Should the therapy of AML be driven by MRD quantification?

Sergio AmadoriDept. HematologyTor Vergata University HospitalRome

COHEM 09/2010

YES

Should the therapy of AML be driven by MRD quantification?

•It makes sense

•Independent predictor of outcome

•Platform for guiding therapy

AML

Biologically heterogenous group of disorders Disease recurrence major obstacle to cure Risk-stratification schemes (based on pre-therapy variables)

inadequate for predicting relapse in individual patients Can we do better in terms of predicting risk and guiding treatment

decisions?

SWOG(Medeiros et al, Blood 2010)

#1: It makes sense

Presence of occult disease (MRD) at morphologic CR is predictive of relapse

Quantification of MRD defines the risk

1012

1010

108

106

104

102

100

Time

No.

of l

euke

mic

cel

ls

Relapse

Cure

CR

MRD

MRD quantification: How? Morphology has no value More sensitive techniques needed

FCM RQ/PCR

Detection of LAIP•Applicable in >90% of pts•Fast, relatively inexpensive•Quantitative•Standard lab needed•Less leukemia specific•Sensitivity 10-3 – 10-5

Detection of LSGT•Applicable in ~60% of pts•Laborious, expensive•(semi-) quantitative•Special lab needed •Leukemia specific •Sensitivity 10-4 – 10-6

FCM: optimal method to test MRD in AML

Minimum 4-colour technology Aberrant LAIP identified at diagnosis in >90% of AMLs Average sensitivity 0.01% (10-4)

Multiple staining at diagnosis

Identification of LAIP(average 3 LAIPs per patient)

Definition of patient-specific “immunologic fingerprint”

Immunologic fingerprint used during follow-up

#2: Independent predictor of outcome

Many studies published in the last decade Main conclusions

MRD monitoring feasibleMost relevant checkpoints

- End of induction- After first consolidation

Independent prognostic factor for- Risk of relapse- Relapse-free survival- Overall survival

Maurillo et al, JCO 2008

Tor Vergata University Hospital (TVUH) 142 adults with AML in CR (median age 52y, range 18-75; 50 ≥ 60y) EORTC-GIMEMA AML-10, AML-12, AML-13 MRD+: ≥ 3.5 x 10-4 (0.035%)

Maurillo et al, JCO 2008

Excel: Ind – Cons –Good: Ind + Cons –

Poor: Ind + Cons +Ugly: Ind – Cons +

Buccisano et al, Blood 2010

Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow-cytometry improves risk stratification in adult

acute myeloid leukemia

TVUH 143 adults with AML in CR (median age 50y, range 18-75; 40 ≥ 60y) EORTC-GIMEMA AML-10, AML-12, AML-13, AML-17 MRD+: ≥ 3.5 x 10-4 (0.035%)

Buccisano et al, Blood 2010

Integrated Risk-ScoreLow-Risk High-Risk

Good K / MRD-Int K / MRD-

Adverse KFLT3+Good K / MRD+Int K / MRD+

#3: Platform for guiding therapy

MRD quantification

Predicts outcome

Refines risk-stratification

MRD-directed therapy“The time has come”

APL: a paradigm for MRD-directed therapy

GIMEMA(Lo Coco et al, Semin Hematol 2002)

PETHEMA(Esteve et al, Leukemia 2007)

Grimwade et al, JCO 2009

Prospective Minimal Residual Disease Monitoring to Predict Relapse of Acute Promyelocytic Leukemia and

to Direct Pre-Emptive Arsenic Trioxide Therapy

Non-APL AML: the next challenge

Improve risk-stratification and guide post-remission therapy Inform timing and type of transplantation in CR1 Detect impending relapse and guide preemptive therapy Improve outcome

MRD monitoring

MRD+ MRD-

Treatment intensificationNovel therapies Treatment reduction

Clinical application of MRD to guide therapy in AML

Limited data available

Retrospective Prospective

TVUH Pediatric AML

alloSCT > autoSCT for MRD+ AML

N=42MRD+ post-cons

N=37MRD- post-cons

Maurillo et al, JCO 2008

B

alloSCT > autoSCT for High-risk AML

auSCT alloSCT Total

L-risk 26 6 32

H-risk 30 17 47

Total 56 23 79

Low-Risk High-RiskGood K / MRD-Int K / MRD-

Adverse KFLT3+Good K / MRD+Int K / MRD+

Buccisano et al, Blood 2010

alloSCT > autoSCT for High-risk AML

0 1 2 3 4 5

Time (yrs)

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Dise

ase

Free

Sur

vival

P=0.003

AlloSCT (ITT)N=21

AlloSCTN=15

AutoSCTN=53

85%

44%

20%

Buccisano et al, 2010 unpublished

AML02: A prospective, multicenter study of risk/MRD-directed therapy

MRD monitored by FCM in 95% of pts MRD+: ≥ 0.1% cells with LAIP among BM mononuclear cells Used to intensify timing or components of subsequent therapy

Day 22 MRD ≥ 0.1% → intensified timing (ADE)Day 22 MRD ≥ 1% → ADE + GOPersistent MRD ≥ 0.1% → eligible for HSCT

SR(with donor)

HR

Enrollment,Randomization,

Initial Risk Assignment

H-ADEADE

±GO

FinalRisk

Assignment

SCT

CI CII CIII

ADE

MRD MRD

LRSR(w/o donor)

SR(with donor)

HR

(Rubnitz et al, Lancet Oncology 2010)

AML02: Main conclusions

Risk- and MRD-adapted therapy resulted in 71% OS Day 22 MRD >1% significantly associated with worse

OS, EFS, CIR

71% ± 4%OS

63% ± 4% EFS

00.10.20.30.40.50.60.70.80.9

1

0 1 2 3 4 5 6 7

19% ± 3%

Years on Study

9% ± 2%

Relapse

Death

N=230CR rate 94%MDR+ 37% (Ind1) MDR+ 20% (Ind2)

St. Jude AML Trials

GIMEMA AML1310: a study of risk-adapted and MRD-directed therapy for adult 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

CR

Indu

ctio

n(1

or 2

cou

rses

)

Con

solid

atio

n 1

autoSCT

alloSCT

alloSCT: MRD, MUD, UCB, HRD

GIMEMA AML1310: Aims

Improve outcome byRefining risk stratificationUsing MRD to guide type of transplant in Int-risk AML

Primary endpointOverall survival

Secondary endpointsCIRDFSEFS

Issues to address

20-30% relapse rate in MRD negative Why are we unable to predict it? Technical reasons

Increase sensitivity/specificityDefine more significant thresholdsDefine more relevant checkpoints

Biological reasonsQuantification of LSC (CLL-1)

Conclusions

Independent predictor of outcome Can be used as an early endpoint to assess efficacy Refines pre-therapy risk-stratification, providing a

framework for development of more tailored treatment approaches

Routinely used to guide management of patients with APL

MRD-directed treatment strategies likely to improve the management of other subtypes of AML

Acknowledgments

Dept. Hematology Tor Vergata Univ. HospitalAdriano VendittiFrancesco Buccisano Luca MaurilloMaria I. Del PrincipeFrancesco Lo CocoWilliam Arcese

GIMEMA GroupMarco VignettiPaola FaziGiulio D’Alfonso

AcknowledgmentsEmperor Caesar Augustus

(63 B.C. – 14 A.D.)

“Sic Est”