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
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
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
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
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
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
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
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
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
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
51. Andreoli et al. Acute Myelogenous Leukemia. Cecil Textbook of Medicine. 2004; 446-447.
Aoki N et el. A comparative double-blind randomized trial of activated protein C and unfractionated
heparin in the treatment of disseminated intravascular coagulation. Int J Hematol. 2002
Jun;75(5):540-7.
Bernard et al. Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An
Evidence Based Review. Journal of Clinical Oncology. Vol 26. June 1 2008.
Bug G et al. Impact of leukapheresis on early death rate in adult acute myeloid leukemia presenting
with hyperleukocytosis. Transfusion. 2007 Oct;47(10):1843-50.
Estey E. Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Patients. Journal of
Clinical Oncology. Vol 25. May 10 2007.
Giles et al. Leuk Lymphoma. 2001 Jun;42(1-2):67-73.
Jabbour EJ, Estery E, Kantarjian HM. Adult Acute Myeloid Leukemia. Mayo Clin Proc. 2006;81:247-
260.
Larson RA. Treatment of Acute Myeloid Leukemia in Younger Adults. Up to Date Online. June 11,
2008.
You tube strong medicine, others.
Lowenberg B, Downing J, Burnett A. Acute Myeloid Leukemia. NEJM. 1999;341:1051-1061.
Randolph T. Acute promyelocytic leukemia (AML M3) – part 1. Clinical Laboratory Science, Spring
2000; 13(2): 98-105.
Schiffer C. Complications of Acute Myeloid Leukemia. Up to Date Online. June 11, 2008.5/21/2020 51
Editor's Notes
XRT – RADIO THERAPY
CHROMOSOMAL TRANSLOCATION IS A CHROMOSOME ABNORMALITY CAUSED BY REARRANGEMENT OF PARTS BETWEEN NONHOMOLOGOUS CHROMOSOMES. A GENE FUSION MAY BE CREATED WHEN THE TRANSLOCATION JOINS TWO OTHERWISE-SEPARATED GENES, IT
IS DETECTED ON CYTOGENETICS OR A KARYOTYPE OF AFFECTED CELLS.
TRANSLOCATIONS CAN BE BALANCED (IN AN EVEN EXCHANGE OF MATERIAL WITH NO GENETIC
INFORMATION EXTRA OR MISSING, AND IDEALLY FULL FUNCTIONALITY) OR UNBALANCED (WHERE THE EXCHANGE OF CHROMOSOME MATERIAL IS UNEQUAL RESULTING IN EXTRA OR MISSING GENES).
RECIPROCAL TRANSLOCATIONS ARE USUALLY AN EXCHANGE OF MATERIAL BETWEEN NON HOMOLOGOUS CHROMOSOMES
CHROMOSOMAL TRANSLOCATIONS OCCURRING IN GAMETOGENESIS, DUE TO ERRORS IN MEIOSIS, RESULTS IN A CHROMOSOMAL ABNORMALITY FEATURED IN ALL CELLS OF THE OFFSPRING, AS IN TRANSLOCATION CARRIERS
TRANSLOCATIONS THAT OCCUR IN CELLULAR DIVISION OF SOMATIC CELLS, DUE TO ERRORS IN MITOSIS ARE KNOWN AS SOMATIC TRANSLOCATIONS.THEY RESULT ININ ABNORMALITIES
FEATURED ONLY IN THE AFFECTED CELL LINE, AS IN CHRONIC MYELOGENOUS LEUKEMIA WITH THE PHILADELPHIA CHROMOSOME TRANSLOCATION
NONRECIPROCAL TRANSLOCATION
NONRECIPROCAL TRANSLOCATION INVOLVES THE TRANSFER OF GENES FROM ONE CHROMOSOME TO ANOTHER NON HOMOLOGOUS CHROMOSOME
CANCER:
SEVERAL FORMS OF CANCER ARE CAUSED BY ACQUIRED TRANSLOCATIONS (AS OPPOSED TO THOSE PRESENT FROM CONCEPTION); THIS HAS BEEN DESCRIBED MAINLY IN LEUKEMIA (ACUTE MYELOGENOUS LEUKEMIA AND CHRONIC MYELOGENOUS LEUKEMIA). TRANSLOCATIONS HAVE ALSO BEEN DESCRIBED IN SOLID MALIGNANCIES SUCH AS
EWING'S SARCOMA
ACUTE PROMYELOCYTIC LEUKEMIA WAS FIRST CHARACTERIZED IN 1957[2][3] BY FRENCH AND NORWEGIAN PHYSICIANS AS A HYPERACUTE FATAL ILLNESS,[WITH A MEDIANSURVIVAL TIME OF LESS THAN A WEEK.[4] TODAY, PROGNOSES HAVE DRASTICALLY IMPROVED; 10-YEAR SURVIVAL RATES ARE ESTIMATED TO BE APPROXIMATELY 77% ACCORDING TO ONE STUDY
PFS RATES DESCRIBE THE PERCENTAGE OF PEOPLE WHO DON’T HAVE NEW TUMOR GROWTH OR CANCER SPREAD DURING OR AFTER TREATMENT . THE RATES INCLUDE THOSE WHOSE DISEASES RESPONDED COMPLETELY OR PARTIALLY TO TREATMENT .THEY ALSO INCLUDE THOSE WHOSE DISEASE IS STABLE
The median age is
approximately 30–40 years,[28]
which is considerably younger
than the other subtypes of AML
q = long arm of chromosome
P = short arm of chromosone
APL, acute promyelocytic leukemia; PML, promyelocytic leukemia; RARα, retinoic acid receptor alpha.
There are numerous variants of the disease. In addition to the prototypical variant that leads to the same PML-RAR fusion transcript, accounting for approximately 6% of variants, there are also different fusion partners for the RARα gene, including PZLF, NPM1, NuMa, and Stat5b. However, the resulting fusion proteins are very rarely seen in APL, accounting for < 2% of cases.[4] The significance of these non-PML-RAR transcript variants is that they may sometimes be resistant to all-trans-retinoic acid (ATRA) and even arsenic trioxide (ATO).
THIS IS NOT A DEFINITE ORDER OF EVENTS .THE ORDER TO FOLLOW IS DEPENDENT ON THE CLINICAL SCENERIO
Gemtuzumab ozogamicin (GO) is also an effective agent for patients with relapsed APL. Although this drug is no longer commercially available
THE DIC IN APL SHOW HYPERFIBRINOLYSIS
THIS HYPERFIBRINOLYSIS IS DUE TO
LEVELS OF PLASMINOGEN
PLASMINOGEN ACTIVATOR
LEVELS OF ALPHA – 2 - PLASMIN INHIBITOR
EXPRESSION OF ANEXIN II A RECEPTOR FOR PLASMINOGEN AND PLASMINOGEN ACTIVATING FACTOR
ANEXIN II IS FOUND ON THE SURFACE OF LEUKAEMIC PROMYELOCYTES
EXPRESSION LEADS TO OVER PRODUCTION OF PLASMIN AND THUS FIBRINOLYSIS