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Myelodysplastic syndrome and acute myeloid leukaemia. Dr. Edmond S. K. Ma Division of Haematology Department of Pathology The University of Hong Kong. Leukaemia classification. FAB MIC 1987 EGIL 1996 REAL Proposed by ILSG in 1994

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myelodysplastic syndrome and acute myeloid leukaemia

Myelodysplastic syndrome and acute myeloid leukaemia

Dr. Edmond S. K. Ma

Division of Haematology

Department of Pathology

The University of Hong Kong

leukaemia classification
Leukaemia classification
  • FAB
  • MIC 1987
  • EGIL 1996
  • REAL
    • Proposed by ILSG in 1994
    • Lymphoma classification, but principles extended to other haemic neoplasms
      • Encompasses all available information
      • Consensus approach
who classification
WHO Classification
  • Collaborative project of:
    • European Association for Haematopathology
    • Society for Haematopathology
  • Started in 1995
  • Steering Committee
    • Working Group Meeting in Lyon, France, November 8 – 11, 2000
  • Clinical Advisory Committee
myelodysplastic syndrome
Myelodysplastic syndrome
  • A group of clonal haemopoietic stem cell disorder characterized by dysplasia and ineffective haemopoiesis in one or more major myeloid cell line
  • < 20% blasts in blood and bone marrow
myelodysplastic syndrome5
Myelodysplastic syndrome
  • A disease of the elderly
  • Incidence : 3 – 20 /100,000
  • Increasing number of therapy related MDS
  • Clinical features: related to cytopenia
  • Etiology: prior chemoradiotherapy, benzene exposure, cigarette smoking, inherited syndromal disorders (e.g. Fanconi’s anaemia)
dyserythropoiesis
Dyserythropoiesis
  • Nuclear budding
  • Inter-nuclear bridging
  • Karyorrhexis
  • Multinuclearity
  • Megaloblastoid maturation
  • Ringed sideroblast
  • Vacuolation
  • PAS +ve
dysgranulopoiesis
Dysgranulopoiesis
  • Small size
  • Nuclear hypolobulation (pseudo-Pelger Heut)
  • Hypersegmentation
  • Hypogranularity
  • Pseudo-Chediak Higashi granules
dysmegakaryocytopoiesis
Dysmegakaryocytopoiesis
  • Hypolobulated micro-megakaryocyte
  • Non-lobulated nuclei in megakaryocyte of all sizes
  • Multiple, widely separated nuclei
abnormal localization of immature precursors
Abnormal localization of immature precursors
  • Presence of 3 or more small clusters of myeloblasts and promyelocytes (5 – 8 cells) in marrow trephine biopsy in the central portion of the marrow away from the vascular structure and the endosteal surface of the bone trabeculae
genetics
Genetics
  • 5q- syndrome
  • del (17p), small hypolobulated or vacuolated neutrophils, p53 mutations, poor prognosis
  • -5/5q-
  • -7/7q-
  • del(20q)
  • 3q21q26 abnormality
cytogenetics and prognosis
Cytogenetics and prognosis
  • Good risk
    • Normal, isoloted 5q-, isolated 20q-, -Y
  • Poor risk
    • Complex changes (> 3 abnormalities)
    • Chromosome 7 abnormalities
  • Intermediate risk
    • All other changes
international prognostic scoring system
International Prognostic Scoring System

Score00.511.5

  • % blasts <5 5-10 - 11-20
  • Karyotype Good Intermediate Poor
  • Cytopenia 0-1 2-3
  • Cytopenia: Hb < 10 g/dL; neutrophils < 1.5 X 109/L; plt < 100 X 109/L
  • Risk groups

Low = 0; Intermediate-1 = 0.5-1; Intermediate-2 = 1.5-2; High = 2.5

refractory anaemia
PB

anaemia,

no or rare (<1%)

blasts

MB

Unilineage dysplasia, restricted to erythroid lineage,

< 5% blasts,

< 15% ringed sideroblasts

Refractory anaemia
refractory anaemia21
Refractory anaemia
  • Exclusion of known secondary causes of dyserythropoiesis
  • If no cytogenetic abnormality present, reassess after 6 months
  • Protracted clinical course, median survival is 66 months, leukaemic transformation 6%
refractory anaemia with ringed sideroblasts
PB

