ACUTE LEUKEMIAS

(AML & ALL)

YEAR III HEMATOLOGY LECTURE SERIES

AAU, CHS, SOM
April 2022
 outline
• Introduction
• Epidemiology
• Classification
• Etiology
• Pathogenesis
• Clinical Presentation
• General Treatment Approach
• AML
• ALL
 Introduction
• Acute Leukemia (AL) is a clonal neoplastic disorder
characterized by the proliferation & accumulation
of immature and malignantly transformed cells in
the BM and PB.
• The abnormal cells replace the normal BM tissue.
• The result is abnormal /insufficient hematopoiesis.
– Anemia
– Thrombocytopenia
– Leukocytosis/leukopenia
• Infiltrate other organ tissues
 Introduction...

• Acute vs Chronic
• Acute leukemia
– Abrupt onset on symptoms
– % of blasts/ immature cells in the BM/PB smear
• FAB definition = >30% blasts
• WHO = >20% blasts
– Exceptions
• Specific cytogenetics regardless of blast %
– E.g – t(15:17) in AML-M3 ( APL), CBF AML
 Introduction...
• Acute Leukemia is basically one of the two
types
– Acute Myelogenous Leukemia(AML)
– Acute Lymphoblastic Leukemia(ALL)
• Other very rare variants of AL
• Acute leukemias of ambiguous lineage
- Acute undifferentiated leukemia
- Mixed phenotype acute leukemia (MPAL)
(B/Myeloid, T/Myeloid …)
• Acute leukemia can be
– De novo
– Secondary/ transformed

• Distinction b/n AML & ALL should be the first

step in the diagnosis and management.
 Epidemiology
Rare disease but has huge impact on cancer
survival statistics
The annual incidence of AML( in Western pop)
 3.6 cases/100,000
 80% of AL
 About 3000 cases/year in Ethiopia
The annual incidence of ALL
 1.4 cases/100,000
 20% of AL
 ≈ 750 cases/year in Ethiopia
The incidence of AML
 Increases with age
 Median age at presentation is 60-65yrs
 Epidemiology...
• The peak incidence of ALL
– 3-4yrs of age
– Incidence decreases after 9yrs of age
– Rare after 40
• Sex distribution
– M:F in AML = 1.3:1
– M:F in ALL = 1.5:1
• The relative frequency of the 4 leukemias
– ALL (11%) AML (46%)
– CLL (29%) CML (14%)
 Classification of AL
• The classification is based on biological
features
– Clinical feature
– Morphology based on Wright or Giemsa stain
– Cytochemical studies
– Flowcytometry
– Cytogenetic or molecular study
 Classification of AL...
• French-American and British(FAB)
– Based on morphology & cytochemical studies
– ALL into L1-L3
– AML into M0-M7
– Clinically applicable
• Immunological classification
– Specially for ALL into the different stages of B-Cell
& T-Cell groups
• WHO classification
– For all hematological malignancies
– Cytogenetic studies included
 Etiology in Acute Leukemias(AL)
• Most Acute leukemia are sporadic
– Acquisition of somatic mutation in hematopoietic
progenitors
• Usually not possible to identify a cause
• Valuable clues from
– Rare heritable leukemia
– Cases related to specific environmental exposure
• Variable latency following exposure to
causative agent
• Genetic Polymorphism
 Etiology in AL...
• Chemical exposure
– Benzene
– Other petroleum products & others
• Ionizing Radiation
• Virus
– HTLV-1
– EBV
• Therapy Related (chemotherapy)
– Alkylating agents
– DNA topoisomerase inhibitors
• Anthracyclins( doxorubicin)
• Epipodophyllotoxins( etoposide)
– Autologous stem cell transplantation
– ? Hematopoietic growth factors
 Etiology in AL...
• Antecedent Hematological Disorders
– Myeloproliferative Disorders
– Myelodysplastic Syndromes(MDS)
– Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Familial Leukemias
– Down’s Syndrome ( trisomy 21)
– Trisomy 8
 Etiology in AL...
• Familial Disorders leading to Leukemias
• Defective DNA repair syndromes
– Bloom’s Syndrome
– Fanconi’s Anemia
– Neurofibromatosis
– Li-Fraumeni Syndrome
– Wiskott-Aldrich Syndrome
– Blackfan-Diamond Syndrome
– Kostmann’s Syndrome ( Infantile Agranulocytosis)
 Pathogenesis
• Single cell of origin of Acute leukemia
– Leukemic Stem Cell
– Clonality
• Like other human malignancies, in AL one or
more of the following somatic mutation and
genetic abnormalities are involved
– Oncogene mutations (Proto-oncogenes)
– Tumor Suppressor gene mutation
– General Genomic instability
• Multistep and multicausal
 Pathogenesis...
• Two –hit hypothesis
– Mutations giving proliferative& survival advantage
– The next step is impairing differentiation
• The two models for the explanation of
heterogeneous groups in AL
– Transformation at one of the several developmental
stages
– Transformation within the primitive multipotent
progenitor cells
• Specific or recurrent genetic abnormalities
leading to certain leukemia types
 Clinical Features of AL
• Certain features are specific to the AL type
– Coagulation abnormality in AML –M3
– Gingival hypertrophy in AML – M4 & M5
• Family history of malignancy
• History of predisposing factors
– Radiotherapy
– Chemotherapy
– Nuclear disasters and survivors
 Clinical Features of AL

