ACUTE MYELOID LEUKAEMIA A TYPE OF ACUTE LEULKAEMIAS ,EMPHASIS ON APL.

1. DR OGECHUKWU MBANU
FAMILY MEDICINE
DEPARTMENT
AKTH, KANO
22nd JANUARY 20185/21/2020 1

2. 5/21/2020 2
 APL AND DIC
 CNS INVOLVEMENT
 DIFFERENCIAL
DIAGNOSIS
 PROGNOSIS
 CONCLUSION
 RESOURCES
 INTRODUCTION
 EPDEMIOLOGY OF AML
 HEAMATOPOIESIS
 RISK FACTORS
 CLASSIFICATION
 APL
 EPIDEMIOLOGY OF APL
 SINGS AND SYMPTOMS
 PATHOGENESIS
 CLINICAL EVALUATION

3.  Leukeamias are cancers that involve heamatopoietic cells
 “Acute” - leukemia can progress quickly if not treated, and would
probably be fatal in a few months.
 “Myeloid” refers to the type of cell this leukemia starts from.
 Acute myeloid leukeamia therefore is a disease in which there is
clonal expansion of myeloid precursor cells with reduced capacity to
differentiate
 Also known as acute myelocytic leukemia, acute myelogenous
leukemia, and acute non-lymphocytic leukemia
 Can metastasize to lymph nodes, liver, spleen, central nervous
system (brain and spinal cord), and testicles.5/21/2020 3

4.  Incidence – 2.7 per 100,000
 12.6 per 100,000 in those over 65 years
 Median age of presentation : 65 years
 More prevalent:
 Males
 European descent
 Hispanic/ latino background (promyelocytic leukemia (AML
M3))
5/21/2020 4

5. 5/21/2020 5

6. Granulopoiesis
5/21/2020 6

7. 5/21/2020 7

8.  Increased incidence
 Genetic fragility
 Bloom syndrome
 Faconi anemia
 Wiskott aldrich
 Down, klinefelter, patau syndromes
 Tobacco
 Herbicides, Pesticides
 Benzene exposure
 Radiotherapy
 Topoisomerase ii inhibitors (e.g. etopisode), alkylating agents
 Myelodysplastic symdromes
 Other cell proliferation disorders
 CML, polycythemia vera, primary myelofibrosis
5/21/2020 8

9.  The prognosis of AML depends on :
 the subtype of AML(determined by lab tests),
 the patient’s age,
 and other lab test
Two of the main systems are used to classify AML into subtypes
 The French-American-British (FAB)
 World Health Organization(WHO) classification
 FAB divided AML into subtypes, M0 through M7 based
 type of cell from which the leukemia develops and
 how mature the cells are.
 The World Health Organization puts into consideration chromosomal
abnormalities5/21/2020 9

10. FAB SUBTYPE NAME
M0 Undifferentiated acute
myeloblastic leukemia
M1 Acute myeloblastic leukemia with
minimal maturation
M2 Acute myeloblastic leukemia with
maturation
M3 Acute promyelocytic leukemia
(APL)
M4 Acute myelomonocytic leukemia
5/21/2020 10

11. M4 eos Acute myelomonocytic leukemia
with eosinophilia
M5 Acute monocytic leukemia
M6 Acute erythroid leukemia
M7 Acute megakaryoblastic leukemia
5/21/2020 11

12.  Subtypes M0 through M5 all start in immature forms of
white blood cells.
 M6 AML starts in very immature forms of red blood
cells,
 while M7 AML starts in immature forms of cells that
make platelets.
5/21/2020 12

13. AML WITH CERTAIN GENETIC ABNORMALITIES
 AML with a translocation between chromosomes 8 and 21
 AML with a translocation or inversion in chromosome 16
 AML with a translocation between chromosomes 9 and 11
 APL (M3) with a translocation between chromosomes 15 and 17
 AML with a translocation between chromosomes 6 and 9
 AML with a translocation or inversion in chromosome 3
 AML (megakaryoblastic) with a translocation between chromosomes 1
and 22
 AML WITH MYELODYSPLASIA-RELATED CHANGES
 AML RELATED TO PREVIOUS CHEMOTHERAPY OR RADIATION5/21/2020 13