Anaemia

No blast

MB

 15% ringed sideroblasts

Erythroid dysplasia only

<5% blasts

Refractory anaemia with ringed sideroblasts
ringed sideroblast
Ringed sideroblast
  • Erythroid precursor
  • One third or more of the nucleus
  • Encircled by 10 or more siderotic granules
refractory anaemia with ringed sideroblasts25
Refractory anaemia with ringed sideroblasts
  • Indolent clinical course
  • Median survival = 6 years
  • Leukaemic transformation 1 – 2 %
refractory cytopenia with multilineage dysplasia
PB

Bicytopenia or pancytopenia

No or rare blasts

No Auer rod

< 1 X 109/L monocytes

MB

Dysplasia in  10% of cells in two or more myeloid cell lines

< 5% blasts

No Auer rod

< 15% ringed sideroblasts

Refractory cytopenia with multilineage dysplasia
refractory cytopenia with multilineage dysplasia and ringed sideroblasts
PB

Bicytopenia or pancytopenia

No or rare blasts

No Auer rod

< 1 X 109/L monocytes

MB

Dysplasia in  10% of cells in two or more myeloid cell lines

< 5% blasts

No Auer rod

 15% ringed sideroblasts

Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
refractory cytopenia with multilineage dysplasia31
Refractory cytopenia with multilineage dysplasia
  • Cytogenetic abnormality seen in 50%

+8

Monosomy 7

del(7q)

Monosomy 5

del (5q)

del (20q)

Complex karyotype

refractory cytopenia with multilineage dysplasia32
Refractory cytopenia with multilineage dysplasia
  • Leukaemic transformation 11%
  • Overall median survival 33 months
  • RCMD and RCMD-RS are similar in clinical course
  • Patients with complex karyotype have similar clinical course to RAEB
refractory anaemia with excess blasts 1
PB

Cytopenia

<5% blasts

No Auer rod

<1% monocytes

MB

Unilineage or multilineage dysplasia

5-9% blasts

No Auer rod

Refractory anaemia with excess blasts-1
refractory anaemia with excess blasts 2
PB

Cytopenia

5-19 % blasts

Auer rod ±

<1% monocytes

MB

Unilineage or multilineage dysplasia

10-19% blasts

Auer rod ±

Refractory anaemia with excess blasts-2
refractory anaemia with excess blasts
Refractory anaemia with excess blasts
  • Blast cells show myeloid phenotype
  • Leukaemic transformation
    • RAEB-1 25%
    • RAEB-2 33%
  • Median survival
    • RAEB-1 18 months
    • RAEB-2 10 months
myelodysplastic syndrome unclassifiable
PB

Cytopenias

No or rare blasts

No Auer rods

MB

Unilineage dysplasia, one myeloid cell line

(non-erythroid)

<5% blasts

No Auer rod

Myelodysplastic syndrome, unclassifiable
5q syndrome
PB

Anaemia

Usually normal or increased platelet count

<5% blasts

MB

Normal or increased megakaryocytes with hypolobulated nuclei

<5% blasts

Isolated 5q- abnormality

No Auer rod

5q- syndrome
acute myeloid leukaemia
Acute myeloid leukaemia
  • Acute myeloid leukaemia with recurrent genetic abnormalities
  • Acute myeloid leukaemia with multilineage dysplasia
  • Acute myeloid leukaemia and myelodysplastic syndrome, therapy-related
  • Acute myeloid leukaemia not otherwise categorized
acute myeloid leukaemia43
Acute myeloid leukaemia
  • The blast % is lowered from 30% (FAB) to 20% (WHO)
  • Median age of onset = 60 yrs
  • Incidence 4 –10 / 100,000
  • Etiology
acute myeloid leukaemia cytochemistry
Acute myeloid leukaemia: cytochemistry

