Definition of Acute

Myelogenous Leukemia

(AML)

• clonal proliferation of abnormal,

neoplastic

cells

(blast

cells),

derived

from

undifferentiated

myeloid precursors, mainly in bone
marrow and peripheral blood

• impaired production of normal

blood cells, resulting in anemia,
neutropenia and thrombocytopenia

Epidemiology of AML

• incidence: 2.3/100 000/per year
• incidence increases with age

(under 65 years - 1.3, above 65
years - 12.2)

• 15-20% of AL in children, 80% of

AL in adults

• more common in men (2.9 vs 1.9)

Clinical features of AML

• fatigue, palpitations, dyspnoe (anemia)
• infections (neutropenia)
• petechiae, epistaxis, prolonged bleeding

after minor cuts (thrombocytopenia)

• splenomegaly and hepatomegaly in 1/3

of pts

• lymphomegaly in monoblastic type
• gingivitis in monoblastic type

Blood and bone marrow

findings in AML

• blood: anemia, thrombocytopenia,

hyperleucocytosis (WBC<5000/ul
in 30% of pts), blasts from 3 to
95% („leukemic break”)

• bone marrow: blast cells

infiltration (20%), decreased or

absent normal hematopoiesis,
dyshematopoietic changes

Cytochemical tests in

AML

• negative PAS reaction
• positive peroxidase reaction
• positive Sudan reaction
• positive non-specific esterase

reaction in monoblastic type

Immunophenotyping in

AML

• detection of characteristic

cytoplasmatic and surface CD
(cluster differentiation) antigens
by flow cytometry with using
of monoclonal antibodies

FAB classification of AML

(1985)

M0 - myeloblastic leukemia minimally

differentiated

M1 - myeloblastic leukemia without maturation
M2 - myeloblastic leukemia with maturation
M3 - promyelocytic leukemia
M4 - myelomonocytic leukemia
M5 - monocytic leukemia
M6 - erythroleukemia
M7 - megakaryoblastic leukemia

Characteristics of M0-M2

acc. FAB

• M0 - large blasts without granules
- POX/Sudan/EST (-)
- CD13+ or CD33 +
• M1 - blasts with rare granules and Auer rods
- POX/Sudan +, EST (-)
- CD13+, CD33+, CD34+, HLA-DR+
• M2 - blasts with common granules and Auer rods
- POX/Sudan ++, EST (-)
- CD13+, CD33+, CD34+, HLA-DR+, CD15+

Characteristics of M3

acc. FAB

• > 50% of hypergranular abnormal

promyelocytes with common Auer rods

• M3v – microgranular variant
• POX/Sudan +++, EST (-)
• CD13+, CD33+, CD15+, HLA-DR(-)
• coagulation disorders associated with DIC and

hyperfibrynolysis

Characteristics of M4-M5

acc. FAB

• M4 - > 20% of myeloblasts and promyelocytes and > 20%
of monoblasts
- POX/Sudan/ +/-, EST +
- CD13+, CD33+, CD15+, HLA-DR+, CD14+,
CD11b+
M4eo – variant with eosinophils > 5%

• M5a - > 80% of monoblasts
M5b - > 80% of promonocytes
- POX/Sudan/ +/-, EST ++
- CD13+, CD33+, CD15+, HLA-DR+, CD14+,
CD11b+

Characteristics of M6-M7

acc. FAB

• M6 - > 50% of erythroblasts, > 20 %

of myeloblasts

- POX/Sudan +/-, EST (-)
- CD33+, HLA-DR+, CD71+,

glycophorin+

• M7 - > 20% of megakaryoblasts
- POX/Sudan (-), EST (-)
- CD33+, HLA-DR+, CD41+, CD61+

Cytogenetic changes in

AML

• Good prognosis
t(15;17), t(8;21), inv(16), t(16;16)
• Intermediate prognosis
normal karyotype, +8, 20q-, -Y
• Poor prognosis
-5, 5q-, -7, 7q-, inv(3), t(6;9),

11q23

WHO classification of

AML (2001)

I. AML with recurrent genetic abnormalities

1. AML with t(8;21)(q22;q22)(CBFα/ETO)
2. AML with abnormal bone marrow eosinophils and
inv(16)(p13;q22) or t(16;16)(p13;q22)(CBFβ/MYH11)
3. Acute promyelocytic leukemia with

t(15;17)(q22;q21)(PML/RARα) and variants

4. AML with 11q23 (MLL) abnormalities

II. AML with multilineage dysplasia
- following MDS
- without antecedent MDS
III. AML therapy-related
IV. AML not otherwise categorized (FAB types)
V. AML biclonal

AML therapy

• The main significance in therapy of AML

has chemotherapy:

