ACUTE LEUKEMIAS

ACUTE LEUKEMIAS
• Define : heterogenous group of malignant
disorders which is characterised by
uncontrolled clonal proliferation and
accumulation of blasts cells in the bone
marrow and body tissues
• Sudden onset
• If left untreated is fatal within a few weeks or
months
 ACUTE LEUKEMIAS
• Classification :
– Acute
• Acute lymphoblastic leukemia (T-ALL & B-ALL)
• Acute myeloid leukemia
ACUTE MYELOID LEUKEMIA
 Definition
• Acute myeloid leukemia (AML) is a
heterogeneous group of neoplastic disorders
with great variability in clinical course and
response to therapy, as well as in the genetic
and molecular basis of the pathology.
 Acute Leukaemogenesis

Epidemiological evidence :
1. Hereditary Factors
• Fanconi’s anaemia
• Down’s syndrome
• Ataxia telangiectasia
2. Radiation, Chemicals and Drugs
 ETIOPATHOGENESIS
Others
• Intracellular control of proliferation
(suppressor)
- p53
- IRF1 (Interferon regulatory factor)

• Immune response
- T and B lymphocytes
- NK cells
 Pathophysiology
• Acute leukemia cause morbidity and mortality
through :
– Deficiency in blood cell number and function
– Invasion of vital organs
– Systemic disturbances by metabolic imbalance
 Pathophysiology
Deficiency in blood cell number or function
results in:
• Infection
- Most common cause of death
- Due to impairment of phagocytic function
and neutropenia
 Pathophysiology
Deficiency in blood cell number or function
results in:

Hemorrhage
- Due to thrombocytopenia or 2o
DIC or liver disease
Anaemia
- normochromic-normocytic
- severity of anaemia reflects severity of disease
- due to ineffective erythropoiesis
 Pathophysiology
Invasion of vital organs (brain, lungs) associated with:
1. Hyperleukocytosis:
- causes increase in blood viscosity
- predisposes to microthrombi or acute bleeding

2. Leucostatic tumour
- Rare
- in vascular system forms macroscopic pseudotumour –>
erode vessel wall cause bleeding
 Pathophysiology
Metabolic imbalance:
due to disease or treatment
- Hyponatremia vasopressin-like subst. by
myeloblast
- Hypokalemia due to lysozyme release by
myeloblast
- Hyperuricaemia- spont lysis of leukemic
blast release purines into plasma
 Epidemiology
• 75-80% of acute leukemias
• Incidence: variable (1.8-3/100,000)
• Rare in childhood (10%-15%)
 Differentatial diagnosis
1. Reactive leukocytosis
2. Mononucleosis
3. Blast crisis CML
4. Bone marrow aplasia
5. CLL
 Diagnostic tests
• Anamnesis + physical examination
• Blood test results + manual smear blood
• Blood type
• Biochemical and coagulation test results
• Imaging studies ( usg, chest radiography)
• Lumbar puncture to detect leukaemic cells in the
cerebrospinal fluid, indicating involvement of the
CNS(ALL and AML M4&M5)
+ histopathological examination & flow cytometry
 Diagnostic tests
1. BM aspiration biopsy
a/ ≥ 20% blasts in the smear
b/ cytochemical study( reactions: POX, PAS, esterase, Sudan)
c/ immunophenotyping ( cluster of differentation-CD):
- immune type
- prognostic factors
- MRD
d/ genetic tests:
- cytogenetic (classical, FISH)
- molecular (PCR)
2. Trepanobiopsy (histopathology)
 Clinical symptoms
* anemia- normochromic, normocytic
* granulocytopenia (WBC –high (usually) >200x109/l,
WBC-low (less) <1.0x109/l and presence of blasts
in PB
* thrombocythopenia : <10x109/l

* bleeding disorder
* fewer of unknown origin
* infections
* weakness
 Clinical symptoms
• splenomegaly
• hepatomegaly
• lymphadenopathy
• skin infiltration
• bone pain
• signs of CNS seizure
• metabolic disorders : hypercalcemia, hyperuricemia
• thromboembolic complications
• DIC
Clinical symptoms-leukemic
infiltration in the tissues
Clinical symptoms-bleeding
disorder
 Classification of AML

