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