Myelodysplasia
Condition characterised by 1. Abnormal apoptosis resulting in ineffective haemopoiesis and cytopenias 2. Transformation to AML
New WHO 2008 criteria
RCUD – Refractory cytopenia with unilineage dysplasia RARS – Refractory anaemia with ringed sideroblasts RCMD – Refractory cytopenia with multilineage dysplasia RCMD-RS – Refractory cytopenia with multilineage dysplasia and ringed sideroblasts RAEB-1 – refractory anaemia with excess blasts-1 RAEB-2 – refractory anaemia with excess blasts-1 MDS-U myelodysplastic syndrome unclassified (MDS-U) MDS del 5q associated with isolated 5q-
MDS/ MPD
Pathogenesis § Hypercellular bone marrow and peripheral blood cytopenias § Primary or acquired DNA damage to haemopoitic precursor cell leads to myelodysplastic clone § Immune damage and increased apoptosis leads to damage of both the clonal and normal haematopoietic cells myelodysplastic syndrome (expanded T-cell population – which can sometimes result in T-cell LGL leukaemia). § Thought to be overlap with PNH, aplastic anaemia and T-LGL leukaemia § Aplastic anaemia – cytogenetic abnormalities rare at diagnosis – 30% by 3 years and 12% develop MDS by 12 years.
Epidemiology § Median age 69 § 4 per 100,000 increasing to >30 per 100,000 over 70 years
Diagnosis § History § Prior exposure to chemo/ radiation § FH of AML/ MDS § Infections, bleeding, bruising § FBC and film § Ferritin, B12, folate § BMA § Not always indicated if not going to change treatment § At least 200 marrow cells and 20 megas should be examined § Dysplastic features in at least 10% § Pseudo-pelger neutrophils, ring sideroblasts, micromegas and blasts correlate strongly with clonality § Neutrophil granularity is particularly soft because of variations in stain quality § BMT § Should be done if BM indicated § ALIPs are prognostic § Allows assessment of cellularity § BM cytogenetics § Confirms clonalilty § Prognostic implications § Exclude § Megaloblastic § HIV § Alcohol § Recent cytotoxic § Severe intercurrent illness
Hypocellular MDS v. AA § Hypocellular MDS responds better to immunosupressive therapy than normocellular MDS § <30% cellularity <60 years § <20% cellularity >60 years § Erythroid dysplasia is found in AA and cannot be used to distinguish § Abnormal karyotype favours MDS but not 100%
International prognostic scoring system
5q- Syndrome § Severe anaemia, thrombocytosis, typical dysmegakaryopoiesis and favourable outcome § F>M, erythroblastopenia § Progression to AML is rare (10%) § Previously iron overload was a major problem § Lenalidomide results in transfusion independence in 2/3, and in 2/3 responses persist after 2 years § Complete pathological and cytogenetic responses may also be achieved § Grade 3 or 4 neutropenia and thrombocytopenia § Preliminary results suggest lenalidomide also active in 5q- with other cytogenetic abnormalities or >5% blasts § Lenalidomide is an immunomodulatory drug § Suppression of pro-inflammatory cytokine production § Enhancement of T and NK cell activation § Antiangiogenic and anti-TNF properties § Non-teratogenic in animal models, but pregnancy still contraindicated § Doesn’t lead to peripheral neuropathy § Land mark paper by List et al § Lenalidomide gave an erythroid response in 50% of transfusion dependant low risk MDS § 83% in patients with del 5q § Large phase II trial of lenalidomide and 5q- § 67% achieved transfusion independence § Median time to independence 4 weeks § Complete cytogenetic response in 45% § Grade 3 or 4 myelosupression in about 50%, tended to improve after 6-8 weeks § Studies combining lenalidomide and other drugs (esp EPO) in low risk MDS with anaemia are in progress
Management § Treatment decisions should be made on basis of IPSS Supportive care § Either for patients with good prognosis or poor prognosis when age or comorbidity prevent other treatments § Anaemia § Up to 80% have HB <10 at diagnosis § Transfusion and iron chelation § Chelation once received 5g iron (25 transfusions) and likely to need long term transfusion support § Audiometry and ophthalmology before desferrioxamine and annually § Target ferritin < 1000 § Desferrioxamine at time of transfusion has no basis § Oral iron chelators now a possibility § Epo +/- GCSF § RA or RAEB, symptomatic of anaemia, with no/ low transfusion requirement (<2/month) and a basal epo of < 200 be considered for a trial of epo at 10,000 daily for 6 weeks § Non-responders, add GCSF or double dose of Epo ¨ GCSF escalated weekly 75-150-300 to maintain wbd between 6-10 § RARS, symptomatic anaemia and basal epo <500, transfusion <2/month § Combined epo and GCSF from outset § Immunosupression § ALG/ CsA § Hypoplastic MDS and PNH § Thrombocytopenia § Platelet support § Antifibrinolytics § Infection § Prophlaxis § No evidence for prophylaxis § Consider GCSF to keep neutrophil >1
Non-intensive chemotherapy § CMML § Hydroxyurea is preferred to oral etoposide § 5-Azacytidine and decitabine show promise § 27% with RA and RARS achieved a CR or PR with INT-1 MDS with aza § 14% with decitabine § Multiple courses are required with a median time to reponse of 2-4 months § Duration of response generally <1 year § Prelimanry analysis of a large trial (>200) with non 5q-, low IPSS MDS treated with lenalidomide reported transfusion independance in 25% § In older patients, unsuitable for transplant 5-aza and decitabine can be considered § Newer agents such as clofarabine have shown promise
Intensive chemotherapy / SCT § Long term EFS in 32-54% in those eligible § Improved outcome § Younger age § Shorter disease duration § HLA compatibility § Primary MDS § <10% blasts § Good risk cytogenetics § IPSS – 60-36-28% in low/int 1, int 2 and high § IPSS low § Not recommended as median survival without treatment is 5 and 12 years (>60 and <60 years) § IPSS Int 1 § <65 years § Assessed for SCT ASAP § <50 years and sibling donor, ablative SCT § 50-65, non-ablative § Intensive cytoreductive therapy prior to SCT is not recommended § IPSS Int 2/ high § Chemotherapy plus SCT § SCT only for those who respond to remission induction chemotherapy § Outcome for non-responders very poor § For those without a sibling or matched donor, consider auto § Chemotherapy alone § >65or younger but not eligible, consider intensive chemo alone § Most have 2 courses |
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