State of the Art Therapy of

Acute Promyelocytic Leukemia

Francesco Lo-Coco, MD

University Tor Vergata, Rome;

GIMEMA Cooperative Group, Italy

DGHO Annual Congress

Hamburg, October 10-14, 2014

• Early death: an unsolved issue

• Current standard Rx in first line

• Latest advances using chemo-free Rx

• Future perspectives in high risk disease

Outline

Early Death in APL: Real World Data

Study ED rate (< 30 d)

Swedish Registry1 29 %

SEER (USA)2 17 %

Stanford University3 26 %

Canadian Registry4 22 %

1Lehman, Leukemia 2011; 2Park, Blood 2011; 3McClellan, Haematologica 2011; 4 Paulson, Br J Haematol 2014

0

5

10

15

20

25

30

35

40

45

50

1997-2006 2007-2012

Perc

en

t E

D

WBC > 10

WBC < 10

ED by WBC at diagnosis

Lehman S, 6° Intl. Symposium on APL, Rome Oct. 2013

Significant improvement in ED and OS over time

1999-2010 Early era

(1999-2004) Late era

(2005-2010) Time since dx Survival% Survival % Survival %

30 days* 85 82 89

1 year 80 74 86

2 year 77 69 84

Paulson K, Br J Haematol 2014

Leukemia Referral Centers (Canada)

Early

Death %

OS at 1

Year, %

OS at 5 Yrs,

%

All patients 22 70 55

<50 years old 11 84 73

≥50 years old 36 52 29

No improvement in ED or OS over time

Paulson K, Br J Haematol 2014

Canadian Cancer Registry

Results for APL (1993-2007)

• Developed a simple 1.5 page treatment algorithm

• Quick diagnosis

• Ad hoc meeting and treatment planning

• Rapid initiation of therapy

• Aggressive management of coagulopathy

• Prevention of differentiation syndrome; early

recognition and management

• Implemented in 2010

A. Jillella et al., EHA 2014

Strategy at Emory Univ Hospital

•Affiliates contact us when a patient is diagnosed with APL

•Email or fax our algorithm

•Discuss patient with treating physician and recommend a treatment plan

•Follow up by phone, email or texting at least 3 to 4 times in the first 10

days- during which 70% of the deaths take place.

Strategy at Affiliated Sites

A. Jillella et al., EHA 2014

Survival Pre and Post Algorithm

A. Jillella et al, EHA 2014

• Early death, an unsolved issue

• Current standard Rx in first line

• Latest advances using chemo-free Rx

• Future perspectives in high risk disease

Outline

CHT ATRA ATRA ATO

Cure of

APL

CHT ATRA ATO

“Third Way”

Current treatment options in APL

Front-line Management of APL

ATRA and CHT: Some Open Issues

• CNS prophylaxis

• Ara-C (high-risk only?)

• Role of Maintenance

• Cost-effectiveness of MRD

• sMDS/AML

• Elderly pts

CHT ATRA ATRA ATO

Cure of

APL

CHT ATRA ATO

Conventional

approach

Alternative

approach

“Third Way”

Four studies reported

good results with the

triple combination

of ATO, ATRA & CHT

1. Hu J, et al. PNAS. 2009;106:3342–7 2. Powell BL, et al. Blood. 2010;116:3751-7 3. Iland HJ, et al. Blood. 2012;120:1570-80 3. Zhu H-H, et al. JCO. 2013;31:4215-21

Current treatment options in APL

Iland HJ, et al. Blood 2010

ATRA + ATO + CHT Australasian Leukemia and Lymphoma Group

Induction Consolidation Maintenance

ATRA + ATO

+ CHT

2 cycles of

ATRA + ATO

5 cycles of sequential use of

ATRA and LD/CHT

Zhu H et al. JCO 2013

* Mitoxantrone was added at a dose of 1.4 mg/m2/day on 5 days 4, 5, 6, 7, and 8 (if WBC >10 x 109/L start

on day 1).

ATRA = all-trans retinoic acid; ATO = arsenic trioxide; RIF = Realgar-Indigo naturalis formula; HA =

homoharringtonine and cytarabine; DA = daunorubicin and cytarabine; MA = mitoxantrone and cytarabine

*

Randomized comparison of oral arsenic vs. IV ATO

ATO+ATRA+CHT

Chinese Cooperative Group

Zhu H et al. JCO 2013

n = 114; CR 113; Relapse 1; Death in CR 1

n = 117; CR 114; Relapse 1

3-year OS 99.1% (95% CI, 97.2% to 99.9%)

3-year OS 96.6% (95% CI, 93.0% to 99.8%

ATO+ATRA Vs. RIF+ATRA

Chinese APL Cooperative Group

• Early death, an unsolved issue

• Current standard Rx in first line

• Latest advances using chemo-free Rx

• Future perspectives in high risk disease

Outline

GIMEMA-SAL-AMLSG MRC – AML 17

ATO+ATRA without CHT

Randomized Studies

R Estey et al. Blood 2006;107:3469-73

Lo-Coco et al. Blood 2010;116:3171-9

Induction

ATRA

ATO

Until CR

Consolidation

ATO ATO ATO ATO

4 weeks on / 4 weeks off

2 weeks on / 2 weeks off

Induction Consolidation Maintenance

ATRA ATRA ATRA ATRA ATRA

MTX + 6MP IDA IDA IDA MTZ

Until CR 2 years 3 monthly cycles

Chemo

arm

ATO

arm

APL0406: Treatment Arms

Lo-Coco et al. NEJM 2013

0406 Trial Results (n=162, median f.up 34m)

What about QoL of patients treated with Arsenic?

