1. Acute Myeloid Leukemia
❑ Also known as :-
Acute myelocytic leukemia
Acute myelogenous leukemia
Acute non -lymphocytic leukemia
2. ● Group of marrow based neoplasms that have clinical
similarities and distinct morphological
immunophenotypic, cytogenetic and molecular features.
● The malignant cell in AML is a blast that most often
shows myeloid or monocytic differentiation
3. ETIOLOGY
o Age:- increase with age
:-median age of 67 yr.
o Sex:- Male > Female.(4:3)
o Race :- Black> White.
o Heredity:-
1.Congenital Defects:-
Down’s syndrome
Bloom syndrome
Monosomy 7 syndrome
Turner syndrome
Klinefelter syndrome
4. 2.Marrow Failure Syndrome
Fanconi anemia
Kostmann agranulocytosis
Familial aplastic anemia syndrome
Schwanchman –Diamond syndrome
3 Germ line mutation of
CCAAT/enhancer binding protein
Runt related transcription factor 1 (RUNX1)
Tumour protein p53
5. o Radiation :- Folley et al. reported an excess risk of leukemia
in1952.
● Minimum latency period -2 to 3 yrs
● Peak at 6 to 8 yr and
● Decline beyond 20 yrs
6. o Smoking:-
smokers of > 40 cigarettes/day.
o Drugs:-
Topoisomerase II inhibitors( Teniposide and
Etoposide)
Alkylating agents
(mechlorethamine,melphalan,cyclophosphamide)
Chloramphenicol
Phenylbutazone
7. ❑ Chemicals and others exposures
● exposure to rubber ,paints ,embalming fluid, pesticides,
ethylene oxide and gasoline
● exposures to benzene and smoking
● maternal alcohol consumption during pregnancy
10. FAB CLASSFICATION
● Based on morphology, cytochemical staining and
immunophenotype.
● Four types ( MO,M1,M2,M3) are granulocytic and differ
according to the extent of maturation.
● M4 is both granulocytic and monocytic, with at least 20%
monocytic cells.
● M5 is monocytic (at least 80% monocytic cells)
● M6 shows primarily erythroid differentiation with dysplastic
feature.
● M7 is acute megakaryocyte leukemia
11. CLASS INCIDENCE
M0 Minimally differentiated
AML
2-3%
M1 AML without maturation 20%
M2 AML with maturation 30-40%
M3 Acute Promyelocytic
leukemia
5-10%
M4 Acute myelomonocytic
leukemia
15-20%
M5 Acute monocytic
leukemia
10%
M6 Acute erythroleukemia 5%
M7 Acute megakaryocytic
leukemia
1%
12. ● The major difference between WHO and FAB –
The blast cut off for diagnosis.
● It is 20% in WHO classification and 30% in FAB Classification.
● Demerits of FAB classification-
1.Interobserver variability
2.Lack of definitive criteria for some of AML
3.Poor correlation with survival.
4.Correlation with immunophenotyping, cytogenetics and
molecular abnormalities were not fully defined.
13. Minimally Differentiated AML(M0)
•The blasts are not recognized as
myeloid based on morphology and
cytochemistry but
immunophenotyping demostrates
myeloid antigens
•These cells are agranular and
lack Auer rods
•Diagnosis of AML M0-
<3% of MPO-positive and
Sudan black B positive cells but
>20% of leukemia cells expressing
myeloid antigens CD13,CD33 and
CD117.
14. M1: AML without maturation
•About 90% of myeloblast
without evidence of
maturation.
•At least 3% of the blast are
reactive with Sudan black or
MPO.
•The blast express myeloid
antigens including CD13,CD14
or CD33.
15. M2: AML with maturation
•The cytogenetic
abnormality associated with
M2 is t(8;21) (q22;q22)
•Typical morphology of M2
is prominent Auer rods,
marrow eosinophilia with
salmon-coloured granules
and cytoplasmic globules.
