W.H.O Classification ofMyeloid MalignanciesProf. Herman Hariman, SpPK (KH). Ph.D (U.K).Prof. Adi Koesoema Aman, SpPK (KH)

Dept. Clinpath, FK-USU

Classification of myeloid malignanciesFABChronic myeloproliferative diseases

Myelodysplastic syndromesAcute myeloid leukaemias

Treatment during that periodThere is no selection or stratificationAll groups are considered as one disease and treated with the same standard treatment.Such as all CML is treated the same manerMyelodysplastic is confusingAML: all FAB type of AML is treated with the same AML therapy except for APL (M3)HOWEVER, the result shows that not all groups gave the same result of response to therapy.

Progression during 20 yearsGenetic background on the pathogenesis becomes clearer.Orientation on the treatment of myeloid malignancies is not based on morphology, selection of the risk groups is based on non-morphological factors such as cytogenetic findings

(French American British) F.A.BBased on MORPHOLOGY> 30% blasts = ACUTE LEUKAEMIA< 5% = normal or Chronic Leukaemia6-29% = MYELODYSPLASTIC SYNDROME with the exception of Erythroleukaemia can be 6-29% blasts but the blast/NEC ratio > 30%

Classification of myeloid malignanciesFABChronic myeloproliferative diseases

Myelodysplastic syndromesAcute myeloid leukaemiasWHOChronic myeloproliferative diseasesMyelodysplastic/myeloproliferative diseasesMyelodysplastic syndromesAcute myeloid leukaemias

Chronic Myeloproliferative DisordersFABChronic myelogenous leukemia (CML)

Agnogenic myeloid metaplasia with myelofibrosis (MF) (Idiopathic myelofibrosis)

Polycythemia vera (EV)Essential thrombocytemia (ET)WHOCML Ph+: t(9;22)(qq34;q11), BCR/ABLChronic neutrophilic leukemiaChronic eosinophilic leukemia/hypereosinophilic syndromeChronic idiopathic myelofibrosisPolycythemia veraEssential thrombocytemia

New ChimerismBCR/Abl oncogeneBCR = Breakpoint Cluster RegionAbl = Abelson

New Chimeric Fusion ProteinBCR/Abl oncogeneBCR/Abl TYROSINE KINASE

PROLIFERATIVE EFFECTARREST OF DIFFERENTIATIONARREST OF APOPTOSIS

Chronic phase CML Low power view of this bone marrow aspirate reveals an increased ME ratio. Eosinophils and larger immature myeloid elements are also evident.

CMLThe most important change is, that only the Ph+ cases are called CML by the WHO. The Ph- cases (which show myelodysplastic signs, and are known to have significantly worse prognosis) are called aCML (atypical CML), and belong to the newly created myelodysplastic/myeloproliferative group. The aCML term is somewhat misleading, because it is not CML at all, but it was kept, having no better alternative.

Myeloproliferative disordersGranulocyte Eryhtroid Megakaryocytic Line Line LineC.G.L (neutro) P.R.V E.T

IMF (Idiopathic Myelofibrosis)

MPD with disrupted Protein KinaseC.G.LSystemic Mast Cell DiseasePRV. ET, IMF (and some Ph(-)ve CGL, CMML, chronic neutrophilic leukemia, megakaryocytic leukemia, MDSHES (Hypereosinophilic Syndrome), CEL (Chronic Eosinophilic Leukaemia)BCR/ablc-kit; PDGFR-

JAK2 (V617F)

PDGFR and

JAK2A new brealthrough in the understanding of MPD

PRV. ET, IMF (and some Ph(-)ve CGL, CMML, chronic neutrophilic leukemia, megakaryocytic leukemia, MDS PathogenesisJAK2Janus Tyrosine Kinase 2Previously known Just Another Kinase

Myeloproliferative disordersGranulocyte Eryhtroid Megakaryocytic Line Line LineC.G.L (neutro) P.R.V E.THES & CEL & CNLPh(-)ve C.G.L & CMML

IMF (Idiopathic Myelofibrosis)

Systemic Mast Cell DiseaseHES: Hypereosinophilic Syndrome, CEL: Chronic Eosinophilic Leukaemia, CNL: Chronic Neutrophilic Leukaemia

MPD with disrupted Protein KinaseC.G.LSystemic Mast Cell DiseasePRV. ET, IMF (and some Ph(-)ve CGL, CMML, chronic neutrophilic leukemia, megakaryocytic leukemia, MDSHES (Hypereosinophilic Syndrome), CEL (Chronic Eosinophilic Leukaemia)BCR/ablc-kit; PDGFR-

JAK2 (V617F)

PDGFR and

Myelodysplastic/myeloproliferative diseases Atypical myelogenous leukemia (aCML); JAK2V617F Chronic myelomonocytic leukemia (CMML); JAK2V617F Juvenile myelomonocytic leukemia (JMML), previously JCML; ras mutations, NF1 inactivating mutations or protein tyrosine phosphatase, non-receptor type 11 (PTPN11) (SHP-2) mutations