14.  AML NOT OTHERWISE SPECIFIED - AML that don’t fall into one of the
above groups, and is similar to the FAB classification.
 AML with minimal differentiation (M0
 AML without maturation (M1)
 AML with maturation (M2)
 Acute myelomonocytic leukemia (M4)
 Acute monocytic leukemia (M5)
 Acute erythroid leukemia (M6)
 Acute megakaryoblastic leukemia (M7)
 Acute basophilic leukemia
 Acute panmyelosis with fibrosis5/21/2020 14

15.  Abnormal accumulation of promyelocytes
 Chromosomal translocation involving the retinoic acid
receptor alpha (rarα or rara) gene
 Responsive to all-trans retinoic acid (atra; also known as
tretinoin) therapy unlike other AML
 1st described in 1957 by french and norwegian physicians
 Laboratory evidence of DIC is present in 70% to 90% of
patients at diagnosis or shortly after.
5/21/2020 15

16.  Hemorrhagic events contribute 10% to 15% excess
mortality during induction chemotherapy
 Morphologically, identified as AML-M3 by FAB
 Cytogenetically (WHO), characterized by a balanced
reciprocal translocation abnormality,
t ( 15 ; 17 ) (q22 ; q12 ); PML - RARA.
 One of the most treatable forms of leukemia
 The 12-yr PFS(progression – free survival) rate , is
estimated to be approximately 70%.5/21/2020 16

17.  10-12% of AML cases
 8% - 15% of pediatric AML
 median age is approximately 30–40 years
 Incidence is higher among Latin Americans or South Europeans
 treatment with topoisomerase II inhibitors(eg anthracyclines
and etoposide) can predispose to APL especially in those with
breast cancers
 Around 40% of patients with APL also have a chromosomal
abnormality such as trisomy 8 or isochromosome 17
5/21/2020 17

18.  DIC
 Fever
 Infection as a result of low
neutrophils (neutropenia)
 Bone tenderness
 Anemia
 Fatigue
 Weakness
 Difficulty breathing (dyspnea)
 thrombocytopenia leading to:
 easy bleeding
 Bruising (ecchymosis)
 Gingival bleeding
 epistaxis
 Menorrhagia5/21/2020 18

19.  In 95% cases , retinoic acid receptor-alpha (rara) gene on
chromosome 17 is involved in a reciprocal translocation with
the promyelocytic leukemia gene (pml) on chromosome 15,
 The translocation is denoted as t(15;17)(q24;q21)
 The RAR-receptor is dependent on retinoic acid for regulation
of transcription
 The translocation results in fusion of the retinoic acid receptor
(RARA) gene on chromosome 17 with the promyelocytic
leukemia (PML) gene on chromosome 15.
 This leads to expression of a hybrid protein with altered
functions5/21/2020 19

20.  The fushion protein binds with enhanced affinity to
sites on the cell's DNA, blocking transcription and
differentiation of granulocyte
 It does so by enhancing interaction of nuclear co-
repressor (NCOR) molecule and histone deacetylase
(HDAC).
 Physiologic quantities of retinoic acid no longer
sufficient to allow for cell differentiation
 Despite the above reactions, additional mutations are
required for the development of leukemia5/21/2020 20

21. 5/21/2020 21

22.  - Eight other rare gene rearrangements have been
described in APL
 In these variants there is fusing RARA to other genes
“variant chromosomal translocations” [e.g., t(11;17),
t(5;17)],
 Can be detected in no less than 5% of APL patients
 The significance of these non-PML-RARA transcript
variants is that they may sometimes be resistant to all-
trans-retinoic acid (ATRA) and even arsenic trioxide
(ATO).5/21/2020 22

23. 5/21/2020 23

24. PML-RARa
t(15;17)(q22;q21)
92%
PML-RARa+ insertions 4%
PML-RARa+ variants 2%
PZLF-RARa
t(11;17)(q23,q21)
0.8%
NPM-RARa
t(5;17)(q35,q21)
0.2%
NuMa-RARa
t(11;17)(q13,q21)
< 0.1%
Stat5b-RARa
der(17)
< 0.1%
No RARa 1%
4. Grimwade D, et al. Leukemia. 2002;16:1959-1973.
5/21/2020 24

25. PATIENT
PHYSICAL
EXAMINATION
GENERAL
PHYSICAL
EXAMINATION
SYSTEMIC
PHYSICAL
EXAMINATION
LABORATORY
INVESTIGATIONS
TREATMENT FOLLOW UP
REFRRAL
HISTORY
1/23/2018 25

