Introduction Epidemiology Classification Etiology Pathogenesis Clinical Presentation General Treatment Approach AML ALL

1. ACUTELEUKEMIAS
ACUTEMYELOGENOUSLEUKEMIA-AML
ACUTELYMPHOBLASTICLEUKEMIA-ALL

2. outline
• Introduction
• Epidemiology
• Classification
• Etiology
• Pathogenesis
• Clinical Presentation
• General Treatment Approach
• AML
• ALL

3. 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

4. Introduction...
• AL is basically one of the two types
– Acute Myelogenous Leukemia(AML)
– Acute Lymphoblastic Leukemia(ALL)
• Other very rare variants of AL
– Biphenotypic Leukemia
– Bilineage Leukemia
– Other rare variant in WHO classification
• AL can be
– De novo
– Secondary/ transformed
• Distinction b/n AML & ALL should be the first step in the diagnosis and
management.

5. 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
 The annual incidence of ALL
 1.4 cases/100,000
 20% of AL
 The incidence of AML
 Increases with age
 Median age at presentation 60-65yrs

6. 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%)

7. Classification of AL
 The classification is based on biological features
 Clinical feature
 Morphology based on Wright or Giemsa stain
 Cytochemical studies
 Electron Microscope
 Flowcytometry
 Cytoplasmic markers
 Cytogenetic or molecular study
 Microarray analysis

8. Classification of AL...
 French-American and British(FAB)
 Based on morphology & cytochemical studies
 ALL into L1-L3
 AML into M0-M7
 Immunological classification
 Specially for ALL into the different stages of B-Cell & T-Cell groups
 WHO classification
 For all hematological malignancies
 Cytogenetic studies included
 Comprehensive but not applicable in all setting

13. Etiology in Acute Leukemias(AL)
• Most AL sporadic
– Acquisition of somatic mutation in hematopioetic progenitors
• Usually not possible to identify a cause
• Valuable clues from
– Rare heritable leukemias
– Cases related to specific environmental exposure
• Variable latency following exposure to causative agent
• Genetic Polymorphism

14. 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

15. Etiology in AL...
 Antecedent Hematological Disorders
 Myeloproliferative Disorders
 Myelodysplastic Syndromes(MDS)
 Paroxysmal Nocturnal Hemoglobinuria (PNH)
 Familial Leukemias
 Down’s Syndrome ( trisomy 21)
 Trisomy 8

16. 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)

17. Pathogenesis
 Single cell of origin of AL
 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

18. Pathogenesis...
• Two –hit hypothesis
– Mutations giving proliferative& survival advantage
– The next 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

19. Clinical Features of AL
 AL 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
 Certain features are specific to the AL type
 Family history of malignancy and history of predisposing factors should be
looked for.

20. Symptoms of AL
 Sxs of anemia
 Sxs of thrombocytopenia
 Fever
 High grade due to infections
 Low grade with systemic sxs due to the 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

21. Signs of AL
 Pallor
 Bleeding
 Mucocutaneous
 DIC
 Fever and other signs of infection accordingly

22. Signs ...
 Signs of tissue or organ infiltration
 Gingival hyperplasia
 LAP
 Hepatosplenomegaly
 Bone(sternal tenderness)
 Chloromas
 Leukemic cutis
 Cranial nerve palsies
 Mengeal irritation signs
 Extramedullary disease
 Prominent LAP & signs of mediastinal LAP

24. Investigation in AL
 Complete history and physical examination
 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

25. 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

26. Investigation in AL...
 LP
 CT Scan
 HLA TYPING
 Cardiac function ( ECG, ECHO)

27. 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 survival, relapse )
 Cure

28. 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

29. 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)

30. Supportive Care
 Vascular access
 Birth control and fertility advice
 Treatment of comorbid conditions
 Psychosocial support