- remission induction
- postremission therapy: consolidation,
maintenance
- hematopoietic stem cell transplantation
(autologous, allogeneic)

Remission induction in

AML

• Complete remission (CR):  5% blasts in bone

marrow, lack of blasts in blood, ANC>1.5 G/l,
PLT>100 G/l

• Golden standard: „3+7” (cytarabine+ daunorubicine)
• Three drugs regimens:

Cytarabine+daunorubicine+etoposide

Cytarabine+daunorubicine+fludarabine
Cytarabine+daunorubicine+cladribine
• New drugs: monoclonal antibodies (anty-CD33,

mylotarg)

Treatment of acute

promyelocytic leukemia

(APL)

• Remission induction: AIDA (All

trans retinoic acid - ATRA +
idarubicine)

• Refractory APL: arsenic trioxide,

anti-CD33

Concomitant therapy

• Prophylaxis and treatment of

infections (antibiotics, antifungal
drugs)

• G-CSF
• Prophylaxis of tumor lysis

syndrome: hydratation, allopurinol

• Erytrocytes and platelets

transfusions

Current results of AML

therapy

• CR rate in non-APL: 60-70%, in APL

90%

• Relapse rate in non-APL: 60-70%, in

APL 20%

• 5-year overall survival in APL – 70%
• 5-year overall survival in non-APL

without HSCT 20-30%

• 5-year overall survival in non-APL with

HSCT 60%

Definition of

Myelodysplastic

Syndromes (MDS)

• heterogenous group of clonal

hematopoietic stem cell disorders
characterized by peripheral
cytopenia, dyshematopoiesis in
bone marrow and variable rates of
progression to AML (preleukemia)

Epidemiology of MDS

• incidence: 4.4/100 000/per year
• incidence increases with age (80%

of pts > 60 years)

• more common in men (3.5 vs 1.5)

Clinical and laboratory

features of MDS

• cytopenia in peripheral blood
• dyshematopoiesis in bone marrow
• fatigue, infections, hemorrhage
• lack of splenomegaly,

hepatomegaly, lymphomegaly

Dyshematopoiesis

features in bone marrow

in MDS

• Dyserythropoiesis
megalopoiesis, vacualization, nuclear

fragmentation, ringed sideroblasts (Prussian blue
stain)

• Dysgranulopoiesis
hypo- or hypersegmentation of neutrophils,

Pelger-Huët abnormality, hypo- or
hypergranulation

• Dysmegakaryopoiesis
mega-megakaryocytes with hyperlobulated nuclei,

micromegakaryocytes

Cytogenetic changes in

MDS

• Good prognosis
normal karyotype, 5q-, 20q-, -Y
• Intermediate prognosis
+8, two changes
• Poor prognosis
-7, 7q-, three and more changes

WHO classification of

MDS

1. RA (Refractory anemia)
anemia, blasts in bone marrow <5%
2. RARS (Refractory anemia with ring sideroblasts)
anemia, blasts in bone marrow <5%, ringed sideroblasts 15%
3. RCMD (Refractory cytopenia with multilineage dysplasia
two or three-line cytopenia and dysplasia, blasts in bone marrow <5%
4. RCMD-RS (Refractory cytopenia with multilinege dysplasia with
ring sideroblasts)
two or three-line cytopenia and dysplasia, blasts in bone marrow <5%,
ringed sideroblasts 15%
5. 5q- syndrome
6. RAEB (Refractory anemia with excess of blasts)
I (blasts in bone marrow 5-9%)
II (blasts in bone marrow 10-19%)
7. MDSu (Myelodysplastic syndrome unclassifiable )

5q- syndrome

• macrocytic anemia
• thrombocytosis
• dysmegakaryopoiesis in bone marrow

(hypolobated micromegakaryocytes)

• isolated 5q-
• older females predominance
• low rate of transformation to AML,

favorable prognosis

Treatment of MDS

• Young patients (< 55-60 years) –

allogeneic bone marrow
transplantation

• Older patients
- with good prognosis – non-

cytostatic therapy

- with poor prognosis –

chemotherapy

Non-cytostatic therapy in

MDS

• All trans retinoic acid – ATRA (Vesanoid)
• Amifostine (Ethyol)
• Thalidomide, lenalidomide (Revlimid)
• Arsenic trioxide
• Antilymphocytic serum
• Erythropoietin, G-CSF
• Blood transfusions
• Iron chelatation

Chemotherapy in MDS

• Low dose cytarabine
- monotherapy
- with ATRA, etoposide,

mitoxantrone

• Hypometylating drugs
5-azacytidine (Vidaza)
5-aza-2’-deoxycytidine (Decitabine)