part 4 acute myeloid leukemia

Myeloid NeoplasmMALIGNANT NEOPLASM OF

HEMATOPOIETIC STEM CELLS ARISE

PRIMARILY IN BONE MARROWALSO SPLEEN, LIVER, LN - To a Lesser

ExtentFLOOD THE CIRCULATING BLOOD

& OTHER ORGANS

3 Broad Categories of Myeloid Neoplasm

1. Acute MyelogenousImmature progenitor cells accumulate in BM

2. Myelodysplastic SyndromesIneffective HematopoiesisPeripheral Cytopenias

3 Broad Categories of Myeloid Neoplasm

3. Chronic Myeloproliferative D/OIncreased production1 or more terminally differentiated

myeloid elementsGRANULOCYTES

Leads to elevated peripheral blood counts

TYPES: CML, Polycthemia vera, Essential

thrombocytosis, primary myelofibrosis

ACUTE MYELOID LEUKEMIA

FeaturesAffects primarily Adults

15 – 39 y/o peak incidenceAcute Onset of symptoms R/T

AnemiaNeutropenia - InfectionsSpontaneous mucosal & cutaneous Bleeding

Bleeding diasthesis is most striking feature

FeaturesEnlargement of liver, spleenLN enlargement is not pronouncedIf untreated, course is rapidly

progressive

PATHOPHYSIOLOGY1. MOSTLY WITH ACQUIRED GENETIC

ALTERATIONS INHIBITION OF TERMINAL MYELOID

DIFFERENTIATIONProliferation of Relatively Undifferentiated

MyeloblastREPLACED NORMAL MARROW ELEMENTSIts replication rate is LOWER than normal

myeloid cellsINDICATING :1. BLOCKED MATURATION2. INCREASED SURVIVAL

2. Chromosomal Abnormalities- AML t(8;21) , inv(16) , t(15,17)De Novo casesAssociated with Myelodysplastic syndromes

Radiation therapy

PATHOPHYSIOLOGY

PATHOPHYSIOLOGYRecurrent Chromosomal Aberrations

Translocation Disrupt genes encoding for Factors needed for NORMAL MYELOID DIFFERENTIATION

Eg. t(8,21) AND inv(16) Chimeric gene New Protein Dominant Negative activity Daughter cells exhibit partial or complete block in terminal differentiation

Additional Collaborative Aberration present Promyelocytic Leukemia (AML-M3)

T(15,17) producing fusion gene RAR aand PMLSuppress the function of RAR a Becomes a Repressor of Transcription Turns off genes needed for full and complete myeloid differentiation

Point mutation in FLT3 constitutive activation of tyrosine kinase promote cellular proliferation & survival

Diagnosis:Dx requires at least 30% of ANC are Myeloblast (ANC- all nucleated cells )WHO criteria

Been lowered to 20% With elimination of of MDS

Refractory anemia w/ excess blastBlast in Transformation

Helpful in the dx is (+) Auer rods in myeloblast cells

Myeloblast

Myeloperoxidase

SBB

Esterase

AUER RODSLinear or SpindleRed- Purple InclusionsIn Myeloblast/myelocyteDerivatives of Azurophilic granulesStain (+) SBB, MPO, ACPEspecially associated w/ M1 to M3

MO Minimally Differentited

AML

2-3 % Blast lack definitive cytologic & Cytochemical markers of myeloblast

M1 AML w/o Differentiation

20 % Very immature > 3% blast (+) peroxidase, Few Auer Rods, Little Maturation beyond blast stage

M2 AML with maturation

30-40%Full range of myeloid Differentiation. Auer rods (+) in most cases. Often associated w/ t(8,21)

M3 Acute Promyelocytic

Leukemia

5-10% Most are Hypergranular promyeloctes, Often many Auer rods per cell, ( 35-40y/o ), DIC, t( 15;17 )

Revised Classification of AML

M4 Acute Myelomonocytic Leukemia

15-20%

Myeloid elements show wide range of differentiationMonoblast (+) NSE Non-specific EsteraseSubset assoc. w/ Inv. (16)

M5 Acute Monocytic Leukemia

10% Older Patients, High incidence of Organomegaly,Lymphadenopathy & Tissue Infiltrationa. Monoblast & Promonocytes Predominates BM & Bloodb. Mature Monocytes predominate Blood

M6 Acute Erythroleukemia

5%  Seen in Advanced Age

M7 Acute Megakaryocytic Leukemia

1%  Myelofibrosis seen in most cases

M6 ErythroleukemiaErythroid precursor predominatesBlast are also IncreasedDx when > 50% of BM cells are

erythroid precursors and Myeloblast represent > 30% of Non-Erythroid cells

M7 Megakaryoblast are identified by Ab

against Platelet-associated Antigens

FACTOR FAVORABLE UNFAVORABLE

AGE <45 yrs <2 YRS, >60 yrs

LEUKOCYTOSIS <25 d >100D

CNS ABSENT PRESENT

RESPONSE TO TX RAPID DELAYED/INCOMPLETE

AUER RODS PRESENT ABSENT

FAB TYPE M2,M3, M4EO M5,M6,M7

CELLMARKERS CD2 /CD19 CD13/CD14/CD33

TREATMENT / PROGNOSISWith ChemoTx

60% Complete remission15-30% remain free from disease for 5 yearst(8;21) , inv(16)

Relative good response to chemoTx Allogenic BM therapy

High risk forms AML Develop from myelodysplastic syndromeRelapse AML

Vit A derivativeOvercome the block in differentiation r/t

t(15,17) and presence of RAR PML fusion protein

Ultimately relapses when used aloneFail to prevent self-renewal of neoplastic

progenitor cells

TREATMENT / PROGNOSIS

Difference of AML & ALLFEATURES/

MxAML ALL

TISSUE INFILTRATION

LESS STRIKINGM4M5- Leukemia cutis/ Gingival infiltrates

MORE COMMON

CNS INVOLVEMENT

LESS MORE COMMON

LYMPHADENOPATHY

LESS MORE COMMON

M1- Blast cells are minimally differentiated Express CD 34 (marker of multipotent stem cells )Negative for CD 64 ( marker of mature myeloid cells )(+) CD33 ( marker for immature myeloid cellsSubset (+) CD 15 ( marker for more mature myeloid cell

AML-M1

Acute Myeloblastic Leukemia w/ Maturation M2

Myeloblast represent 20% (WHO) to 89% of total marrow cells

> 10% of NEC are promyelocyte to neutrophils

Auer rods are usually present –mulitple

ACUTE PROMYELOCYTIC LEUKEMIA M3(35-40y/o)

Promyelocytespredominate

Azurophilic granulesabundant & stain

intenselyHypergranular promyelocytes

Auer rods almost always (+) , multiple or clusters

Hemorrhagic complications frequent due to DIC Initiated by PROCOAGULANT

materials from Leukemic cell Granules

ACUTE MONOCYTIC LEUKEMIA M5Promyelocytes and BlastGum Infiltrates2 types

Poorly Differentiated M5A LARGE BLAST >80% OF MARROW MONOCYTIC CELLS

Differentiated M5B FEWER MONOBLAST < 80% OF MARROW MONOCYTIC CELLS MORE PROMONOCYTES & MONOCYTES

ERYTHROLEUKEMIA M6Erythroblast predominates Myeloblast are also Increased

> 50% NC of BM are Erythroblast>20% (WHO) of NEC are Myeloblast

MEGAKARYOCYTIC M7Undifferentiated BlastMegakaryoblast identified by Ab against Platelet

associated antigensMarrow Fibrosis