31. 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

32. DDX
 MDS
 Aplastic Anemia
 Infectious Mononucleosis ( LAP & atypical lymphocytes)
 BM failure syndromes & infiltration
 Severe infection with leukocytosis & shift
 Aggressive & very aggressive NHL
 ITP

33. ACUTE
MYELOGENOUS
LEUKEMIA
GENERAL REMARKS
CLASSIFICATION
TREATMENT

34. 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

35. 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

36. 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

45. AML WITH
RECURRENT
GENETIC
ABNORMALITY
AML with t(8;21)(q22;q22), (AML1/ETO)
AML with abnormal bone marrow eosinophils and
inv(16)(p13q22) or t(16;16)(p13;q22), (CBF/MYH11)
Acute promyelocytic leukemia with t(15;17)(q22;q12),
PML/RAR-alpha and variants
AML with 11q23 (MLL) abnormalities
AML WITH
MULTILINEAGE
DYSPLASIA
Following MDS or MDS/MPD
Without antecedent MDS or MDS/MPD, but with dysplasia in at
least 50 percent of cells in two or more myeloid lineages
AML &MDS,
THERAPY
RELATED
Alkylating agent/radiation-related type
Topoisomerase II inhibitor-related type
Other

46. AML, NOT
OTHERWISE
CATEGORIZED
AML, minimally differentiated
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/acute monocytic leukemia
Acute erythroid leukemia (erythroid/myeloid and pure
erythroleukemia variants)
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma

47. AML WITH
RECURRENT
GENETIC
ABNORMALITY
AML with t(8;21)(q22;q22), (AML1/ETO)
AML with abnormal bone marrow eosinophils and
inv(16)(p13q22) or t(16;16)(p13;q22), (CBF/MYH11)
Acute promyelocytic leukemia with t(15;17)(q22;q12),
PML/RAR-alpha and variants
AML with 11q23 (MLL) abnormalities
AML WITH
MULTILINEAGE
DYSPLASIA
Following MDS or MDS/MPD
Without antecedent MDS or MDS/MPD, but with dysplasia in at
least 50 percent of cells in two or more myeloid lineages
AML &MDS,
THERAPY
RELATED
Alkylating agent/radiation-related type
Topoisomerase II inhibitor-related type
Other

48. AML, NOT
OTHERWISE
CATEGORIZED
AML, minimally differentiated
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/acute monocytic leukemia
Acute erythroid leukemia (erythroid/myeloid and pure
erythroleukemia variants)
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma

49. 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

50. 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

51. Karnofsky score >60 percent
CD34-negative phenotype
MDR 1-negative phenotype
WBC <30,000/µl
No antecedent hematologic
disorder or prior
chemo/radiotherapy
t(8;21), inv(16)/t(16;16),
t(15;17)
NPM1 mutation, CEBPA mutation
Karnofsky score <60 percent
CD34-positive phenotype
MDR 1-positive phenotype
WBC >30,000/µl
Therapy-related AML, prior
myelodysplastic syndrome,
myeloproliferative or other hematologic
disorder
Complex karyotypic abnormalities, -5, -
7, 3q26 aberrations, t(6;9), 11q23
aberrations except for t(9;11),
"monosomal karyotype"
FLT3/ITD mutation, MLL partial tandem
duplication, BAALC overexpression

52. ACUTE
LYMPHOBLASTIC
LEUKEMIA (ALL)
GENERAL REMARKS
CLASSIFICATION
TREATMENT

53. 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

54.  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

55. 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

56.  FAB Classification for ALL
 L1
 L2
 L3

60. 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

61. 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

62. 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)

63. 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

64. 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
genetics
t(9;22)/BCR-ABL or t(4;11)/ALL1-AF4
Treatment response Late achievement of CR >3 or 4 weeks
MRD positivity

65. Specific Treatment in ALL
 Stem Cell Transplantation
 Reserved for relapse or refractory ALL
 Types
 Allo-SCT
 Auto-SCT
 MUD & NMSCT

66. Thankyou!
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