APL 0406: QoL Outcomes

5 functioning scales: physical, role, emotional, cognitive, social

3 symptom scales: fatigue, nausea/vomiting, pain

6 single-item scales: dyspnoea, sleep disturbances, appetite loss

constipation, diarrhea, financial impact

Global QoL scale

EORTC QLQ-C30

Questionnaire

A total of 162 pts enrolled between Oct 2007 and Sept 2010

156 patients received at least one dose of the assigned Rx

ATRA-Chemotherapy

Post induction

Post consolidation

ATRA-ATO

Post induction

Post consolidation

156 patients

N= 53 N= 62

N= 61 N= 58

N= 150 expected

N= 142 expected

Compliance 77%

Compliance 84%

Results and QoL compliance

Functional aspects / Global QoL

Estimated differences in EORTC QLQ-C30

mean scores and 95% CIs between Rx arms

*Clinically meaningful difference; (based on Cocks K, et al., JCO 2011).

Symptoms

*Clinically meaningful difference; (based on Cocks K, et al., JCO 2011).

Estimated differences in EORTC QLQ-C30

mean scores and 95% CIs between Rx arms

Overall, current QoL findings further support the use of ATRA plus ATO

as preferred first-line treatment in low-intermediate risk APL patients.

Post-induction:

Patients treated with ATRA-ATO reported statistically

significant less fatigue, and other clinically relevant better

outcomes for appetite loss, nausea/vomiting, constipation,

physical and cognitive functioning

Post-consolidation:

No major difference in QoL between treatment at the end

of 3rd consolidation course

Results on QoL in APL0406 study

Best AIDA

(Italian)

Chemo-free

(ATRA-ATO)

APL patients

(Low/Int and

high risk) R

MRC-AML17 APL Protocol: 2009-2013

Alan K Burnett

School of Medicine, Cardiff University

United Kingdom

Rome, October 2013

APL: Less is just as good

Week 1- 4 9 - 12 17- 20

Week1- 2

25 - 28

9-10 13-14 5-6 17-18 21-22 25-26

ATRA

ATO

d1 d60

3-monthly

BM for PCR

to 36mo from diagnosis

PCR

ATRA

PCR

CHEMO-FREE

AIDA

Ida Ida Mitox Ida

3-monthly

BM for PCR

to 36mo from diagnosis

MRC-AML17 APL Protocol: 2009-2013

Induction: ATO 0.3mg/kg days 1-5 week 1

0.25mg/kg X 2 per week

Consolidation: ATO 0.3mg/kg X2 per week, in wk1

0.25mg/kg X2 per week x3 weeks

(4 courses)

ATO Schedule in AML17

• Early death, an unsolved issue

• Current standard Rx in first line

• Latest advances using chemo-free Rx

• Future perspectives in high risk disease

Outline

ATO+ATRA+Ida vs ATRA+CHT for high-risk APL

APOLLO-Trial

Open label, randomized, prospective, intergroup

phase III study

Inclusion criteria:

Newly diagnosed and genetically confirmed APL

Age: ≥ 18 and ≤ 65 yrs

WBC at diagnosis > 10 x 109/L

ECOG performance status 0-2

The first 4 days of therapy are identical in the two arms

Treatment Arms

• to show superiority of the experimental arm:

clinically relevant increase of 10% in EFS at 2 yrs

(from 77% in the AIDA study* to ≥87%)

Aim

* Lo-Coco et al, Blood 2010

Primary efficacy endpoint:

•EFS

Key secondary endpoint(s):

•CR, OS and CIR

•Quality of life

•Toxicity profile

•Rate of early death

•Kinetics of MRD

•Cumulative incidence of secondary MDS or AML

•Hospitalization

•Cost analysis

Objectives

GROUPS Country PI

SAL Germany U.Platzbecker

GIMEMA Italy F. Lo-Coco

AMLSG Germany R. Schlenk

ALSG Germany E. Lengfelder

OSHO Germany D. Niederwieser

French-Belgian-Swiss France P. Fenaux

PETHEMA Spain M. Sanz

HOVON Netherlands E. Vellenga

EORTC EU F. Baron

NCIC-CTG Canada S. Couban

Participating groups

Early death is still the main obstacle to cure

High cure rates can be achieved with optimized

combinations of:

• ATRA + CHT

• ATRA + ATO

• ATRA + CHT + ATO

ATO+ATRA appears superior to ATRA-CHT for

Low-intermediate risk. However:

• Not yet approved for this indication in most countries

• Not yet assessed in high-risk (R studies needed)

Conclusions

Acknowledgements

L. Cicconi

M. Divona S.K. Hasan

M. Breccia

F. Ferrara

E. Di Bona

M. Breccia

A.M. Carella

F. Fabbiano

G. Leone

S. Orlando

E. Morra

G. Specchia

P. Fazi

M. Vignetti

G. Avvisati

A. Rambaldi

G. Rossi

S. Amadori

C. Ciardi

M. Divona

S. Iacobelli

F. Mandelli

H. Döhner

A. Ganser

K. Dohner

J. Krauter

R.F. Schlenk

E. Estey

(Seattle, USA)

Acknowledgements

M.A. Sanz

P. Montesinos

(Valencia, Spain)

A.K. Burnett

D. Grimwade

(NCRI, UK)

G.Ehninger

C. Thiede

C. Brandts

H. Link

W. Aulitzky

M. Hänel

K. Schäfer-Eckart

S. Krause

K.-H. Pflüger

N. Schmitz

M. Sauer

U. Platzbecker