16. M3: Promyelocytic Leukemia (faggot cell)
•Faggot cells with
bundles of Auer rods
•90% of patients have
hemorrhagic
manifestations secondary
to DIC.
•Genetic translocation
t(15;17)
•Young median age :
35-40 yrs.
17. M4: Acute Myelomonocytic Leukemia (AMML)
•Monoblasts, promonocytes,
neutrophil precursors seen
•Mixture of eosinophils and
large atypical basophilic
granules.
•Staining with Sudan black
,PAS and chloroacetate
esterase and nonspecific
esterase identify neoplastic
cells.
18. M5: Acute Monoblastic Leukemia
•Monoblasts and immature
monocytic cells (myeloperoxidase
negative, nonspecific esterase
positive) predominate;
• Auer rods are usually absent;
• older patients;
• the M5b subtype has
predominance of
mature-appearing monocytes in
the peripheral blood, whereas only
immature cells are seen in the M5a
subtype.
19. M6: Acute Erythroid Leukemia
•Morphologic finding in P.S.-
Schistocytes, Tear drop, and
basophilic stippling, dysplastic
platelets features .
• Abundant dysplastic erythroid
progenitors;
•>20% of cells of the marrow
nonerythroid cells are
myeloblasts,;
•following exposure to mutagens
(e.g., chemotherapy).
20. M7: Acute Megakaryoblastic
Leukemia
•Peripheral blood
•Micromegakaryoblasts
•Megakaryocyte fragments
•Dysplastic segmented
neutrophils and platelets
•Bone marrow
•Often get “dry tap”
•Fibrosis
•Myelofibrosis or increased
marrow reticulin often
present;
• Auer rods are absent.
21. Clinical feature
● The most common complaint is nonspecific fatigue or
malaise .
● Half of patient had symptoms < 3 months before
diagnoses.
● Fever are seen in about 20% to 30% of the patients.
● Haemorrhagic sign and symptoms like petechiae, epitaxis,
and easy bruising.
● Weight loss- about in 50% case.
22. ● Bone pains occurs in 20% of the cases.
● Organomegaly and adenopathy in the 50% of cases.
● Gum infiltration is found in M5.
● Cardiac - cardiac abnormalities is mainly due to
electrolyte imbalance particularly hypokalemia.
● Pulmonary symptoms include infections and haemorrhage
(more in M3).
23. ● Leukemic skin infiltration or leukemia cutis occur in
the 13% of patient with AML and associated with
involvement of other extramedullary sites.
● The skin lesion may precede the diagnosis.
● The lesion are often violaceous and nodular and are
more common in monocytic component of AML
24. • The lesion are often violaceous and nodular
and are more common in monocytic
component of AML
25. ❖ CNS manifestation –
● meningeal disease in about 5 %to 20% of children.
● Cranial nerve palsies ,particularly V and VII.
● Ocular involvement may result in blindness.
● Intracerebral masses rarely coexist.
● Leukocytosis causes headache and blurred vision.
26. ❖ Myeloid (granulocytic) sarcoma or
myeloblastoma-
● is an extramedullary tumour that occurs in 2 to
14 % of the AML pts.
● Also called as chloromas because some appear
green or turn green in diluted acid secondary to
expression of MPO.
27. ● Site- bone periosteum, soft tissue, lymph node or
skin.
28. LABORATORY FINDINGS
● Blood counts vary, usually are elevated, 25% to40%
have counts <5000, < 20% have >1lakh cells/c.mm.
● Blast found in peripheral smear, Aeur rods and Phi
bodies – pathognomonic.
● Aleukemic leukemia( no blast in peripheral smear) is
rare.
● Cytopenias are common, contribute to symptoms.
29. ● Hyperuricemia noted in 50% of cases.
● Levels of lysozyme are elevated in some forms(M4 ,M5),
these causes renal tubular damage.
● Hyper-Leukocytosis: blood blast count> 100,000/cu.mm.,
rare, but a medical emergency.