26. History Fatigue ,weakness ,dyspnea, from aneania
Easy bruising or bleeding from
thrombocytopenia
Fever from infection due to leukocytosis
(10% to 30% present with leukocytosis)
Headaches from CNS involvement
Physical
examination
Pallor , petechial , ecchymosis ,bleeding
from the gum , epistasis
,coagulopathy ( DIC) ,
flow murmur from severe aneamia5/21/2020 26

27. Morphological
Immunophenityping
Cytogenics
Molecular geneticc
5/21/2020 27

28.  CBC - RBC  PLATELETS  WBC
 Blood film – blast cells , auer rods lineage identified
morphologically , comfirmed by immunophenotyping
 Bone marrow aspirate -  erythropoiesis
 megakaryocytes  cellularity ,replacement by blast cells>20%
 Lineage confirmation by FISH(fluorescent in situ hybridization )
or immunostaining ,cytogenetics ,and molecular genetics
 Reverse transcriptase -PCR:
- Can detect minimal residual disease (MRD).
- Gold Standard
5/21/2020 28

29. 5/21/2020 29

30. 5/21/2020 30

31.  “Sanz” criteria (Sanz score).
This depends on WBCs and Platelets count at presentation.
WBC count Platelet
count
3- yr relapse
free survival
Low risk <10 >40 98%
intermediate <10 <40 89%
High risk >10 <40 70%
5/21/2020 31

32. Treatment
Induction
Consolidation
Maintenance
5/21/2020 32

33.  Sensitive to All-trans retinoic acid (ATRA; tretinoin), the acid
form of vitamin A unlike the other leukemia's
 it targets the oncogenic transcription factor instead of directly
killing the malignant cells
 combined with an anthracycline (e.g.daunorubicin,
doxorubicin, idarubicin or mitoxantrone()
 Sometimes also with cytarabine (ara-c).
 Another option is to give ATRA plus arsenic trioxide (Trisenox).
 This is often used in patients who can’t tolerate an
anthracycline drug, but it’s an option for other patients as well.
5/21/2020 33

34. 5/21/2020 34

35.  Gemtuzumab ozogamicin, has been used successfully but is associated
with high toxicity
 But Less cardiotoxicity than anthracycline-based treatments -
preferable in these patients.
 Induction therapy is continued until remission to a maximum of 90 days
 ATRA causes retinoic acid syndrome .
 dyspnea, fever,
 weight gain,
 peripheral edema
 Pseudotumour Cerebri
 these side effects are treated With dexamethasone
5/21/2020 35

36.  What drugs are used depends on what was given for
induction
 Some of the options include :
 An anthracycline along with ATRA for a few cycles
(sometimes different anthracyclines are used in different
cycles)
 An anthracycline plus cytarabine for at least 2 cycles
 Arsenic trioxide for 2 cycles (over about 2½ months), then
ATRA plus an anthracycline for 2 cycles
 ATRA plus arsenic trioxide for several cycles5/21/2020 36

37.  After stable remission is induced,patient undergoes 2 years of maintenance
chemotherapy with
 methotrexate,
 mercaptopurine and
 ATRA
 Arsenic trioxide is currently being evaluated for treatment of relapsed
/refractory disease.
 tamibarotene, is already in use for of relapsed /refractory cases in some parts
of the world..
5/21/2020 37

38.  Arsenic Trioxide (ATO) is the standard ttt of relapsed APL,
+/- ATRA
 Gemtuzumab ozogamicin (GO) is also an effective agent for
patients with relapsed APL.
 Strongly consider CNS-directed treatment with
intrathecal chemotherapy
 Remission rates of greater than 90% with AML M3 patient
treated with ATRA and chemotx (eg, anthracyclines
(idarubicin)) with 60-70% disease free survival
 Arsenic trioxide in those that relapse – achieves complete
remission in >90%5/21/2020 38

39.  The mechanism for APL-induced DIC is not fully understood
 Incresed production of cancer procoagulant such as tissue factor
 Tissue factor forms a complex with factor VII to activate factors X and
IX.
 Activation of the coagulation cascade  more blood clots
 There is also a state of hyperfibrinolysis due to
 Low levels of plasminogen
 Alpha – 2- plasmin inhibitor
  expression of anexin II a receptor for plasminogen and plasminogen
activating factor on the surface of leukemic promyelocytes  over
production of plasmin and fibrinolysis
5/21/2020 39

