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)