● Associated with leukostasis in CNS and Lungs.
● Leukapheresis is considered early, but its a temporary
measure and chemotherapy should be initiated as soon as
possible.
30. Pre Treatment Evaluation
● Evaluate overall functional integrity of major organs.
● Factors that have prognostic importance should be
assessed.
● Leukemic cells are obtained and cryopreserved.
● HLA typing for allogenic HSCT. (haematopoietic stem
cell transplant)
● Placement of Central venous catheter.
31. CLINICAL PROGNOSTIC FACTORS
CLINICAL FAVOURABLE UNFAVOURABLE
AGE <45 <2YR, >60 YRS.
LEUKEMIA DE NOVO ANTECEDENT
MYELODYSPLASIA,MP
INFECTION ABSENT PRESENT
LEUKOCYTOSIS <25,000 >1,00,000
SERUM LDH NORMAL ELEVATED
EXTRAMEDULLARY
DISEASE
ABSENT PRESENT
CNS DISEASE ABSENT PRESENT
CYTOREDUCTION RAPID DELAYED
36. Treatment
● Divided into 2 phases.
● First is attainment of complete remission(CR)
following induction therapy.
● Next is post- remission therapy.- contains
consolidation or intensification therapy.
37. Treatment end points
● Assessment of induction chemo is done by- BMA 2
wks following initiation.
● Complete remission refers to morphologic complete
remission, i.e
● red cell transfusion independence,
● absolute neutrophil count>1000/ul,
● plt count> 1 lakh,
● < 5% blast in aspirate, absence of blast with auer rods,
absence of extra medullary leukemia.
38.
39. ● Use of cyto genetics and molecular testing in
remission:
● CRc: reversal to normal marrow karyotype at CR in
patient with an abnormal karyotype at presentation.
● CRm: relevant in some subtypes only .
● Residual disease indentified by RT-PCR in AML with
t(15;17)i.e { PML –RARa}.
● CRm is recognised as therapeutic objective in PML, but in
other subsets its use is still controversial.
40. ● Morphological CR with incomplete blood recovery(
Cri):
● Fulfilment of all the criteria CR except for residual
neutropenia <1000, or thrombocytopenia <1 lac.
41. REMISSION INDUCTION FAILURE
● Divided into 3 categories:
● Treatment failure due to resistant disease: Patients
surviving at 7 days after treatment having persistent
AML in marrow or blood.
● Treatment failure due to complications from aplasia:
Patients surviving at least 7 days after treatment
completion and die while cytopenic and with post
treatment marrow demonstrating aplasia.
42. ● Patients with treatment failure of indeterminate
cause: those who die within 7 days after treatment or
>7 days with blood not showing persistent leukaemia
and marrow was not examined.
43. Induction chemotherapy
● Most common regimen used is cytarabine (Ara –C)
and an anthracycline.
● Cytarabine administered as continous infusion,
100mg/sq.m/day for 7 days.
● Anthraycline given as I.V push daily on first 3 days of
cytarabine therapy, combination called “7 and 3”.
44. ● Daunorubicin is the antracyclin used commonly,
dose: 30-60mg/sq.m
● The addition of Etoposide for 3 days has shown some
benefit.
45. Modifications
● Idarubicin for daunorubicin:
● Development of drug resistance is reduced with
idarubicin relative to other anthracyclines.
● Idarubicin does not induce P-glycoprotein expression.
● Idarubicin 12 mg/m2
gives better complete remission
rates in younger adults than does daunorubicin.
46. HIGH DOSE CYTARABINE
● Given in high dose , more cytarabine enters cell, saturates
inactivating enzymes , increases the inhibition of DNA,
thus overcoming resistance.
● Increases toxicity( myelosuppression, pulmonary and
cerebellar toxicity) compared to conventional doses,
especially in older patients
● High-dose cytarabine does not increase CR rates.
● Disease-free survival is better in patients younger than 50
years.
