part 4 acute myeloid leukemia
DESCRIPTION
TRANSCRIPT
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