risk-adapted therapy of aml in younger adultssolalettura].pdf · risk-adapted therapy of aml in...
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Risk-adapted therapy of AMLin younger adults
Sergio AmadoriTor Vergata University HospitalRome
Pescara 11/2010
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AML: treatment outcome
Better treatment strategies needed
<10<202550>60
40451075<60
6060585<15
OS %DFS %ED %CR %Age
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Molecular-cytogenetic heterogeneity
Otheradverse14%
MLL‐PTD5%
inv(3)/t(3;3)/EVI‐13%
FLT3‐ITD/NPM1wt12%
21%
CEBPAmut(biallelic)/FLT3‐ITDneg3%NPM1mut/FLT3‐ITDneg/WT1wt18%
inv(16)/t(16;16)/CBFB‐MYH115%
t(8;21)/RUNX1‐RUNX1‐T18%
t(15;17)/PML‐RARA11%
INTERMEDIATE
ADVERSE
FAVORABLE
Grimwade & Hills, ASH 2009
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Factor CommentAge Major impact at diagnosis
WBC Continuous variable
Prior therapy or MDS? Karyotype may be more important
Extramedullary disease Variable
Day 14 blast count Higher percentage worse
# cycles of induction One better than two
Cytogenetic/molecular profile Major impact at diagnosis
Gene expression profile Can further subdivide patients
MicroRNA expression Needs validation by other groups
Gene sequencing Future application
MRD detection at CR Independent predictor of outcome
AML: prognostic factors
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How do we treat younger patients withAML in 2010?
ν Treatment stratification based on age andgenotypeCytogeneticsMolecular diagnostics
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AML therapy: current standard
ν Remission induction chemotherapyAnthracycline + Ara-C (3+7 or variants)
ν Post-remission therapyID/HD-Ara-C based consolidation (1 or more courses)Auto-SCTAllo-SCT
Decision based on risk and doctor/patient preference
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Strategies to improve current standard
ν Add and/or intensify cytotoxic drugsν Add new agentsν Add immunotherapy (IL-2) as
maintenance
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Add and/or intensify cytotoxic drugs
ν Addition of VP-16 or 6-TG or HD-Ara-Cproduced no survival advantage
ν Which anthracycline?ν Anthracycline doseν How much treatment?
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Which anthracycline?
Mandelli et al, JCO 2009
DNR 50x3MXR 12x3IDA 10x3
EORTC-GIMEMA AML-10
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Anthracycline dose
Is DNR “90” better than “45/50”?
ECOG 1900
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ECOG 1900: Outline
Daunorubicin45 mg/m2 x 3
+SDAC
AllogeneicSCT
CRDaunorubicin90 mg/m2 x 3
+SDAC
HighRisk
HiDAC x 2PBSCH after2nd course
GO 6 mg/m2
(1 mo pre-SCT)
AutologousSCT
A
B
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ECOG 1900: Results
ν Phase 3ν 657 pts (median age 48y, range 17-60)ν CR%: 57.3 (SD) vs 70.6 (HD), (P = 0.001)ν ID%: 4.5 (SD) vs 5.5 (HD)ν OS (median/mos): 15.7 (SD) vs 23.7 (HD), (P=0.003)
Age >50: no survival benefit (HD)Adverse cytogenetics: no survival benefit (HD)
Fernandez et al, NEJM 2009
But…
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ECOG 1900 vs MRC AML15
ν ECOG 1900Overall CR rate 63.9%HD 70.6%SD 57.3%
ν Median survivalHD 23.7 mosSD 15.7 mos
ν MRC AML15DNR 50x3Overall CR rate 79.8%
ν Median survivalWhole cohort 29.9 mos
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SWOG 0106 vs ECOG 1900
Appelbaum F, EHA 2010
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How much treatment?(MRC: 4 vs 5 courses)
Burnett A, 2010
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How much treatment?(MRC: 3 vs 4 courses)
Overall Good Risk
Poor RiskInt Risk
Burnett A, 2010
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Add new agents
ν New cytotoxicsNucleoside analogs
ν Targeted agentsGemtuzumab (GO)FLT3 inhibitorsATRA
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ν 673 pts age 18 to 60 yrs randomized to DA + ara-C (DAA n=223), DA +fluda (DAF; n=219), DA + cladribine (DAC; n=210)
ν Median follow up 34 m:
ν Early death rates: 9-11% (NS)
Holowiecki et al, ASH 2009
Outcome DAC DAF DAA p (vs DAA) p (vs DAF)
CR (%) 68 59 56 .013 .08
CR post 1 (%) 62 55 51 .017 .016
3-yr OS (%) 46 30 31 .02 .02