47. Hematopoietic Cytokines
● G-CSF and GM –CSF were used in untreated leukemia
to recruit more leukemia cells in S phase in order to
render them susceptible to Ara-C – “Growth Factor
Priming”.
● But these trials did not show any clinical benefit ,
hence not recommended.
48. Duration Of Induction
● Patients who have persistent leukemia after the 1st
course of induction chemotherapy are given a second
similar course.
● Long-term outcome is worse, with 10% survival at 5
yrs.
● 40 % of patients with persistent AML after one course
of induction therapy have a complete remission after
a second course
49. Post Remission Therapy
● In its absence cure rate is 0.
● It attempts to eliminate or decrease disease , delays
relapse, increases likelihood of cure.
● But there is no consensus regarding the best
approach.
50. ● The decision to utilize autologous or allogeneic HSCT
or high-dose cytarabine alone for consolidation is
individualized.
● Multiple cycles of high dose cytarabine( 4cycles of
3gm/sq.m every 12 hrs on day 1, 3 and 5) has been the
standard choice for patient<60yrs with good or
intermediate cytogenetics.
51. ● For older patients with good performance status,
normal renal function, favourable cytogenetics,
modified HiDAC is considered.
● In patients with adverse prognostic factors , who have
a donor, allogeneic SCT is treatment in first
remission.
● No significant difference in disease-free survival
between allogeneic marrow transplant (42 percent)
52. STEM CELL TRANSPLANTATION
● Allogeneic stem cell transplant used in patients age<70-75
with high risk genetics with HLA compatible donor.
● Relapse following allogeneic transplant occurs in small
fraction only.
● Treatment related toxicity is high.
● GVHD, veno-occlusive disease, infections are common.
53. ● RCT comparing intensive chemotherapy /autologous /
allogeneic HSCT have shown improved duration of
remission with allogeneic HSCT.
● However, overall survival is not different; the
improved disease control with allogeneic HSCT is
erased by its toxicity.
● The toxicity is relatively low with autologous HSCT
(5% mortality rate), but the relapse rate is higher.
54. ● General approach - allogeneic HSCT in first CR for
high-risk karyotypes.
● Patients with CN-AML who have other poor risk factors
● e.g., an antecedent hematologic disorder,
● or failure to attain remission with a single induction course
● and patients lacking a favourable genotype (e.g., patients
who do not have CEBPA mutations / NPM1 mutations)
● are also potential candidates.
55. NOVEL AGENTS
● Several newer chemotherapeutic agents are being
examined.
● Decitabine , used in low doses in elderly, even with
unfavourable karyotypes has good yield of CR.
● Clofarabine, a nucleoside analogue has show activity in
AML, overall response rate of 48% is achieved.
● Cloretazine, alkylating agent in phase 2 trials used with
Ara-C.
56. ANTI-CD33.
● The CD33 antigen is expressed on 90 percent of AML
blasts , is not expressed by the pluripotent HST; thus,
it is a target for Ab-mediated destruction of blasts.
● Gemtuzumab ozogamicin is a recombinant
humanized anti-CD33 monoclonal antibody.
● Produced CR in 16 percent and CR with incomplete
platelet recovery in 14 percent .
● FDA approved this drug to be used in >65 yr old
patients.
57. FLT3 Inhibitors
● FLT3 receptor mutations - 30 percent of patients
● Small-molecule FLT3 tyrosine kinase inhibitors:
● inhibit FLT3-ITD phosphorylation,
● induce apoptosis in vitro,
● and have efficacy in mouse models of human leukemia.
● These agents are in phase I and II trials.
58. IMMUNOTHERAPY
● They are explored for minimal residual disease
following post remission.
● Immunotherapy with IL-2 and histamine
dihydrochloride significantly improved 3 yr leukemia
free survival.
59.
