with good prognosis MDS, it is often feasible to undertake a period of observation without needing to introduce specific therapy. Where possible, this 'wait and watch' approach to management may also be useful for patients with more advanced MDS, allowing one to appraise the stability of the disease process and to assess the need to introduce treatment.
Management of Anaemia
Red cell transfusion and iron chelation therapy
Recommendations for iron chelation treatment in myelodysplasia are based on limited data (evidence grade B, level III). Iron chelation should be considered once a patient has received 5 g iron (approximately 25 units of red cells) but only in patients for whom long-term transfusion therapy is likely, such as those with pure sideroblastic anaemia or the 5q- syndrome. Desferrioxamine 20–40 mg/kg should be administered by 12 hour subcutaneous infusion 5–7 days per week. Audiometry and ophthalmology review are essential prior to commencement of desferrioxamine. The target ferritin concentration should be < 1000 microg/L; if the ferritin concentration falls below < 2000 microg/L, the dose of desferrioxamine should be reduced and should not exceed 25 mg/kg. Vitamin C 100–200 mg daily should be commenced after 1 month of desferrioxamine therapy. Vitamin C should be taken when the infusion is set up. Repeat audiometry and ophthalmology review should be performed at least annually. The use of twice daily subcutaneous bolus injections of desferrioxamine may be considered where infusions are not tolerated, but the common practice of adding a single dose of desferrioxamine at each transfusion episode has no basis and should be discouraged.
Erythropoietin (EPO) +/– granulocyte colony-stimulating factor (G-CSF)
Many studies have clearly demonstrated that EPO ± G-CSF can increase haemoglobin concentration and reduce/eliminate red cell transfusion in selected MDS patients, and a summary outline of these is provided in Tables IVA and B of the original guideline document. These studies were small cohort studies (< 120 patients in each) and only one (small) placebo-controlled randomized study (of EPO therapy alone) has been reported. Given the small size of this placebo-controlled trial of EPO therapy alone (87 patients), the grade of recommendation for EPO therapy alone should be considered as grade A/B (level Ib/IIa). The evidence for efficacy of the combination of EPO + G-CSF therapy is grade B (level IIa/IIb).
Overall there is sufficient evidence for the efficacy of EPO ± G-CSF therapy in appropriately selected patients. It is recommended that those patients with refractory anaemia (RA) and RA with excess blasts (RAEB, not eligible for chemotherapy/stem cell transplantation [SCT]) who are symptomatic of anaemia, with no/low transfusion requirement (< 2 units/month) and a basal EPO level of less than 200 U/L (measured at the haemoglobin nadir in transfusion-dependent patients) be considered for a trial of EPO alone at a dose of 10,000 units daily for 6 weeks. For non-responders, consideration should be given to either the addition of daily G-CSF, doubling the dose of EPO, or both for a further 6 weeks. The dose of G-CSF should be escalated weekly from 75 microg, to 150 microg to 300 microg (multiple sampling from single vials kept at 4°C) to maintain the white blood cell count between 6 and 10 × 109/L.
In responding patients, once the maximum response has been reached, the G-CSF can be reduced to thrice weekly and the EPO to 5 days then 4 d to 3 days per week at 4 weekly intervals to the lowest dose that retains response.
For patients with RA with ringed sideroblasts (RARS), symptomatic anaemia, basal EPO levels of < 500 U/L and a transfusion requirement of less than 2 units per month, it is recommended that combined therapy with EPO and G-CSF is used from the outset. Dosing recommendations are as for RA/RAEB with consideration given to dose escalation of EPO at 6 weeks in non-responders for a further 6 weeks.
Immunosuppression
The data support a recommendation for a trial of immunosuppressive therapy with anti-lymphocyte globulin (ALG) at least for patients with hypoplastic MDS (evidence grade B, level IIb).
Management of thrombocytopenia
The role of platelet transfusions in MDS patients should be based on the Royal College of Physicians of Edinburgh Consensus Conference Statement. Antifibrinolytic agents (grade C, level IV) and Danazol (grade B, level IIb) are occasionally useful but cannot be routinely recommended.
