Acute Promyelocytic Leukemia (APL) is a subtype of AML characterized by the t(15;17) translocation resulting in the PML-RARA fusion gene. APL has a high cure rate with all-trans retinoic acid (ATRA) and chemotherapy due to its differentiation of promyelocytes. Complications include disseminated intravascular coagulation, ATRA syndrome, and pseudotumor cerebri. Modern treatment protocols using risk stratification and ATRA with chemotherapy have increased survival to over 80% for APL.

1. Acute Promyelocytic Leukemia
Ranjita Pallavi,MD
Internal Medicine
PGY-2

2. Acute Promyelocytic Leukemia
• FAB: AML M3
• WHO 2008: AML with recurrent genetic abnormalities
– APL with t(15;17)(q22;q12);(PML-RARA)
• 10-15% of all AML cases (~1300/year in US)
• 80-90% cure rate, though morbidity and mortality is high before
and during induction
• Disseminated intravascular coagulation relatively common at
diagnosis
• Highly sensitive to anthracyclines
• t(15;17) and PML-RARa fusion gene required
• All-trans retinoic acid (ATRA) targets RARa
• Arsenic trioxide (ATO) targets PML
• Patients have high cure rates, once they survive induction

3. Molecular Features of APL
• PML/RARa gene product forms
homodimer
• Homodimer represses target
genes needed for differentiation
• Mechanisms act via aberrant
histone modification and DNA
methylation
• Mechanism of ATRA:
• ATRA causes a conformational
change of the PML/RARa protein
• Downstream targets that had
been repressed become
activated, leading to normal
differentiation
Wang, Blood,
2008

4. Acute Promyelocytic Leukemia
• Without treatment, APL is the most malignant form of AML with a
median survival of less than one month.
• Modern therapy has dramatically changed its prognosis and APL is
now associated with the highest proportion of AML patients who
are cured of their disease.
• APL represents a medical emergency with a high rate of early
mortality, due mainly to hemorrhagic complications from a
characteristic coagulopathy.
• The first golden rule that has to be followed as soon as the
diagnosis of APL is suspected based upon cytologic criteria is: to
immediately start treatment with all-trans retinoic acid (ATRA)
without delay, even before definitive (cyto)genetic confirmation of
the diagnosis has been made.
• If the diagnosis is not confirmed, ATRA can always be discontinued
and treatment changed to that used for other types of AML.

5. A review of blasts

6. APL morphology: Hypergranular
Tallman, Blood, 2009

7. APL Morphology: Microgranular
Tallman, Blood, 2009

8. The Action of Differentiation
Wang, Blood, 2008

9. Treatment Approaches
• Can the patient tolerate anthracyclines?
• What is the risk-stratification based on the Sanz criteria? (WBC and
platelet count)
• Induction
• Consolidation
• Maintenance
• Relapse
• Several established treatment protocols
• Important not to “mix and match” induction from one trial with
consolidation from another

10. Risk Stratification
• Low: WBC < 10,000 and
platelets > 40,000
• Intermediate: WBC <
10,000 and platelets <
40,000
• High: WBC > 10,000
Sanz, Blood, 2000

11. Treatment Guidelines

12. Treatment Guidelines

13. Treatment Guidelines

14. Treatment Guidelines

15. Treatment Guidelines

16. APL and DIC
• APL associated with significant coagulopathy.
• Coagulation parameters (fibrinogen, FDP/XDP, PT, aPTT,
and platelet counts) should be monitored closely.
• Transfusions of platelets or fresh frozen plasma are
traditionally used to maintain the platelet count above 20,000
to 30,000/μL and the plasma fibrinogen concentration above
150 mg/dL.
• 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.

17. ATRA and Coagulopathy

18. ATRA and Coagulopathy
• Principal pathways of APL cell interactions with the hemostatic
system, which can be affected by ATRA. APL cell expresses: (a)
cellular procoagulants (TF and CP) that activate the clotting
cascade; ATRA decreases the expression of both TF and CP, thus
reducing the procoagulant activity; (b) fibrinolysis proteins (u-PA, t-
PA, PAI) and receptor (u-PAR); ATRA increases both plasminogen
activators and inhibitors, resulting in unchanged or reduced
fibrinolytic activity; (c) nonspecific proteases, including granule
elastase, that proteolyze fibrinogen/fibrin and other coagulation
factors; ATRA does not affect this cellular mechanism; and (d)
cytokines, including IL-1β and TNF-α, that induce the endothelium
thrombogenicity; ATRA increases the production of cytokines.