60. RELAPSED AML
● Once relapse occurs, patients are rarely cured with
further standard-dose chemotherapy
● Patients eligible for allogeneic HSCT should receive
transplants expeditiously
● The most important factors predicting response at
relapse are:
● the length of the previous CR,
● whether initial CR was achieved with one or two
courses of chemotherapy,
● and the type of postremission therapy.
61. ● For patients without HLA-compatible donors:
● Early relapse: newer therapy are tried.
● Late relapse: have a higher chance of attaining a CR.,
drug sensitive relapse.
62. AML IN OLDER PATIENTS
● Patients>60 yrs., more worse outcome.
● Different biology, cytogenetics, co-morbid illness,
drug resistance.( expression of MDR1)
● But chemo should not be withheld.
63. ● CR ranges-35-60%.,
● Mitoxantrone plus etoposide have been used in
elderly.
● Anti CD33 have been used in relapse.
64. Treatment Of PML
● Tretinoin is an oral drug that induces the
differentiation of leukemic cells bearing the t(15;17).
● APL is responsive to cytarabine and daunorubicin but
10% die of DIC.
● Tretinoin produces APL differentiation syndrome.
65. APL DIFFERENTIATION SYNDROME
● Within 3 weeks of treatment onset.
● Fever, fluid retention, dyspnea, chest pain, pulmonary
infiltrates, pleural and pericardial effusions, and
hypoxemia.
● The syndrome is related to adhesion of differentiated
neoplastic cells to the pulmonary vasculature
endothelium.
● Glucocorticoids, chemotherapy, and/or supportive
66. ● Tretinoin (45 mg/m2
per day orally until remission is
documented) plus concurrent anthracycline-based
chemotherapy is the most effective for APL.
● CR rates of 90–95%.
● Following CR, patients should receive at least two
cycles of anthracycline-based chemotherapy.
67. Arsenic trioxide has significant antileukemic activity
and is being explored as part of initial treatment.
In a randomized trial, arsenic trioxide improved
outcome if utilized after achievement of CR and
before consolidation.
Combination of drugs are used in high risk APL at
diagnosis.
68. ● Assessment of residual disease by RT-PCR amplification of
chimeric gene product( PML-RARA) is done following the
final cycle of chemotherapy.
● Disappearance of the signal is associated with long-term
disease-free survival.
● its persistence invariably predicts relapse.
● Sequential monitoring of RT-PCR for t(15;17) is now
considered standard.
69. SUPPORTIVE THERAPY
● Supporting patients through several weeks of
granulocytopenia and thrombocytopenia are critical
to the success of AML therapy.
● Adequate and prompt blood bank support is critical .
● Platelet transfusions should be given to maintain a
platelet count> 10,000/L, or even during febrile period
or DIC.
70. ● RBC transfusions should be administered to keep the
hemoglobin level> 8 g/dL.
● Blood products leukodepleted to avert
alloimmunization as well as febrile reactions.
● Blood products should be irradiated to prevent
(GVHD).
● Cytomegalovirus (CMV)-negative blood products
should be used for candidates for allogeneic HSCT.
71. INFECTIONS
● Infectious complications remain the major cause
of morbidity and death during chemotherapy for
AML.
● Antibacterial (i.e., quinolones) and antifungal
(e.g, fluconazole, posaconazole) prophylaxis in the
absence of fever is likely to be beneficial.
● Fever develops in most patients with AML, but
infections are documented in only half of febrile
72. ● Empiric antibiotic therapy include monotherapy with
● imipenem-cilastin/ meropenem,
● piperacillin/tazobactam,
● an extended-spectrum antipseudomonal cephalosporin
(cefepime or ceftazidime);
● an aminoglycoside in combination with an
antipseudomonal penicillin.
● Empirical vancomycin should be initiated in
neutropenic patients with catheter-related infections.
73. ● Caspofungin or liposomal amphotericin B is
considered if fever persists 4–7 days following
initiation of empiric antibiotic therapy in a patient
who has received fluconazole prophylaxis.
● Antibacterial and antifungal antibiotics should be
continued until patients are no longer neutropenic.
