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Acute Promyelocytic
Leukemia (APL)
Ryan Mattison, MD
University of Wisconsin
February 23, 2010
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
Unique Features of APL
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
APL History and Milestones
1957- first described by Hillestad (Sweden), correlating promyelocytes and severe bleeding
1973- Bernard showed disease sensitive to daunorubicin
1977- Rowley and colleagues showed t(15;17) in APL
1985- Chinese investigators showed ATRA leads to differentiation
Mid 1990’s- Role of arsenic trioxide (ATO) established
2000’s- Risk stratification and role of regimens based on ATRA and ATO without chemotherapy
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
Proliferation via FLT3 and KIT as well are required
Wang, Blood, 2008
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
Diagnosis
Early diagnosis is key!
If APL is considered, start ATRA first, ask
questions later
The hematopathologist may not always be
around to help
A review of blasts
APL morphology: Hypergranular
Tallman, Blood, 2009
APL Morphology: Microgranular
Tallman, Blood, 2009
The Action of Differentiation
Wang, Blood, 2008
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
Induction Supportive Care
Start ATRA once diagnosis is suspected
Maintain platelets > 50,000/uL and fibrinogen
> 150mg/dL
Avoid leukapheresis, LP, and central line
placement
Avoid myeloid growth factors
Be aware of differentiation syndrome
Tallman, Blood, 2009
The Importance of Induction
Supportive Care
Jacomo, Haematologica, 2007
A: Overall Survival
From Time of
Diagnosis
B: Overall Survival
After Induction
Therapy Completed
Differentiation Syndrome
Fever, dyspnea, hypoxia, pleural or pericardial
effusion
Associated with WBC > 10,000 and especially >
30,000
Treat with dexamethasone 10mg BID for 3-5
days with a 2 week taper
Consider holding ATRA until symptoms resolve
Consider pre-emptive dex when WBC > 30,000
Tallman, Blood, 2009
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
Treatment Approaches
Several established treatment protocols
Important not to “mix and match” induction
from one trial with consolidation from another
Low/Intermediate Risk Disease
Induction and Consolidation Options
8 days
15 days each
Spanish PETHEMA
French-Belgian-Swiss APL Group
Ades, Blood, 20087 days each
High Risk Induction and
Consolidation-Option 1
Powell, ASCO
2007, North
American
Intergroup
Results
High Risk Induction and
Consolidation-Option 2
Induction: ATRA 45 mg/m2 + idarubicin 12
mg/m2 on day 2, 4, 6, 8
Consolidation: ATRA 45 mg/m2 x 15 days
Idarubicin 5mg/m2 and cytarabine 1g/m2 x 4 days
Mitoxantrone 10mg/m2/day x 5 days
Idarubicin 12 mg/m2 x 1 dose and cytarabine
150mg/m2 q 8hours x 4 days
Sanz, ASH, 2008 PETHEMA LPA2005
Induction/Consolidation Points
Pick a regimen and stick with it. Don’t mix one induction recipe with another consolidation treatment.
Do not perform a bone marrow biopsy after induction marrow will usually be positive due to the mechanism of treatment.
Arsenic therapy requires
Assessment of QTc interval (keep < 500 ms)
K > 4, Mg > 1.8
Post-Consolidation Therapy
Check PCR for PML-RARa after consolidation is complete
Negative?
Maintenance with 1-2 years of ATRA +/- 6MP and methotrexate
Monitor PCR every 3 months for 2 years
Positive?
Repeat within 4 weeks
Treat for relapse if still positive
Relapsed APL
Treat with arsenic +/- ATRA
Strongly consider CNS-directed treatment with
intrathecal chemotherapy
Morphologic remission?
Yes
PCR Negative-Auto SCT vs. Arsenic x 6 cycles
PCR Positive-Allo SCT vs. Gemtuzumab
No
Gemtuzumab followed by allo SCT
NCCN AML 2010
Is Chemotherapy Needed?
82 patients with APL
treated with ATRA and
ATO
GO added in high risk
patients
65 sequential (A), then
17 concurrent (B)
Ravandi, JCO, 2009
Is Chemotherapy Needed?
Ravandi, JCO, 2009
Future Directions
Is cytarabine or arsenic better for consolidation
in high risk patients?
Can ATRA and arsenic replace chemotherapy in
low risk patients? High risk patients (along with
GO)?
S0535, ongoing trial comparing
ATRA, ATO, GO
Daunorubicin, ATRA, ATO, GO
Recommended