2-yr LFS (%) 47 40 39 NS NS
Adding Cladribine
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Clofarabine in combination with a standardremission induction regimen in patients 18-60years old with previously untreatedintermediate and poor risk acute myelogenousleukemia (AML) or high risk myelodysplasia(MDS): a phase 1-2 study
Adding ClofarabineEORTC-GIMEMA AML-14A
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Study design (2)
ν Remission inductionIdarubicin: 10 mg/m2/d, on d1, d3, d5
Ara-C: 100 mg/m2/d ci on d1-d10 Clofarabine (1 hrs inf./push injection): test dose on d2, d4, d6, d8, d10 if PR after 1st induction: 2nd induction if CR: start consolidation
ν ConsolidationAra-C (c.i.): 500 mg/m2/12h (2-hr infusion) on d1-6Idarubicin (i.v): 10 mg/m2/d on d4-6
Step TDClofarabine
(mg/m2)
Arm A: Arm B:
dose/day(mg/m2)
Nrof pts
dose/day (mg/m2)
Nrof pts
-2 25 5 3 5 3
-1 37.5 7.5 3 7.5 3
0 50 10 3 10 3
1 75 15 6 15 3
2 100 20 3 20 3
3 125 25 3 25 3
4 150 30 3 30 3
EORTC-GIMEMA AML-14A (phase 1)
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No furtherTreatment
DA 3+10
+/- GO
FLAG-Ida
+/- GO
DA
3+8
FLAG
-Ida
MACE
+/- GO MidAc
AC 3g/m2
+/- GO AC 3g/m2
AC 1g/m2
ADE10+3+5
+/- GOADE
8+3+5
AC 1.5g/m2
+/- GO AC 1.5g/m2 R
Course 1 Course 2 Course 3 Course 4
R
Course 5
RISK
ASSESSMENT
R
Adding GO: MRC AML15
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GO: MRC AML15
Burnett A, 2010
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GO: MRC AML15
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GO: SWOG 0106
RANDOMIZATION
DNR+Ara-C+GO (6 mg/m2)
HiDAC
3 courses
RANDOMIZATION
GO x 3(5 mg/m2 monthly)
No therapyDNR+Ara-C
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GO: SWOG 0106
ν No improvement in CR rate, RFS or OSν Higher fatal AE rate during induction in GO armν No improvement in DFS on GO maintenanceν GO may improve RFS and OS in pts with favorable
cytogenetics
Petersdorf et al, ASH 2009
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Adding FLT3 inhibitors
Stone et al, ASH 2009
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PKC412
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PKC412
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Schlenk et al, Leukemia 2004
Adding ATRAAge 61+
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Schlenk et al, Haematologica 2009
Adding ATRA
Age 61+
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Adding ATRA: MRC AML12
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MRC AML12
Burnett et al, Blood 2010
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MRC AML12
Burnett et al, Blood 2010
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ν IL-2 activates T and NK cellsν Rationale for efficacy in preventing relapse
based on preclinical dataν No benefit in any of 6 large randomized trials
using IL-2 monotherapyν Histamine (HDC) protects T and NK cells from
inactivation by myeloid cells (induced by ROSproduction)
Add IL-2 immunotherapy as maintenance
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Reference: Hellstrand et al., J. Immunol. 153: 4940-7 (1994)
How HDC may improve IL-2 efficacy
Romero et al, Scand. J. Immunol. 2009
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IL-2/HDC maintenance in AML
Brune et al, Blood 2006
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Strategies to improve current standard
ν Refine pre-therapy risk stratificationthrough incorporation of MRD data
Buccisano et al, Blood 2010
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alloSCT > autoSCT for High-risk AML
792356Total
471730H-risk
32626L-risk
TotalalloSCTauSCT
Adverse KFLT3+Good K / MRD+Int K / MRD+
Good K / MRD-Int K / MRD-
High-RiskLow-Risk
Buccisano et al, Blood 2010
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GIMEMA AML1310: a study of risk-adapted and MRD-directed therapy foradult AML
Low-risk: CBF/Kitwt; NPM1+/FLT3-Int-risk: all othersHigh-risk: Adverse K; FLT3+
Diagnosis
Low-risk
Int-risk
High-risk
MRD-
MRD+
MRD marker
LAIP
Risk stratif
CG, molecular
MRD assess
LAIP
FLA-I salvageNo CR CR
CRIn
duct
ion
(1 o
r 2 c
ours
es)
Con
solid
atio
n 1
autoSCT
alloSCT
alloSCT:MRD, MUD,UCB, HRD
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AML: personalized therapy