Myelodysplastic SyndromeFABRefractory anemia (RA)Refractory anemia with ringed sideroblasts (RARS)Refractory anemia with excess blasts (RAEB)Refractory anemia with excess blasts in transformation (RAEB-T) (X)Chronic myelomonocytic leukemia (CMML)WHORefractory anemia: with ringed sideroblasts (FAB: RARS) without ringed sideroblasts (FAB: RA)Refractory cytopenia with multilineage dysplasia (new)Refractory anemia with excess blasts (FAB: RAEB)5q- syndrome (new)unclassifiable (new)

PSEUDO-PELGER

Ring Sideroblast

RCMD

World Health Organization Classification and Criteria for the Myelodysplastic Syndromes (MDS)MDS SubtypeBlood FindingsBone Marrow FindingsRefractory anemia (RA) No or rare blasts Anemia Erythroid dysplasia only

5q- MDS (Belgian RA)Older personsFemale predominantBone marrow: numerous unilobular nucleated megakaryocytesKaryotyping deletion of chromosome 5

5q- syndrome

Major ChangesThe RAEB-T of the FAB is now considered to be acute leukemia, not an MDS type. CMML of the FAB was put into the new MPD/MDS group by the WHO.A new group was formed from those cases previously classified as RA or RARS where the dysplasia affected more than one cell line, because the prognosis has been found worse for these cases (refractory cytopenia with multilineage dysplasia).A new subgroup is 5q- syndrome (the loss of the long arm of chromosome 5).

WHO classification of (AML)FABIt is solely based on morphologyIt does not tell about treatment approach andRisk strategyWHOIt is designed to have physician had strategy for treatmentBased on risk factor especially on the recurrent cytogenetic abnormality

All treatment nowadays is based on STRATIFICATION

Acute Myeloid LeukaemiaFABM0: minimally differentiatedM1: myeloblastic leukemia without maturationM2: myeloblastic leukemia with maturationM3: hypergranular promyelocytic leukemiaWHOAML with recurrent cytogenetic translocationsAML with t(8;21)(q22;q22) AML1/CBFalpha/ETOAcute promyelocytic leukemia:AML with t(15;17)(q22;q12) and variants PML/RARalphaAML with abnormal bone marrow eosinophils inv(16)(p13;q22) vagy t(16;16)(p13;q22) CBFbeta/MYH1AML with 11q23 MLL abnormalities

FAB WHOM4: myelomonocytic leukemiaM4Eo: variant, increase in marrow eosinophilsM5: monocytic leukemiaM6: erythroleukemia (DiGuglielmo's disease)M7: megakaryoblastic leukemiaAML with multilineage dysplasiaWith prior MDSWithout prior MDSAML with myelodysplastic syndrome, therapy relatedAlkylating agent relatedEpipodophyllotoxin related

FAB WHOAML not otherwise categorizedAML minimally differentiatedAML without maturationAML with maturationAcute myelomonocytic leukemiaAcute monocytic leukemiaAcute erythroid leukemiaAcute megakaryocytic leukemiaAcute basophilic leukemiaAcute panmyelosis with myelofibrosis

Recurrent Cytogenetic abnormalitiesCytogenetic test Molecular study

Karyotyping qRT-PCR

INV(6), t(16;16) CBFb/MYH11

t(8;21)(q22;q22) AML1/ETO

t(15;17)(q22;q21) PML/RAR

t(11;17)(q23;q21) PLZF/RAR

11q23 HRX or MLL

Good Risk Standard/ Poor Risk t(18;21), t(15;17) IntermediateRisk Relapsed Inv(16) w/wo other No favourable nor unfavourable >15% blasts after C1 Cytogenetic cytogenetic abnormalities -5, -7, abn(3q), complex abnormalities 5-15% marrow blasts after C1 wo favourable cytogenetics Whatever blasts after C1 t(15;17) AML de Novo or secondaryInvestigation of risk factors Induction-C1 Induction-C1

Induction-C2 Induction-C2

2 CoursesConsolidation Consolidation ADE FLA G-CSF G-CSF Course-4 BMT Course-4 ATRA ATRA

Course-5 BMT Course-5 Off BMT Consolidation

Good Risk Standard/ Poor Risk t(18;21), t(15;17) IntermediateRisk Relapsed Inv(16) w/wo other No favourable nor unfavourable >15% blasts after C1 Cytogenetic cytogenetic abnormalities -5, -7, abn(3q), complex abnormalities 5-15% blasts after C1 genetic abnormalitiesAML de Novo or secondaryInvestigation of risk factors Induction-C1 Induction-C1

Induction-C2 Induction-C2

2 CoursesConsolidation Consolidation ADE FLA G-CSF G-CSF Course-4 BMT Course-4 ATRA ATRA

Course-5 BMT Course-5 Off BMT Consolidation t(15;17)

Good Risk Standard/ Poor Risk t(18;21), t(15;17) IntermediateRisk Relapsed Inv(16) w/wo other No favourable nor unfavourable >15% blasts after C1 Cytogenetic cytogenetic abnormalities -5, -7, abn(3q), complex abnormalities 5-15% blasts after C1 genetic abnormalitiesCytogenetic, the most significant factors t(15;17)Majority of patients are assigned In the intermediate group

FAB WHO

FAB is still important to designate this groupAML not otherwise categorizedAML minimally differentiatedAML without maturationAML with maturationAcute myelomonocytic leukemiaAcute monocytic leukemiaAcute erythroid leukemiaAcute megakaryocytic leukemiaAcute basophilic leukemiaAcute panmyelosis with myelofibrosis

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