19. Coagulation markers in newly diagnosed APL patients (n = 9) receiving ATRA for
induction therapy.
Barbui T et al. Blood 1998;91:3093-3102
©1998 by American Society of Hematology

20. Differentiation Syndrome
• Previously named “Retinoid acid syndrome“
• Occurs in 10–25% of APL patients within 2 to 21 days after initiation of
treatment.
• More frequently in patients with a high white blood cell count at diagnosis.
• Characterized by fever, peripheral edema, pulmonary infiltrates, hypoxemia,
respiratory distress, hypotension, renal and hepatic dysfunction, and serositis
resulting in pleural and pericardial effusions.
• Symptoms of fever, hypotension, dyspnea, and pulmonary infiltrates can
mimic sepsis.
• Sometimes, the syndrome is accompanied by hyperleukocytosis
• Early recognition and aggressive management with dexamethasone therapy
(10 mg IV every 12 hours for 3-5 days with a 2 week taper ) has been
effective in most patients.
• Continue to hold ATRA till symptoms resolv.e
• ATRA or ATO can be restarted in most cases once the syndrome has resolved.

21. Differentiation Syndrome

22. Differentiation Syndrome

23. Hyperleucocytosis
• Marked increase in WBC count due to the rapid maturation induced
by ATRA of a large mass of leukemic cells, may result in leukostasis.
• Most current remission induction regimens now combine ATRA
with cytotoxic chemotherapy, the frequency of hyperleukocytosis
has decreased.

24. Pseudotumour Cerebri
• Idiopathic intracranial hypertension (IIH), commonly called
pseudotumor cerebri, can complicate the treatment of APL with
ATRA.
• More common in children and adolescents treated with ATRA and
the incidence in this population decreased with the use of lower
dose ATRA (25 mg/m2/day).
• Diagnosis of IIH is suspected in patients with
headache, papilledema, and/or vision loss.
• Evaluation includes a physical examination including lumbar
puncture, cerebral imaging studies (computed tomography or
magnetic resonance) and fundus oculi.
• diagnosis is confirmed in patients with increased intracranial
pressure, normal cerebrospinal fluid, and negative cerebral imaging
studies.
• If symptoms persist, therapeutic options include the temporary
discontinuation or dose reduction of ATRA, analgesics, and/or the
administration of steroids and acetozolamide.

25. Management of special situations: Pregnant Women
• Treatment approach depends largely upon the trimester of
pregnancy during which APL is diagnosed.
• First Trimester: Both ATRA and ATO are considered to be highly
teratogenic and are contraindicated during the first trimester of
pregnancy.
• if elective termination of the pregnancy is unacceptable to the
patient, the only available treatment option is the administration of
chemotherapy alone.
• If treatment with chemotherapy alone is chosen, daunorubicin may
be the preferred anthracycline for pregnant women because there
is greater experience with this drug during pregnancy.
• If a remission is achieved and the pregnancy continues normally,
ATRA may be added during the second or third trimester.

26. Management of special situations: Pregnant Women
• Second or Third Trimester: Two main options are available:
1.Remission induction with ATRA alone and chemotherapy postponed
until after delivery.
2.Simultaneous administration of ATRA plus chemotherapy.
• Simultaneous administration of ATRA plus chemotherapy offers the
best chance of cure.
• Vaginal delivery is generally preferred since it is associated with a
reduced risk of bleeding.
• After delivery, breastfeeding is contraindicated while on
chemotherapy or ATO.

27. Management of special situations:
Therapy related APL
• Develops usually less than 3 years after a primary neoplasm
(especially breast carcinoma).
• Particularly with topoisomerase II–targeted drugs (anthracyclines or
mitoxantrone and less often etoposide).
• t-APL appear to have a similar prognosis as de novo APL and benefit
from standard APL therapy.
• In patients with a history of anthracycline exposure or cardiac
impairment that limits their ability to receive further treatment
with anthracyclines, alternative regimens, such as ATRA plus ATO
may be used.

28. Management of special situations:
Genetic variants of APL
• More than 90% of patients with APL have t(15;17)(q22;q12)
translocation resulting in the PML/RARA fusion gene.
• Very rarely have been described alternative fusion genes resulting
in leukemias classified as "AML with a variant RARA translocation"
• Some of these conditions are sensitive to ATRA therapy while
others are not.
• In general, patients with alternative fusion genes ATRA-sensitive are
treated with standard ATRA-based therapy.
• Patients with variants known to be resistant to ATRA are treated
with standard AML induction therapy.

29. Management of special situations:
Genetic variants of APL
• The following are the alternative fusion genes identified as ATRA-
sensitive:
• NuMA/RARA and t(11;17)
• NPM1/RARA and t(5;17)
• FIP1L1/RARA
• The following are ATRA-resistant variants:
• STAT5b/RARA and interstitial chromosome 17 deletion
• PLZF/RARA and t(11;17)
• In case APL patients have additional cytogenetic abnormalities, as
trisomy 8, or particular molecular abnormalities (gene mutations in
FLT3) the prognosis is not worsened and they are considered to
have the same prognosis as standard APL.