This document discusses acute leukemia, including definitions of blast cells, leukemia, and the differences between lymphoid and myeloid cells. It covers the pathophysiology of acute leukemia, techniques for diagnosis, classifications of acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML), treatment approaches, and prognosis. Key points include that ALL is most common in children while AML is more common in adults, cytogenetics help determine prognosis and treatment for both, and the cure rate for ALL can be as high as 90% in children but only 30% in adults.

1. ACUTE
LEUKEMIA
Justiniano Castro MD

2. BLAST CELL: DEFINITON

Blast cells are immature cells found in the bone
marrow. They are not fully developed, and
therefore, do not carry out any normal function
in the blood. More than 5% of these cells in the
bone marrow is abnormal and need to be
evaluated for the possibility of a malignant
disorder of the hematopoietic system.

3. LEUKEMIA: DEFINITION

Leukemia is a malignant clonal condition of the
bone marrow and blood. It is characterized by
the acumulation of blast cells in the marrow,
usually more than 20%. These blast cells are
frequently seen in the peripheral blood.

5. LYMPHOID VS. MYELOID
CELLS
Immature lymphoid cells have minimal
differentiation
 Myeloid blast has some differentiation
 Cytoplasmic granules in myeloid cells (auer
rod)
 Cytochemical stains (mpo and pas)
 Immunological markers, Ig and TCR


6. Figure 1. Arrow marks an Auer rod in this myeloid blast
Maslak, P. ASH Image Bank 2004;2004:101101
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

7. Figure 1. Blasts may appear "rounded" or "regular" with scant cytoplasm
Maslak, P. ASH Image Bank 2005;2005:101390
Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

8. PATHOPHYSIOLOGY OF AL

Leukemias typically fill up the marrow with abnormal
cells, displacing normal hematopoiesis. The marrow here
is essentially 100% cellular, but composed almost
exclusively of leukemic cells. Normal hematopoiesis is
reduced via replacement (a "myelophthisic" process) or by
suppressed stem cell division. Thus, leukemic patients are
prone to anemia, thrombocytopenia, and
granulocytopenia and all of the complications that ensue,
particularly complications of bleeding and infection.

Bone marrow failure secondary to leukemic infiltration
producing anemia, neutropenia and thrombocytopenia

Maturation arrest and lineage infidelity

Chromosomal abnormalities involving oncogenes and
tumor suppressor genes

9. TECHNIQUE FOR ACUTE
LEUKEMIA DIAGNOSIS
Morphologic features
 Cytochemical stains
 Flow cytometry and markers
 Chromosomal analysis
 Fluorescence In Situ hybridization (FISH)
 PCR (polymerase chain reaction)


10. ACUTE LYMPHOBLASTIC
LEUKEMIA
This a clonal disorder of hematopietic cells
 There is accumulation of immature cells
and tissue infiltration.
 Risk factors (chemicals, family history,
radiation and chemotherapy)


11. Figure 2. A high power view reveals coarse chromatin with an irregular nuclear contour
Maslak, P. ASH Image Bank 2007;2007:6-00053
Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

12. Figure 11. Blasts have scant cytoplasm
Maslak, P. ASH Image Bank 2004;2004:101018
Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

13. ACUTE LYMPHOBLASTIC
LEUKEMIA
Accumulation of lymphoblast
 Most common in children and better
prognosis than adults (3-7years)
 Disease in children is different than the
adults
 Rise incidence after 40 years with a very
poor prognosis


14. CLASSIFICATION: ALL B VS.
T
•
Precursor
B
cell
lymphoblastic
leukemia/lymphoma, also called precursor B
cell acute lymphoblastic leukemia (precursor B
cell ALL)
•
Precursor
T
cell
lymphoblastic
leukemia/lymphoma (precursor T-LBL), also
called precursor T cell acute lymphoblastic
leukemia (precursor T cell ALL)

15. CLASSIFICATION OF ALL
 FAB
(L1, L2 and L3)
 Immunological (B vs. T lineage)
 B cell 80% of all ALL. Tcell 20% of all
ALL.
 B cell precursor ALL (80% ALL)
 CD10,CD19,CD20
and CD22) markers
 Early pre-B, CD10 neg (infant). Usually CD34+
 Pre-B, CD10+ (common ALL)
 B-ALL (Burkitt’s type or L3, large vacuole and
surface immunoglobulin). Its now consider a
lymphoma
 T-cell
ALL (TdT, CD3, CD5 and CD7)

