Management ofAcute Promyelocytic Leukemia:

Less is better ?

Francesco Lo-Coco, M.D.

University Tor Vergata, Roma, Italy

1° World Congress on Controversies in HematologyRome, 2-5 September 2010

GIMEMA trials in newly diagnosed APL

• 77-81: DNR

• 82-88: IDA

• 89-93: IDA vs IDA+AraC

• 93-99: AIDA 0493

• 00-05: AIDA 2000

• 06-10: AIDA vs A2O3+RA

Avvisati et al. Blood 2002

EFS by type of chemo

The hazards of chemo

Induction death

Death in CR

Cardiotoxicity

Second tumors

Fertility

Other long-term sequaele

Causes of induction deaths with chemo + ATRA

Hemorrhage Infection Other

PETHEMA 5% 2-3% 1%

GIMEMA 3% 1-2% 1%

French-Belgian-Swiss 3% 2-3% 0.5-1%

MRC 5% 2% 1%

US-Intergroup 6-7% 1-6% 1-2%

PETHEMA LPA99 TrialMortality in remission (by Sanz)

0.9%5.4%

23.1%

2.3%

Sanz et al, 2010

Post-Induction toxicity in the AIDA 2000

420 in CRafter induction

377/420 (90%)evaluable afterconsolidation

43 (10%) off-study for:

17 toxicity (11 deaths)14 missing data

7 major protocol violation3 lost to follow-up

1 refusal1 other

362/377 (96%) testedfor RT-PCR

post-consolidation

358/362 (99%)PCR-negative

proceeded to maintenance Lo-Coco et al, Blood 2010

AIDA 0493 drop-outs during consolidation

1st 3rd(747)

2ndConsolidation Courses

(728) (681)CR

(n 761)

RelapseToxicity

Other causes

-13

6

329

9

2-

6Violation - 3 9

Lost to FU - 1 -

Refusal - 2 -1-6

32

2

747 728 681 664Remaining Pts

PETHEMA LPA99 TrialOther post-remission events (Sanz’s data)

1313

22

1414

3737

77

CNSCNS

** Montesinos ** Montesinos et al.et al., J Clin Oncol 2010, J Clin Oncol 2010

****

3737

Cardiac function in long-term survivors after the AIDA regimen

Cimino et al., submitted

--7 (3-10)

Median Follow-up from stop therapy (yrs.) (range)

6/34--

14/342/340/347/34

6/3418/3410/346/341/3410/34

Cardiovascular risk factors Hypertension (at diagnosis of APL) Hypertension at time of present evaluation Smoker Hypercholesterol Diabetes mellitus Family history of CHD

--NoneCardiovascular disease at diagnosis

1420

1619

Sex Male Female

45(24 - 62)

48.5(27 – 60)

Median Age (years) (range)

Controls(n=34)

Pts(n=34)

Features

Echocardiographic parameters

Pts(n = 34)

Controls(n = 34)

p

Mean EF (SD) (%)

56.53 (4.40) 58.58 (4.66) 0.013

Mean LAV (SD)(ml)

52.24 (17.16) 31.41 (10.36) < 0.0001

Mean E/A ratio (SD) 1.04 (0.31) 1.38 (0.21) < 0.0001

SWM abnormalities: hypokinesis akynesis dyskinesis

11(32%)*00

000

< 0.0001

Diastolic Disfuction:MildModerateSevere

18(52%)00

000

< 0.0001

ECHO parameters recorded in pts and controls

All recorded differences between pts and controls were sub-clinical

Cimino et al., submitted

Hem. CR Mol. CR Long-term CR

Anthracyclines + + +

Retinoids + - (*) - (*)

Arsenic Trioxide + + ?

Mylotarg (GO) + + ?

Active compounds in APL

(*) Mol and long-term CR reported with lipo-ATRA

Reasons why chemo might be unnecessary

• Liposomal ATRA monotherapy curative in 12/28 pts with WBC < 10,000

• ATO induces mol. CR in 80% rAPL • ATO + ATRA superior to ATO or ATRA alone

• Effectiveness of GO+ATRA in untreated and mol-relapsed APL

Estey, Blood 2006; Soignet, JCO 2001; Shen, PNAS 2004; Lo-Coco, Blood 2004

78%

51%

0

50

100

Baseline Induction Consolidation

Prop

ortio

n N

egat

ive

Molecular response by cyclewith single agent ATO for rAPL

Soignet et al. JCO 2001

ATO as single agent for newly diagnosed APL

Mathews et al. Blood 2006

Estey, Blood 2006

ATO + ATRA ± GO for newly diagnosed APL

NCI-CALGB study in newly diagnosed APL

• 582 patients, randomly assigned to: Standard Rx with ATRA+CHT Standard Rx + ATO 2 cycles after CR

• 3 yrs DFS: 77% in the ATO arm, vs 59%

• 3 yrs OS: 86% in the ATO arm, vs 77%

Powell et al, Blood 2010

By courtesy of E. Estey

EFS in APL trials at MDACC

Problems with ATO “no chemo” trials

Few numbers & limited follow-up

Only historical controls vs. chemo available to date

Duration of ATO unclear (Maintenance ? How long ?)

Long-term toxicity of ATO unknown

GIMEMA/SAL/AMLSG APL 0406 study

AIDA 2000 (including AraC for consolidation)

High-risk (wbc >10.000)

Low-risk(wbc<10.000)

R

AIDA 2000 (anthracycline-based consolidation)

ATRA + ATO (MDACC approach)

GIMEMA/SAL/AMLSG APL 0496: Study End-points

EFS at 2 yrs CR rate after inductionOS rate at 2 yrsCIR rate at 2 yrsToxicity episodesMolecular CR after 3rd cons Kinetics of PML/RARa Hospitalisation days during RxQuality of life

Primary

Secondary

Conclusive remarks

Need to discriminate high vs. low-risk pts

PCR-monitoring carried out in highly experienced labs may serve as a “safety guide” in experimental

(e.g. no chemo) trials

Results of ongoing R trials comparing “no chemo” vs. standard AIDA (Gimema, MRC) soon available