40. 5/21/2020 40
 Defined as Fibrinogen level < 150 mg / dl OR 2 of
the following criteria;
(1) Fibrinogen 150-200 mg / dl.
(2) FDP (D-dimer).
(3) PT 3 sec. Longer than control
 It is usually a medical emergency
 In 40% of untreated patients ,pulmonary and cerebral
hemorrages can occur

41. Systemic activation
of coagulation
Intravascular
deposition of fibrin
Depletion of platelets
and coagulation factors
Thrombosis of small
and midsize vessels
and organ failure
Bleeding
1/28/2018 41

42. 1/23/2018 42

43.  It takes 5 – 8 days for coagulopathy to improve with
treatment
 Heparin must not be used for prophylaxis in this setting.
 In case of life-threatening bleeding, inhibitors of fibrinolysis
should be considered.
 Invasive procedures such as central venous catheterization,
lumbar puncture, and bronchoscopy should be avoided
before and during induction remission
5/21/2020 43

44.  Common symptoms/findings
 Weakness (anemia), infections/fever (malfunctioning wbcs)
 Petechiae, ecchymoses, hematuria, bleeding from venipuncture sites
 Migratory thrombophlebitis (trousseau’s syndrome)
 Nonbacterial thrombotic (marantic) endocarditis
 DVT
 Lab findings
 Prolonged PT/INR, PTT
 Microangiopathic anemia (schistocytes)
 Thrombocytopenia
 Elevated fibrin degradation products( d-dimer)
 Low fibrinogen
5/21/2020 44

45.  Treatment
1. Supportive therapy
 Platelets
 Cryoprecipitate (fibrinogen)
 FFP( fresh frozen plasma)
2. Treatment for obvious thrombosis (e.g thrombophlebitis, mural thrombus)
 UFH (unfractionated heparin or low molecular weight heparin)
 activated protein C
3. Treatment of underlying malignancy
 In the case of AML M3 → All-Trans Retinoic Acid (PML-RARα)
 Induces differentiation beyond promyelocyte phase
 Only with the more common t(15;17) translocation; - t(11;17) and t(5;17)
do not respond to ATRA
5/21/2020 45

46.  Occurs in less than 5% of AML patients (highest incidence in
relapsed promyelocytic (M3) variant)
 Routine LP is not performed unless symptoms suggestive of
CNS pathology
 Common symptoms
headache
mental status changes
CN palsies (commonly CN III or VI)
 CSF findings
 blast cells
 moderate increase in protein and moderate decrease in
glucose5/21/2020 46

47.  Treatment
 Intrathecal chemotherapy (methotrexate or cytarabine)
+/- whole brain radiotherapy)
addition of radiotherapy depends on response to
intrathecal chemotx and whether there is cranial nerve
involvement
high relapse rate
 Commonly administer prophylactic intrathecal chemotx
in relapsed promyelocytic disease
5/21/2020 47

48. 5/21/2020 48
 Acute lymhpoblastic leukeamia
 Aplastic aneamia
 Folic acid deficiency
 Myelodysplastic syndrome
 Peripheral pancytopenia

49.  Prognosis is generally good relative to other leukemias
 early death is comparatively more common usually due
to severe bleeding, often intracranial hemorrhage.
 Risk factors for early death due to hemorrhage include
 delayed diagnosis,
 late treatment initiation, and
 high white blood cell count on admission
 Relapse rates are low.
5/21/2020 49

50.  Acute promyelocytic leukemia(APL) was first identified as a
distinct subtype of acute myeloid leukemia in 1957.
 APL is characterized by three features;
- accumulation of abnormal promyelocytes.
- occurrence of fibrinogenopenia and DIC.
- presence of the specific chromosomal translocation
t(15;17)(q22;q21).
 Currently it is one of the most treatable forms of acute leukemia
 Treatment must begin before the diagnosis is confirmed in
patients with suspected APL, as early treatment is the key for
survival.5/21/2020 50

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 Schiffer C. Complications of Acute Myeloid Leukemia. Up to Date Online. June 11, 2008.5/21/2020 51