• FAB classification- based on morphological features,

completed by cytochemistry and
immunophenotyping

• WHO classification
- based on genetic abnormalities
 FAB Classification
M0 minimally differentiated acute myeloblastic leukemia
M1 acute myeloblastic leukemia, without differentation
M2 acute myeloblastic leukemia, with granulocytic maturation
t(8;21)(q22;q22), t(6;9)
M3 promyelocytic, or acute promyelocytic leukemia (APL) t(15;17)
M4 acute myelomonocytic leukemia inv(16)(p13q22), del(16q)
M4eo myelomonocytic together with bone marrow eosinophilia inv(16),
t(16;16)
M5 acute monoblastic leukemia (M5a) or acute monocytic leukemia
(M5b) del (11q), t(9;11), t(11;19)
M6 erythroid leukemia, including erythroleukemia (M6a) and very rare pure
erythroid leukemia (M6b)
M7 acute megakaryoblastic leukemia t(1;22)
M8 acute basophilic leukemia
 WHO Classification
Acute myeloid leukemias with specific genes alterations
AML with t(8;21)(q22;q22)(AML1/ETO)
AML with inv(16)(p13;q22) or t(16;16)(p13;q22)(CBFβ/MYH11)
APL with z t(15;17)(q22;q21)(PML/RARα) and variants
AML with 11q23 (MLL); t(9;11)(p22;q23)(MLLT3/MLL)
AML with t(6;9)(q23;q34)(DEK/NUP214)
AML with inv(3)(q21;q26.2) or t(3;3)(q21;q26.2)(RPN1/EVI1)
Acute megakaryoblastic leukemia with
t(1;22)(p13;q13)(RBM15/1MKL1)
AML with NPM1 mutation
AML with CEBPA mutation
 WHO Classification
II. AML followed by MDS lub MDS/MPD
III. AML associated with the previous treatment
IV. Myeloid sarcoma
V. AML associated with Down syndrome
 Prognostic factors at the time of the
diagnosis
High risk 79% (CR: 40-60%, EFS: 5-10%)
- meet any of the criteria:
* age >60 years old
* severe state at the diagnosis
* secondary AML
* Initial leukocytosis >20G/l
* Unfavorable cytogenetic factors:
11q23, del9q, monosomy 5, 7, del(5q),
del(7q), t(3,3), inv(3), t(6,9), t(9,22), 20q, 21q,
17p, complex karyotype changes ≥ 3
 Prognostic factors at the time of
the diagnosis
Intermediate 16% (CR: 70 - 80%, EFS: 20-40%)

Patients non meeting two other criteria with:

normal karyotype, trisomy +8, +6, +21, +22, del-Y

 Prognostic factors at the time of
the diagnosis
Favorable 5% (CR: 80-90%, EFS: 50-70%)
- meet all of the criteria:
* age <60 years old
* good initial state
* AML de novo
* leukocytosis <20G/l
* favorable cytogenetic alterations:
t(8,21), inv(16), t(16,16), t(15,17), t(11;17), t(15;17), dup(17)
 Management
Supportive care
1.Central venous catheter inserted to :
• facilitate blood product
• adm. of chemotherapy and antibiotics
• frequent blood sampling
 Management
2.Blood support :
• platelet con. for bleeding episodes or if
the platelet count is <10x109/l with fever
• fresh frozen plasma if the coagulation screen
results are abnormal
• packed red cell for severe anaemia
 Management
3.Prevention and control infection
• barrier nursed
• Intravenous antimicrobial agents if there is a
fever or sign of infection
 Specific Treatment
Cytotoxic chemotherapy.
• Aim :
• To induce remission
• (absence of any clinical or conventional
laboratory evidence of the disease)
• To eliminate the hidden leukemic cells
 Specific treatment
• Anti-metabolites
– Methotrexate
– Cytosine arabinoside
• Act: inhibit purine & pyrimidine synt or incorp into DNA
• S/E : mouth ulcer, cerebellar toxicity
• DNA binding
– Daunorubicin
• Act : bind DNA and interfere with mitosis
• S/E : Cardiac toxicity, hair loss
 Specific treatment
• Mitotic inhibitors
– Vincristine
– Vinblastine
• Act : Spindle damage, interfere with mitosis
• S/E : Neuropathy, Hair loss
• Others
– Corticosteroid
• Act : inhibition or enhance gene expression
– Trans-retinoic acid
• Act : induces differentiation
 First step of AML treatment

Remission induction: 1012 of blasts (1kg) -> 109

of blasts (1g)

Complete remission(CR): < 5% blasts in the BM, normal blood test results, no
changes in physical examination

APL : AIDA regimen (Tretynoin + Idarubicin)

Other regimens: DA 3+7 (Daunorubicin + Cytarabin)

PALG: DAC (Daunorubicin + Cytarabin + Cladribine)
 The next steps of AML treatment
Consolidation of remission: 109 of blasts (1g)->
<1012 of blasts (1kg) -> <106 of blasts (1 mg)
Regimens with HD Ara-C

Maintenance
- Elderly patients
- AML associated with low risk of relapse

Transplantation
- Autologous
- Allogenic
ACUTE LYMPHOBLASTIC
LEUKEMIAS
 EPIDEMIOLOGY

