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LEUKEMIAS

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... or Evolve from MDS ( RAEB, RCMD) DD's: RAEB, AML M2 with increased ... If 20% are Non Erythroid blasts---RAEB. ACUTE MEGAKARYOCYTIC LEUKEMIA (AMgL): M7 ... – PowerPoint PPT presentation

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Title: LEUKEMIAS


1
LEUKEMIAS
  • Definition
  • Molecular biology
  • Chromosomal abnormalities
  • Etiology
  • Acute leukemias (AML and ALL).

2
Molecular biology of Leukemogenesis
  • Inappropriate expression of genes that regulate
    basic steps in cell proliferation.
  • Proto-oncogenes?Oncogenes.
  • Point mutations, Gene amplification,,
    translocation.
  • Philadelphia chromosome in CML ALL.
  • ABL on Chr-9, BCR on Chr-22.

3
Chromosomal abnormalities
  • Very common in leukemias.
  • Diagnosed by banding techniques.
  • t (821), t(922), inv(16), t(1517).
  • gt50 of cases of leukemias have Chr.
    abnormalities.
  • Helps in diagnosis, prognosis, treatment
    outcome….. Etc.

4
Etiology
  • Radiation Ionizing, Non ionizing.
  • Chemicals Benzene, alkyalating agents.
  • Viruses Leukemogenic viruses with RT enzyme,
    HTLV-1.
  • Genetic factors Downs, Blooms, Fanconis,
    Ataxia talengiectasia.

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Acute leukemias
  • Aggressive course.
  • High mortality.
  • Dominant cell is the Blast.
  • Classification based on morphology of PS, BM,
    Cytochemistry,Immunophenotyping.
  • Criteria is more than 20 blasts in BM or PS
  • 8 AML morphological types 3 ALL types.

7
ACUTE MYELOID LEUKEMIAS (AML)
  • AML with Recurrent Cytogenetic Abnormalities.
  • AML with Multilineage Dysplasia.
  • AML MDS Therapy related.
  • AML not otherwise Categorized (M0-M7)
  • AML with Ambiguous Lineage.

8
Clinical features of AML
  • Primarily in adults and in infants less than 1 yr
  • 15 to 20 of all leukemias
  • More No. of cases after age 50 yrs.
  • Abrupt onset of symptoms.. Within weeks to months.

9
  • Palor, fatigue, weakness, anaemia.
  • Bleeding, bruising, petichial hemorrhages.
  • Infections, pneumonia, meningitis
  • Spleenomegaly, hepatomegaly, lymphadenopathy.
  • DIC in AML-M3, skin infiltration soft tissue
    masses in AML- M5 etc.

10
Diagnosis of AML
  • High index of clinical suspicion
  • Family history, past history.
  • Simple PS examination.
  • PS, Bone marrow, Cytochemistry,
    Immunophenotyping, Cytogenetics,
  • Other lab tests Serum uric acid, LDH, RFT,
    Sr.Ca, electrolytes

11
Cytochemistry
  • Sudan black B, Myeloperoxidase (MPO)
  • Periodic acid schiff (PAS)
  • Non- specific esterase (NSE)
  • Acid phosphatase

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14
MONOCLONAL Ab IN THE CLASSIFICATION OF ACUTE
LEUKEMIAS
  • Hematopoetic precursors CD 34, HLA-DR, TdT, CD
    45
  • B-LineageCD 19, CD 20, Cyto CD 22, CD79a.
  • T Lineage CD 2, Cyto CD 3, CD 5, CD 7.
  • Myeloid MPO, CD 117, 13, 33, 15.
  • Monocytic CD 14, 116, 11c, 36, Lysozyme
  • Megakaryocytic CD 41, 61
  • Erythroid CD 36, 71, Glcophorin A.

15
Blood picture
  • Anaemia, Thrombocytopenia,
  • WBC Range from 10,000 to more than 1 lakh /
    cumm.
  • Leukemia presenting as pancytopenia!!!
  • Blasts in PS and neutropenia.
  • Buffy coat smear may be useful.
  • Predominantly immature stages of maturation.

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AML not otherwise CATEGORISED
  • AML-Minimally differentiated M0
  • AML without Maturation M1
  • AML with Maturation M2
  • Acute promyelocytic leukemia M3
  • Acute Myelomonocytic Leukemia M4
  • Acute Monocytic Leukemia M5
  • Acute Erythroid Leukemia M6
  • Acute Megakaryocytic Leukemia M7

18
AML-Minimally Differentiated M0
  • No evidence of Myeloid differentiation on Light
    microscopy.
  • Immunophenotyping EM-Cytochemistry.
  • Adults, 5 of AML.
  • Cytochem MPO, SBB, NSE ve or
  • MPO in lt3, EM-MPO .
  • DDs ALL, AML-M7, Mixed Leukemia, Leukemic phase
    of LCL.

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AML-Minimally Differentiated M0
  • Immunophenotyping
  • Panmyeloid markers CD 13, 33, 117 .
  • BT Lymphoid markers CD 3, 22, 79a ve.
  • Stem cell Markers CD 34, 38 HLA-DR
  • Myelomonocytic markers CD 11b,15,14,65-ve.
  • TdT Positive in 30 of Pts.
  • Genetics- Nothing Unique
  • PrognosisPoor, Low remission, Increased Relapse,
    Shorter survival.