16. DIAGNOSIS OF ALL
 Peripheral
smear with blast cells
 Bone marrow with >20% of blasts
 Immunophenotype
B
vs. T cell, markers
 Help to differentiate from myeloid
 Chromosomal
analysis (Hyper
vs.hypodiploidy, t(9;22) or Ph+,
t(4;11), t(v;11q23),t(12;21) and t(1;19))

17. SPECIAL TEST IN ALL
Due to high incidence of CNS involvement a
lumbar puncture is usually required and
intrathecal treatment
 CT’s Scan for T cell and Burkitt
 Testicular us
 Tumor lysis syndrome


18. CYTOGENETICS IN ALL
Philadelphia Chromosome present in 30% of
adult ALL with a very poor prognosis.
 T(4;11) association with secondary leukemia
 T(v;11q23),t(12;21) and t(1;19)
 TEL and AML1 genes are present in 30% of
childhood ALL and is associated with a good
proognosis.
 Tyrosine Kinase inhibitors are included in
treatment strategies


19. TREATMENT OF ALL
 Cytotoxic
chemotherapy include
induction, consolidation,
intensification and maintenance
 Complete response after induction is
80%
 Cure 35-40% in the adult population
 T cell and L3 ALL require special
consideration
 Response and cure in children could
be as high as 90%

20. PROGNOSIS IN ALL
 Cure
rate of 75-90% in children’s
 Cure rate in adults of 30%
 CD10 negative ALL has worse
prognosis
 A presentation with a WBC >
30,000/m3 is associated with a poor
prognosis
 Cytogenetics
 Slow response to induction is
considered a poor prognosis feature

21. SUPPORTIVE CARE IN
AL
Blood
products
Hydration and treatment
with allopurinol
Prevention of N/V
Aggressive antibiotic cover
Central line catheters

22. SALVAGE THERAPY IN
AL
Bone
marrow transplant
Cord Blood Transplant
Experimental treatment

23. ACUTE
MYELOGENOUS
LEUKEMIA

24. CLINICAL OVERVIEW
Acute myeloid leukemia (AML) is the most common acute
leukemia in the adult
 AML is cancer of the blood-forming tissue (bone marrow).
 Normal bone marrow produces red cells, white cells, and
platelets.
 AML causes bone marrow to produce too many immature
white blood cells (blast cells) .
 Suppresses normal blood cell production.
 Anemia, leucopenia, thrombocytopenia


25. RISK FACTORS

Age


Older adults are more likely to develop AML
Smoking
20% of AML cases are linked to smoking
 Doubles the risk of disease in people > 60 y/o


Genetic disorders


High doses of radiation


Long-term survivors of atomic bombs
Previous chemotherapy treatment


Down syndrome, Fanconi’s anemia
Breast cancer, ovarian cancer, lymphoma
Exposure to industrial chemicals

Benzene long term exposure

26. STATISTICS
Incidence:
3-5 new cases expected per 100,000 population
Mortality:
8,900 estimated deaths/year M:54%, F:46%
Prognosis:
5-year survival rate in adults under 65 is 33%
Prognosis:
5-year survival rate in adults over 65 is 4-5%
Prognosis:
20-30% experience remission or are cured
Sources: American Cancer Society; The Leukemia & Lymphoma Society,

27. CLINICAL FEATURES
OF
AML
 Bone
marrow failure
 Coagulopathy (DIC) specially in
APL
 Tumor infiltration of monocytic
leukemia
 Tumor lysis syndrome specially
with the initial chemotherapy

29. CLASSIFICATION BY FAB

Mo

Undifferentiated(5%)
M1 no maturation(20%)
 M2 maturation(30%)
 M3 Promyelocytic (7%)
 M4 myelomonocytic
 M5 monocytic

M6 Erythroleukemia
(very rare)

M7 Megakarioblast
(very rare)

30. AML BLAST WITH AUER ROD

31. THE WHO
CLASSIFICATION
Reduce
the percentage of
blast to 20%
Emphasis in the Cytogenetic
characteristics
Recognize therapy related
leukemia's
Recognize AML from
previous Myelodyplasia

32. CYTOGENETIC IN AML
 Good
prognostic
group
T(15;17)
T(8;21)
Inv (16)
(p13q22) with
eosinophilia
Poor prognostic
group
Deletion of
chromosome 5/7
t(11;q23)
t(6;9)
+8
Complex
rearrangement

33. CYTOCHEMICAL STUDIES
AND MARKERS
 MPO
or Sudan black
 Nonspecific esterase
 Periodic Acid Shift (PAS)
 Markers CD13, CD33 an CD15 are
only helpful for diagnosis of AML