• Acute Leukemia presents acutely

– Exception- transformed/secondary AL

• In general patients manifest signs & symptoms

related to
– Abnormalities of the 3 blood cell lines
– Infiltration of organs & tissues
– Metabolic abnormalities related high cell turn
over
 Symptoms of AL

Sxs of anemia
Sxs of thrombocytopenia
Fever
 High grade due to infections
 Low grade with systemic sxs due to the leukemia
 Symptoms of AL

Sxs due to CNS involvement

 Seizure, headache, cranial nerves dysfunction
 Vomiting, blurring of vision, altered mentation
Abdominal fullness & other GI sxs due to
organomegaly and electrolyte disturbance
Oliguria
 Signs of AL
• Pallor
• Bleeding
– Mucocutaneous
– DIC
• Fever and other signs of infection accordingly
 Signs ...
• Signs of tissue or organ infiltration
– Gingival hyperplasia
– LAP
– Hepatosplenomegaly
– Bone(sternal tenderness)
– Chloromas
– Leukemic cutis
– Cranial nerve palsies
– Meningeal irritation signs
• Extramedullary disease
• Prominent LAP & signs of mediastinal LAP
 Investigation in AL
• After complete history & P/E
• CBC, differential, platelets, ESR, Blood group
• Serological screening ( HIV, HBV, HCV, CMV...)
• Examination of peripheral smear
• BM aspiration & biopsy
– Morphology
– Flowcytometry
– Cytochemical studies
– Cytogenetic study
– Molecular study
 Investigation in AL...
• CXR
• Coagulation profile
• Biochemical tests
– Liver & renal functions
– Serum electrolytes
– Uric acid
– Serum LDH
– Serum lysozymes
• Blood and other specimen for culture
 Investigation in AL...
• LP
• CT Scan
• HLA TYPING
• Cardiac function ( ECG, ECHO)
 DDX
MDS
Aplastic Anemia
Infectious Mononucleosis ( LAP & atypical
lymphocytes)
BM failure syndromes & infiltration
Severe infection with leukocytosis & shift
( Leukomoid reaction)
Aggressive & very aggressive NHL
ITP
 Treatment
Requires comprehensive team & good setup
Starts with the confirmation of specific AL dx
& prognostication.
In general has 2 important components
 Supportive
 Specific/ Definitive
Certain parameters/ goals related to specific
therapy
 Remission ( CR, PR)
 Survival (leukemia free, overall , relapse free )
 Cure
 Supportive Care
Fluid & electrolyte management
Blood component therapy
 Packed red cells transfusion
 Platelet transfusion
Treatment of infection
 Broad spectrum IV antibiotics(
empiric/emergency)
 culture and other studies
Prevention of uric acid nephropathy & tumor
lysis syndrome
 hydration
 Allopurinol & other agents
 Supportive Care
Recombinant growth factors (GM-CSF, G-CSF,
EPO, IL-11, Thrombopoietin)
Hyperleukocytosis/hyperviscosity, leukostasis
 Associated with various complications
 Leukopheresis
 Emergency irradiation of whole-brain
 Adminstration of drugs for cytoreduction
Hydroxyurea, steriods
Early dx & Rx of coagulation abnormality
Reverse-barrier ( reverse – isolation)
 Supportive Care
• Vascular access
• Birth control and fertility advice
• Treatment of comorbid conditions
• Psychosocial support
 Specific Treatment
• Chemotherapy
– Specific regimen of the AL types
– Phases
• Remission Induction
• Postremission
• Hematopoietic Stem Cell Transplantation
– Allogeneic-SCT
– Syngeneic-SCT
– Autologous-SCT
• Investigational Therapy
– Clinical trails
ACUTE MYELOGENOUS
LEUKEMIA
GENERAL REMARKS
CLASSIFICATION
TREATMENT
 General remarks about AML
• A complex disease
• Heterogenous group
– Phenotypically
– Genotypically
• More than 100 recurrent cytogenetic
abnormalities.
• Patients die of leukemia or Rx complication
• Still a challenge both clinically & in genetic
study
• Certain groups with excellent prognosis
 Classification
• FAB
– Based on morphology & cytochemical studies
– Blast % in the BM for Dx
– Simple & still in wide clinical use but does not
incorporate the recent advances in molecular
study
• WHO
– Comprehensive
– Detail molecular and cytogenetic studies
– Currently not universally applicable
FAB DESCRIPTION %

