Less is better ? Francesco Lo-Coco, M.D. University Tor Vergata, - - PowerPoint PPT Presentation

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Less is better ? Francesco Lo-Coco, M.D. University Tor Vergata, - - PowerPoint PPT Presentation

Nov 24, 2023 133 likes •358 views

Management of Acute Promyelocytic Leukemia: Less is better ? Francesco Lo-Coco, M.D. University Tor Vergata, Roma, Italy 1 World Congress on Controversies in Hematology Rome, 2-5 September 2010 GIMEMA trials in newly diagnosed APL

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SLIDE 1

Management of Acute Promyelocytic Leukemia: Less is better ?

Francesco Lo-Coco, M.D.

University Tor Vergata, Roma, Italy

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

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SLIDE 2

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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SLIDE 3

Avvisati et al. Blood 2002

EFS by type of chemo

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SLIDE 4

The hazards of chemo

 Induction death  Death in CR  Cardiotoxicity  Second tumors  Fertility  Other long-term sequaele

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SLIDE 5

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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SLIDE 6

PETHEMA LPA99 Trial Mortality in remission (by Sanz)

0.9% 5.4% 23.1% 2.3% Sanz et al, 2010

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SLIDE 7

Post-Induction toxicity in the AIDA 2000

420 in CR after induction 377/420 (90%) evaluable after consolidation 43 (10%) off-study for: 17 toxicity (11 deaths) 14 missing data 7 major protocol violation 3 lost to follow-up 1 refusal 1 other 362/377 (96%) tested for RT-PCR post-consolidation 358/362 (99%) PCR-negative proceeded to maintenance Lo-Coco et al, Blood 2010

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SLIDE 8

AIDA 0493 drop-outs during consolidation

1st 3rd

(747)

2nd Consolidation Courses

(728) (681)

CR

(n 761) Relapse Toxicity Other causes

  • 13

6 3 29 9 2

  • 6

Violation

  • 3

9 Lost to FU

  • 1
  • Refusal
  • 2
  • 1
  • 6

3 2 2

747 728 681 664

Remaining Pts

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SLIDE 9

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

13 13 2 2 14 14 37 37 7 7 CNS CNS ** Montesinos ** Montesinos et al. et al., J Clin Oncol 2010 , J Clin Oncol 2010 ** ** 37 37

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SLIDE 10

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

  • 14/34

2/34 0/34 7/34 6/34 18/34 10/34 6/34 1/34 10/34 Cardiovascular risk factors Hypertension (at diagnosis of APL) Hypertension at time of present evaluation Smoker Hypercholesterol Diabetes mellitus Family history of CHD

  • None

Cardiovascular disease at diagnosis 14 20 16 19 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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SLIDE 11

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%)* < 0.0001

Diastolic Disfuction: Mild Moderate Severe

18(52%) < 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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SLIDE 12
  • 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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SLIDE 13

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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SLIDE 14

78% 51%

50 100

Baseline Induction Consolidation Proportion Negative

Molecular response by cycle with single agent ATO for rAPL

Soignet et al. JCO 2001

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SLIDE 15

ATO as single agent for newly diagnosed APL

Mathews et al. Blood 2006

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SLIDE 16

Estey, Blood 2006

ATO + ATRA ± GO for newly diagnosed APL

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SLIDE 17

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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SLIDE 18

By courtesy of E. Estey

EFS in APL trials at MDACC

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SLIDE 19

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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SLIDE 20

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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SLIDE 21

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

EFS at 2 yrs CR rate after induction OS rate at 2 yrs CIR rate at 2 yrs Toxicity episodes Molecular CR after 3rd cons Kinetics of PML/RARa Hospitalisation days during Rx Quality of life

Primary Secondary

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SLIDE 22

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