34. AML – PEROXIDASE
STAIN
 Blast
with + MPD

35. Acute Myelogenous Leukemia M2
 T(8;21)
(q22;q22) RUNX1-RUNX1T1
(TEL and AML1 genes)
 Constitute 7% of AML
 Auer rods are easily identified and
cytoplasm is generally basophilic
 Favorable prognosis in adults but not
in children

36. Myeloid maturational arrest is demonstrated in this image, AML M2

38. ACUTE MYELOGENOUS
LEUKEMIA M4
 Approximately
20% of AML but 5% of
them are AML M4 with eosinophilia
and inv(16)
 Mixture of blast with myeloid and
monocytic features
 Better prognosis with the inv(16)
expression.

39. The dysphasic eosinophil precursors , AML M4 inv(16) eos

40. ACUTE PROMYELOCYTIC
LEUKEMIA
DIC very frequent
 t(15;17) is present in almost every case
 RAR gene present in chromosome 17
juxtaposition with PML gene in chrom 15
producing a maturation arrest
 All transretinoic acid (ATRA) induce maturation


41. AML M3 FAGGOT

42. Cells with multiple Auer rods (arrow) may be appreciated AML M3

43. ACUTE PROMYELOCYTIC
LEUKEMIA
 Retinoid
acid syndrome is
associated with an increase in WBC
counts with respiratory problems,
fever and hypotension
 Arsenic trioxide is active in this
leukemia
 Antracyclines are essential in the
treatment

44. Proliferation: FLT3, Normal
Cytogenetics



A receptor tyrosine
kinase expressed in 70 –
100% of AML cases.
Activating mutations in
FLT3 are seen in ~30%
of AML cases.
 Tandem duplication
of the
juxtamembrane
region.
 Point mutation
within the activation
loop of the kinase
domain.
Activation of FLT3
leads to deregulated
proliferation of AML
cells.

45. MANAGEMENT OF
AML
Supportive treatment similar to all AL
 AML M3 need special attention to DIC
 Monocytic leukemia's can infiltrate CNS,
gingival and skin
 Induction chemotherapy produce 70% CR
 Usually 3 consolidation treatments
 Cure between 35 to 40% of the patients
 MUGA scan is necessary as one of the initial
test for evaluation of cardiovascular
function


46. SALVAGE TREATMENT IN
AML
Allogeneic
BMT can cure high
risk and relapse AML
Monoclonal antibodies
Experimental therapy

47. MYELODYSPLASTIC
SYNDROME
A
heterogeneous group of
hematopoietic disorders
characterized by peripheral blood
cytopenias and hypercellular marrow
 Clonal malignant disorder of the
hematopoietic cells
 Transformation to AML is frequent

48. FAB CLASSIFICATION IN
MDS
 Refractory
 Chronic
anemia
 RA with ring
sideroblast
 RA excess of
blast
myelomonocytic
leukemia
 RA with excess
of blast in
transformation
(RAEBT)

49. MDS WITH DYSERYTHROPOIESIS

50. Figure 7. Refractory anemia with ringed sideroblasts (RARS)
Vardiman, J. W ASH Image Bank 2001;2001:100189
Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

51. WHO CLASSIFICATION OF MDS
RA
 RARS
 Refractory anemia with multilineage dysplasia
(RCMD)
 RAEB
 5q- syndrome
 Unclassifiable


52. Figure 9. Refractory cytopenia with multilineage dysplasia (RCMD)
Vardiman, J. W ASH Image Bank 2001;2001:100188
Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

53. PROGNOSIS OF MDS
Presence of blast indicate poor prognosis
 Uniformly fatal disorder due to infection and
bleeding
 Chromosomal abnormalities are frequent
including partial loss of chromosome 5, 7 and
trisomy 8
 5q- syndrome usually involve band q13 to q33
with anemia but no thrombocytopenia
 The International Prognostic Index ( % blasts
cells, cytogenetic and number of cytopenias)


54. PATHOGENESIS OF MDS
Toxic exposure and genetic predisposition
 Immune response
 Hypermethylation and angiogenesis
 RAS mutation as a late effect
 Transformation


55. TREATMENT OF MDS
BY RISK
STRATIFICATION
Cytogenetics
 Blast %
 No. cytopenias

Antiangiogenic
Factor( Lenalidomi
de and thalidomide)
 Hypomethylating
agents Azacytidine
and dezacitidine)
 Bone Marrow
Transplantation
