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Myelodysplasia

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-

 

WHO

WHO 2008

Blood

Marrow

Survival

RA (5-10%)

 

Refractory cytopenias with unilieage dysplasia

Unicytopenia

<1% blasts

 

Unilineage dysplasia

>10% of the affected lineage are dysplastic

<5% blasts

66

RARS (10%)

 

 

Anaemia

 

Erythroid dysplasia only

<5%blasts, >15% RS

 

72

RCMD (24%)

 

 

Bi or pancytopenia

Dysplasia in at least 10% in more than 2 cell lines

33

RCMD-RS (15%)

 

 

Bi or pancytopenia

Dysplasia in more than 2 cell lines and >15% ring sideroblasts

33

RAEB-1 (40% 1&2)

 

 

Cytopenia < 5% blasts

Uni / multilineage dysplasia 5-9% blasts

18

RAEB-2

 

 

Cytopenia 5-19% blasts

Uni / multilineage dysplasia 10-19% blasts or Auer rods

10

MDS-U

 

 

Cytopenias

<1% blasts

Unequivocal dysplasia in <10%

<5% blasts

 

MDS del 5q (5%)

 

 

Anaemia; normal or increased platelets

Megakaryocytes with hypolobated nuclei <5% blasts

116

 

 

 

 

 

 

 

 

 

 

MDS/ MPD

Disease

Blood

Bone marrow

CMML

M >1

BCR-ABL neg

<20% blasts

Dysplasia in one or more myeloid line

<20% blasts

Atypical CML (BCR-ABL negative)

Neutrophil dysplasia

Neutrophil precursors >10% leucocytes

Blasts <20%

Monocytes <10%

Neutrophil dysplasia

<20% blasts

JMML

M >1

<20% blasts

Wbc >10

< 20% blasts

MDS/ MPNu

 

< 20% blasts

RARS-T (with thrombocytosis)

Plts >450

Anaemia

As per RARS

Abnormal megakaryocytes

 

 

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

 

0

0.5

1

1.5

2

BM blasts

<5

5-10

 

11-20

>20

Karyotype

Good

-Y, del(5q), del (20q)

Intermediate

Others

Poor

Complex (>3) or Chr 7 anomalies

 

REABt no longer considered to part of MDS = AML with multilineage dysplasia

Cytopenias

Hb<10

N <1.8

plts <100

0/1

2/3

 

 

 

 

 

Age <60

Age >60

Treatment

Low risk = 0

11.8 years

4.8

Supportive care

Intermediate risk 1 = 0.5 – 1

5.2

2.7

Age <65 SCT work up (non ablative if >50)

Intermediate risk 2 = 1.5 – 2

1.8

1.1

Chemotherapy and SCT if respond (non responders have very poor prognosis

Poor risk = >2

0.3

0.5

 

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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