● The most common type before the age of 15 and at the same time
represents 76% of all acute leukemias in this age group, peak
disease - 2-5 years (6.2 per 100 000)
● The lowest incidence at age 25-45 years (0.4 per 100 000)
later, steady growth (2.4 per 100 000 - more than 75 years)
● Adult ALL represents about 20% of all types of acute leukemias
Morphology of lymphoblasts
Types L1, L2, L3 acc. FAB
Morphology of lymphoblasts
Types L1, L2, L3 acc. FAB
 The FAB classification

Precursor B ALL Precursor T ALL

Pro-B (pre-pre-B) HLA-DR+CD19+ Pro-T (pre-pre-T) cytCD3+CD7+

Common HLA-DR+CD19+CD10+ Cortical cytCD3+CD1a+

Pre-B HLA-DR+CD19+cytIgM+CD10-/+ Pre-T cytCD3+CD2+ i/lub CD5+

Mature-B HLA-DR+CD19+sIgM+ Mature-T sCD3+

 WHO proposed classification of acute
lymphoblastic leukemia
cytogenetic subtypes
Precursor B ALL
I. ALL with strictly specified genetic abnormalities
t(9;22)(q34;q11.2); BCR-ABL
t(v;11q23); rearangements within MLL
t(12;21)(p13;q22); TEL-AML1
ALL associated with hyperdiploidy
ALL associated with hypodiploidyr
t(5;14)(q31;q32)IL-3-IGH
t(1;19)(q23;p13.3) E2A-PBX1
II. Precursor B ALL non specified
III. Precursor T ALL
 ALL BCR/ABL+
Clinical characteristics:
● ALL BCR/ABL+ -elderly patients

● pre-B with co-expression of CD34, CD13, CD33 >T-ALL (< 1% vs 22%)

● associated with WBC (58,0 G/l vs 49,0 G/l)

● frequent infiltration of CNS (in relapse)

● OS (22% vs 41%)
 MRD investigation in ALL
● MRD (Minimal residue disease) -> only genetic/flow cytometric tests can reveal
the presence of blasts when complete hematological remission was achieved
● Persistent cell blasts can cause leukemia and full relapse (60-70%)

● Other tests:
1. Immunophenotyping - allows the detection of a 1 leukemic cell in 1,000 -10,000
marrow cells (0.1 to 0.01%) and may use two strategies :
- a qualitative study based on the phenotype aberrantny(„quadrans”)
- quantitative study based on a study power of expression of antigens
(„empty spaces”)
2. RQ-PCR - to detect rearrangments within the genes encoding immunoglobulin(B-
ALL), TCR (T-ALL)/ rearrangments in fusion genes like BCR/ABL+
This method allows the detection of a 1 leukemic cell in 100000 - 1 mln of bone
marrow cells (0,001% do 0,0001%)
 Risk in ALL acc. PALG
Standard risk (SR)
Meet all of the criteria:
• Age < 35 years old
• WBC < 30 G/l
• common lub pre-B lub cortical-T
• Ph(-) / BCR/ABL(-)
• t(4;11)(-) / MLL/AF4(-)
• MRD(-) post induction/or consolidation

High risk(HR)
meet only one criteria:
• Age > 35 years old
• WBC > 30 G/l
• pro-B lub mature-B lub pro-T lub pre-T lub mature-T
• Ph(+) / BCR/ABL +)
• t(4;11)(+) / MLL/AF4(+)
• MRD(+) post induction/or consolidation
• no CR after one induction
 Treatment - Induction I

Pre-treatment
Prednisone 60 mg/m2 po (≥ 35 lat: 40 mg/m2); days: -7 do -1

Induction - EVAP
Prednisone 60 mg/m2 po (≥ 35 lat: 40 mg/m2); dni 1 do 28
Vincristin 1,5 mg/m2 (do 2 mg); days: 1, 8, 15, 22
Epirubicin 50 mg/m2 (≥ 35 lat: 40 mg/m2); days: 1, 8, 15, 22
Peg-Asparaginase 1000 IE/m2 ; day 13

3 x lumbar puncture with administration of MTX / Ara-C / Dexa

In case of agranulocytosis – G-CSF

After 34-35 days – control BM biopsy -> clinical response and MRD
 Post remission ALL

Standard risk group

Consolidation
Remission maintenance– evaluation of MRD every 3 months.

High risk group

Patients with donors (related/unrelated) – allo
Patients without donors– auto
Patients with ALL Ph+, without donors– autoBMT with administration of
imatinib and searching for a donor (then alloBMT)
 Novel drugs
Cytostatics
Clofarabine, nelarabine, forodesine

Hypomethylating drugs
Azacytidine, decytabine

Monoclonal antibodies
gemtuzumab (anty- CD33)

TKI
Imatinib, dazatinib, nilotinib, FLT3 inhibitors (ABT-869;
AC 220)

Farnesyltransferase inhibitors
Tipifarnib
Thank you