21
AML without MATURATION M1
  • 10 of AML, Adults.
  • Increased BM Blasts
  • No significant evidence to show Maturation
  • gt 90 Blasts are Non-Erythroid.
  • Morphology Auer rods?, MPO, SBB gt3
  • IPT At least two Myelomonocytic antigens CD13,
    33, 117 or MPO are . CD34 often
  • Negative for Monocytic Ag CD 11b, 14.
  • Ab to MPO Positive.
  • Prognosis Aggressive course

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AML with MATURATION M2
  • Bimodal age presentation.
  • 30-45 of AML
  • Criteria gt20 Blasts in PS/BM, gt10 Neutrophils
    in Diff. Stg of Maturation, lt20 Monocytes.
  • MorphologyBlasts with or without Azurophilic
    granules. Auer rods .
  • Cytogenetics del 12p, t(69) assoc. with BM
    Basophilia. T(816) assoc. with Hemophagocytosis.

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AML with MATURATION M2
  • IPT One or more Myeloid Ag CD13, 33, 15 are .
  • Many express CD117, 34, HLA-DR
  • Prognosis Responds to Aggressive treatment.
    Survival rates vary.
  • t(821)- Favorable prognosis.
  • t(69)- Poor prognosis.

28
AML M3
  • Hypergranular or Typical APL
  • Hypogranular APL.
  • 5-8 of AML, Middle aged Adults.
  • Hypogranular Assoc. with High WBC count
    increased Doubling Time.
  • Morphology FAB-AML-M3.
  • MPO Strongly , NSE weakly in 25.
  • Homogenous CD33, Heterogeneous CD13
  • Sensitive to Rx with ATRA

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31
ACUTE MYELOMONOCYTIC LEUKEMIA (AMMoL) M4
  • 15-25 of AML.
  • All ages, MC in older persons. Few Pts are with
    H/O CMML.
  • Criteria Blasts in PS/BM gt20, Neutrophil
    precursors gt20, Monocytes gt20.
  • Cytochemistry MPO in gt3, NSE .
  • IPT Myeloid markers CD 13, 33, Monocytic
    markers CD14,11b,11c,64,36
  • Prognosis Increased BM Eosinophils are assoc.
    with inv16- Good prognosis.

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33
ACUTE MONOCYTIC LEUKEMIA (AMoL) M5
Morphology Auer rods rare, NSE is Intense
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ACUTE MONOCYTIC LEUKEMIA (AMoL) M5
  • IPT Variable expression of Myeloid markers CD
    13, 33, 117. Monocytic markers are CD 14, 4,
    11b, 11c, 64, 68. CD 34 -Ve.
  • Genetics AMoL with del 11q23 (MLL).
  • t(816)- M5b assoc. with Hemophagocytosis
    Coagulopathy.
  • Prognosis Both types have aggressive clinical
    course.

36
ACUTE ERYTHROID LEUKEMIA M6
37
ACUTE ERYTHROID LEUKEMIA M6
  • Morphology Iron stain shows RS. PAS diffuse
    pattern in Erythroid precursors. MPO/SBB in
    Myeloblasts.
  • IPTMyeloid markers ve.Anti MPO is ve.
    Glcophorin A, Hb-A Ab . Myeloblasts show CD13,
    33, 177 .
  • Genetics No specific
  • Prognosis 6a- Aggressive clinical course.
  • 6b- Rapid clinical course.

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ACUTE ERYTHROID LEUKEMIA M6
  • What to Do?
  • Differential count of all the Nucleated cells to
    be done.
  • If Erythroid precursors are gt50 of the cells
    then……
  • Do Separate DC of all Non-Erythroid cells.
  • If ?20 are Non Erythroid blasts----M6a
  • If lt20 are Non Erythroid blasts---RAEB

41
ACUTE MEGAKARYOCYTIC LEUKEMIA (AMgL) M7
  • 3-5 of cases of AML.
  • gt50 cells in BM are Megakaryocytic lineage.
  • Can present as Denovo, Rx related, Post MPD/MDS.
  • Dry marrow is common, Osteolysis/ osteosclerosis,
    Raised LDH.
  • EM shows Platelet peroxidase .

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43
ACUTE MEGAKARYOCYTIC LEUKEMIA (AMgL) M7
  • IPT Most of Myeloid Lymphoid markers are ve.
    Rarely CD 33, 34.
  • Megkaryocyte lineage markers CD 41, 42b,
    61,Factor VIII related Ag .
  • Genetics t(122)- Infants with Extensive
    organomegaly.
  • Prognosis Downs syndrome do well. Pts with
    Myeloscerosis- Bad. t(122) Poor prognosis.

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AML WITH RECURRENT CYTOGENETIC ABNORMALITIES
  • AML with t(821), (AML1/ETO)
  • AML with inv16 or t(1616) (CBF?/MYH11)
  • AML with t(1517) (PML/RAR?)
  • AML with 11q23 (MLL) abnormalities.

46
AML WITH RECURRENT CYTOGENETIC ABNORMALITIES
  • Mainly Balanced Translocations also are seen
    Inversions and Deletions.
  • Associated with High rate of Complete Response
  • Favorable prognosis
  • Cytogenetics have low sensitivity.
  • Molecular genetics ( RT-PCR) shows high yield.

47
AML with Multilineage Dysplasia
  • AML with gt20 blasts in PS/BM Dysplasia in 2 or
    more cell lines including Megakaryocytes.
  • gt50 cells to show Dysplasia
  • 1. With prior MDS 2. With out Prior MDS
  • These features to be present in Pre Treatment
    specimen.
  • Terminology AML Evolving from a MDS

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AML MDS Therapy related
  • 1. Alkylating agents
  • 2. Topoisomerase II inhibitors
  • Diagnosis is appropriate if Specific morphology,
    Genetic category Therapy is present.
  • ALL can also be seen ( with Topoisomerase II
    Inhibitors)

50
Prognostic Factors in AML-Clinical
51
Prognostic Factors in AML-Morphology
52
Prognostic Factors in AML-IPT, GENETIS
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