francesco lo-coco, m.d. - comtecgroup coco presentation.pdf · management of acute promyelocytic...
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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
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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
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Avvisati et al. Blood 2002
EFS by type of chemo
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The hazards of chemo
Induction death
Death in CR
Cardiotoxicity
Second tumors
Fertility
Other long-term sequaele
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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%
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PETHEMA LPA99 TrialMortality in remission (by Sanz)
0.9%5.4%
23.1%
2.3%
Sanz et al, 2010
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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
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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
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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
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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
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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
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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
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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
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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
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ATO as single agent for newly diagnosed APL
Mathews et al. Blood 2006
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Estey, Blood 2006
ATO + ATRA ± GO for newly diagnosed APL
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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
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By courtesy of E. Estey
EFS in APL trials at MDACC
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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
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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)
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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
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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