Myeloperoxidase

Sudan Black B

Non-specific esterase

a-naphthyl butyrate

a-naphthyl acetate

acute myeloid leukaemia role of immunophenotyping
Acute myeloid leukaemia: role of immunophenotyping
  • Distinction of minimally differentiated AML from acute lymphoblastic leukaemia
  • Recognition of AML-M7
  • Recognition of specific AML sub-categories (e.g CD56+ve AML)
  • Diagnosis of biphenotypic leukaemia
  • However, immunophenotyping is not mandatory in typical cases of AML, unlike in ALL where a phenotypic diagnosis is needed in every case
panel of monoclonal antibodies in classification of acute leukaemia
Panel of monoclonal antibodies in classification of acute leukaemia
  • Haemopoietic precursors: CD34, HLA-DR, Tdt, CD45
  • B-lineage: CD19, CD20, CD22, CD79a
  • T-lineage: CD2, CD3, CD5, CD7
  • Myeloid: CD13, CD33, CD117, anti-MPO
  • Megakaryocytic: CD41, CD61
acute myeloid leukaemia with recurrent genetic abnormalities
Acute myeloid leukaemia with recurrent genetic abnormalities
  • Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO
  • Acute myeloid leukaemia with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13;q22); CBFb/MYH11
  • Acute promyelocytic leukaemia (AML with t(15;17)(q22;q12); PML/RARa and variants
  • Acute myeloid leukaemia with 11q23 (MLL) abnormalities
acute myeloid leukaemia with t 8 21 q22 q22 aml1 eto
Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO
  • t(8;21) is the commonest translocation in AML
  • Associated with AML-M2 morphology
  • Tumour masses (granulocytic sarcoma)
acute myeloid leukaemia with t 8 21 q22 q22 aml1 eto56
Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO
  • Morphology
    • Large blasts, heavily granulated
    • Frequent Auer rods
    • Variable dysplasia in granulocytic series
    • Rare cases with blast count < 20%
  • Immunophenotype
    • CD13+ CD33+ anti-MPO+
    • CD19+ CD34+ CD56±
acute myeloid leukaemia with t 8 21 q22 q22 aml1 eto63
Acute myeloid leukaemia with t(8;21)(q22;q22); AML1/ETO
  • Prognosis
    • Good response to chemotherapy and high complete response rate
    • Long term disease free survival
    • Adverse factors
      • additional chromosomal changes e.g. 9q-
      • CD56 +ve
acute myeloid leukaemia with inv 16 p13q22 or t 16 16 p13 q22 cbf b myh11
Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBFb/MYH11
  • Granuolocytic and monocytic features
  • AML-M4 (acute myelomonocytic leukaemia) morphology
  • Abnormal eosinophils with coarse basophilic granules
acute myeloid leukaemia with inv 16 p13q22 or t 16 16 p13 q22 cbf b myh1166
Acute myeloid leukaemia with inv(16)(p13q22) or t(16;16)(p13;q22); CBFb/MYH11
  • Cytochemistry
    • Abnormal eosinophils are CAE +ve
  • Immunophenotype
    • Granulocytic and monocytic markers
    • Co-expression of CD2 in blast population
  • Prognosis
    • Favourable
acute promyelocytic leukaemia
Acute promyelocytic leukaemia
  • AML with t(15;17)(q22;q12); PML/RARa and variants
  • Characteristic morphology
  • Associated with disseminated intravascular coagulation
acute promyelocytic leukaemia71
Acute promyelocytic leukaemia
  • Immunophenotype
    • CD33+ CD13+
    • HLA-DR and CD34 negative
    • Co-expression of CD2 and CD9
  • Genetics
    • t(15;17)(q22;q12)
    • Variants: t(11;17)(q23;q12) PLZF/RARa; t(5;17)(q32;q12) NPM/RARa; t(11;17)(q13;q12) NuMA/RARa
acute promyelocytic leukaemia73
Acute promyelocytic leukaemia
  • Treatment
    • All-trans retinoic acid (ATRA)
    • Arsenic for relapse cases
    • RARa variants: resistant to ATRA
  • Prognosis
    • Favourable when treated optimally with ATRA followed by anthracyclines
acute myeloid leukaemia with 11q23 abnormalities
Acute myeloid leukaemia with 11q23 abnormalities
  • Infant leukaemia
  • Therapy related AML after exposure to DNA topoisomerase II inhibitors
  • Acute monocytic and myelomonocytic leukaemia
  • Associated with MLL rearrangement
acute myeloid leukaemia with multilineage dysplasia
Acute myeloid leukaemia with multilineage dysplasia
  • Following MDS or MDS/MPD
  • Without antecedent MDS
  • Dysplasia in  50% of cells in at least 2 lines
  • Poor prognosis
aml and mds therapy related
AML and MDS, therapy related
  • Alkylating agent related
  • Topoisomerase type II inhibitor related
acute myeloid leukaemia not otherwise categorized
Acute myeloid leukaemia not otherwise categorized
  • Equivalent to FAB classification
    • AML minimally differentiated
    • AML without maturation
    • AML with maturation
    • Acute myelomonocytic leukaemia
    • Acute monoblastic and monocytic leukaemia
    • Acute erythroid leukaemia
    • Acute megakaryoblastic leukaemia
    • Acute basophilic leukaemia
    • Acute panmyelosis with myelofibrosis
    • Myeloid sarcoma
acute leukaemia of ambiguous lineage
Acute leukaemia of ambiguous lineage
  • Mixed myeloid and lymphoid characteristics
  • Biclonal (two clones)
  • Biphenotypic (two characteristics on same blast cell)