Management of infection
Prophylactic
There are no published data to support the routine use of antibacterial or antifungal prophylaxis in neutropenic MDS patients. Consideration may be given to the use of prophylactic low-dose G-CSF therapy in severely neutropenic patients to maintain the neutrophil count > 1 × 109/L (grade B, level IIb)
Therapeutic
Neutropenic sepsis in MDS patients should be treated with intravenous antibiotics as for other patients with neutropenia (e.g. post chemotherapy).
Chronic myelomonocytic leukaemia (CMML)
CMML often has a myeloproliferative component, and cytoreductive chemotherapy is frequently indicated. Hydroxyurea is considered the standard treatment for CMML, in preference to oral etoposide (evidence grade A, level Ib)
Intensive chemotherapy/stem cell transplantation
It is recommended that clinicians discuss all patients eligible for stem cell transplantation with their local transplant unit.
IPSS Low
Neither intensive chemotherapy nor stem cell transplantation can currently be recommended for this group whose median survival without treatment is 4·8 (> 60 years)-11·8 years (< 60 years).
IPSS INT-1
All patients < 65 years should be assessed for fitness/eligibility for allogeneic SCT as soon as possible after diagnosis, as SCT outcome is improved if performed early. If eligible and a sibling donor is available, it is recommended that patients < 50 years are offered ablative allogeneic SCT (evidence grade B, level IIb) and patients > 50 < 65 years are considered for non-ablative allogeneic SCT, within clinical trials where available (evidence grade C, level IV). Patients with no sibling donor, but with an unrelated donor should also be considered for ablative unrelated-donor SCT (< 40 years, evidence grade B, level III) or non-ablative unrelated-donor SCT within clinical trials (> 40 years, evidence grade C, level IV), though the transplant related mortality (TRM) from these procedures remains high. Intensive cytoreductive chemotherapy prior to SCT is not recommended for this group (evidence grade B, level IIb).
Patients > 65 years or < 65 years and not suitable for SCT should be offered supportive care and/or considered for growth factor therapy (e.g., EPO). Recommendations for the management of IPSS INT-1 MDS patients < 65 years are outlined in Figure 2 of the original guideline document.
IPSS INT-2/High
Chemotherapy plus SCT
All patients < 65 years should again be considered as to fitness/eligibility for stem cell transplantation early after diagnosis. In this group of high-risk patients, stem cell transplantation should only be considered for those responding to remission induction chemotherapy (complete/good partial response) as the outcome for non-responding patients is very poor (evidence grade B, level IIb). For patients < 65 years, eligible for SCT and responding to chemotherapy, recommendations for SCT consolidation are outlined in Figure 3 of the original guideline document.
Chemotherapy alone
Both patients > 65 years and those < 65 years who are ineligible for stem cell transplantation should be considered for intensive chemotherapy alone.
Cohort studies suggest that of all high-risk MDS patients (> INT-2), those with RAEB in transformation (20–30% marrow blasts) and lacking an independent adverse risk factor [karyotype, age, performance status, length of antecedent haematological disorder] respond best to intensive 'AML-type' chemotherapy (evidence grade B, level IIb). Thus, intensive chemotherapy alone is recommended for consideration in these patients.
In all other high-risk MDS patients (namely those for whom intensive chemotherapy alone is not recommended), intensive remission-induction chemotherapy (two courses) should be offered only if stem cell transplantation is proposed as consolidation (Figure 3 of the original guideline document).
Supportive Care/Investigational Therapy
If patients do not fall into any category for which chemotherapy ± SCT is recommended they should be offered supportive care or investigational therapies within clinical research protocols.
Definitions:
Levels of Evidence
Ia Evidence obtained from meta-analysis of randomized controlled trials.
1b 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 studies.
IV Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.
Grades of Recommendations
Grade A, evidence level Ia, Ib
Required - at least one randomised controlled trial of good quality and consistency addressing specific recommendation.
Grade B, evidence level IIa, IIb, III
Required - availability of well-conducted studies but no randomised controlled trials on the topic of recommendation.
Grade C, evidence level 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.