M0 AML, minimally differentiated 3

M1 AML without maturation 19

M2 AML with maturation 32

M3 Acute Promyelocytic Leukemia 7

M4 Acute Myelomonocytic Leukemia 23

M5 Acute Monoblastic Leukemia 12

M6 Acute Erythroleukemia 3

M7 Acute Megakaryoblastic Leukemia 0.3

 Specific Rx for AML
Chemotherapy
 Remission induction
7+3 regimen ( cytarabine + daunorubicin/doxorubicin)
Alternative ( cytarabin + Idarubicin + etoposide)
Elderly patients – modification
Double induction
 Postremission therapy
The best regimen not yet settled
Consolidation/Intensification chemotherapy
Allo-SCT
Auto-SCT
BM transplantation
 Specific Rx for AML...
CNS prophylaxis or Rx
 M4 & M5
Relapsed and refractory AML
 Early vs late relapse
Treatment of M3(APL)
 Special entity(t(15;17)) & Favourable outcome
 All- Trans-Retinoic Acid(ATRA) with other chemo
 Maintenance therapy
 Arsenic TriOxide(ATO)
Treatment of secondary/ therapy related AML
FAVORABLE UNFAVORABLE
Age <50 Age >60
Karnofsky score >60 percent Karnofsky score <60 percent
CD34-negative phenotype CD34-positive phenotype
MDR 1-negative phenotype MDR 1-positive phenotype
WBC <30,000/µl WBC >30,000/µl
No antecedent hematologic Therapy-related AML, prior myelodysplastic
disorder or prior syndrome, myeloproliferative or other
chemo/radiotherapy hematologic disorder

t(8;21), inv(16)/t(16;16), t(15;17) Complex karyotypic abnormalities, -5, -7,

3q26 aberrations, t(6;9), 11q23 aberrations
except for t(9;11), "monosomal karyotype"
NPM1 mutation, CEBPA mutation FLT3/ITD mutation, MLL partial tandem
duplication, BAALC overexpression
ACUTE LYMPHOBLASTIC
LEUKEMIA (ALL)
GENERAL REMARKS
CLASSIFICATION
TREATMENT
 General remarks about ALL
ALL is a malignant d/s characterized by
accumulation of lymphoblasts.
Different treatment outcomes in children &
adults. Cure rate
 Children 2/3
 Adults 1/3
Reason for poor outcome in adults with ALL
 High rate of adverse prognosis(Ph-chromosome)
 high degree of toxicity with the drugs
 Different pharmacodynamics
Much less heterogeneous in general and less
common ( 20% of AL) in adults
• Stratification of patient into high- risk & low-
risk is required to select therapy
– More intensive chemotherapy
– Stem cell transplantation
• CNS involvement and relapses are the features
 Classification of ALL
FAB classification of ALL
 L1, L2, L3
 Based on the morphology of lymphoblasts
 Less relevant in predicting outcome
Immunological classification of ALL
 Based on cell marker and other studies
 B or T cell variant with their stage of development
 Comprehensive
 Relevant in predicting outcome
• FAB Classification for ALL
– L1
– L2
– L3
 Immunological Classification of ALL
Children(%) Adults(%)
B-Lineage
Precursor B ( Pro-B ALL) 5 11

Common ALL 65 51
Pre-B ALL 15 10
Mature B-ALL 3 4

T-Lineage

Early T (T-Precursor) ALL 1 7

Cortical ( Thymic) T-ALL

Mature T-ALL 11 17
 Specific Treatment in ALL
• Chemotherapy
– Several phases
• Remission Induction
• CNS prophylaxis or Treatment
• Consolidation/Intensification
• Maintenance
– Upfront cytoreduction
• Cyclophosphamide and steriods
– 75-85% of adults achieve Complete Remission
 Specific Treatment in ALL
• Consolidation/ Intensification
– Difference b/n consolidation & intensification
– Early intensification
• Maintenance
– Continues for upto 22months
– Monthly pulse doses (Dexa + Vincristine)
– Methotrexate /wk + 6-mercaptopurine/d (orally)
 Specific Treatment in ALL
• Remission Induction
– 4-6 weekly cycles with the aim of CR
– Vincristine + Predinsolone + daunorubicin
– +/- L-Asparaginase
• CNS prophylaxis or Treatment
– Intrathecal(cytarabin,Methotrexate, hydrocortisol)
– High dose systemic chemo
– Cranial Irradiation
 Adverse Prognostic Factors for Remission Duration in
Adult ALL
Clinical characteristics Higher age >50 yrs, >60 yrs

High WBC >30000/µL in B-lineage

Immunophenotype Pro B (B-lin., CD10-)

Early T (T-lin., CD1a-, sCD3-)

Mature T (T-lin., CD1a-, sCD3+)

Cytogenetics/molecular t(9;22)/BCR-ABL or t(4;11)/ALL1-AF4

genetics

Treatment response Late achievement of CR >3 or 4 weeks

MRD positivity
 Specific Treatment in ALL
• Stem Cell Transplantation
– Philadelphia Chromosome
– Reserved for relapse or refractory ALL
– Types
• Allo-SCT
• Auto-SCT
• MUD & NMSCT
Thank you!