Should the therapy of AML be driven by MRD quantification? Sergio - PowerPoint PPT Presentation

Should the therapy of AML be driven by MRD quantification? Sergio Amadori Dept. Hematology Tor Vergata University Hospital Rome COHEM 09/2010

Should the therapy of AML be driven by MRD quantification? YES • It makes sense • Independent predictor of outcome • Platform for guiding therapy

AML SWOG (Medeiros et al, Blood 2010)  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?

#1: It makes sense Relapse 10 12 No. of leukemic cells 10 10 CR 10 8 10 6 MRD 10 4 10 2 Cure 10 0 Time  Presence of occult disease (MRD) at morphologic CR is predictive of relapse  Quantification of MRD defines the risk

MRD quantification: How?  Morphology has no value  More sensitive techniques needed FCM RQ/PCR Detection of LAIP Detection of LSGT • Applicable in >90% of pts • Applicable in ~60% of pts • Fast, relatively inexpensive • Laborious, expensive • Quantitative • (semi-) quantitative • Standard lab needed • Special lab needed • Less leukemia specific • Leukemia specific • Sensitivity 10 -3 – 10 -5 • 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 feasible  Most 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-Score Low-Risk High-Risk Good K / MRD- Adverse K Int K / MRD- FLT3+ 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 PETHEMA (Lo Coco et al, Semin Hematol 2002) (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 MRD monitoring MRD+ MRD- Treatment intensification Treatment reduction Novel therapies  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

Clinical application of MRD to guide therapy in AML Limited data available Retrospective Prospective TVUH Pediatric AML

alloSCT > autoSCT for MRD+ AML N=42 N=37 MRD+ post-cons MRD- post-cons B Maurillo et al, JCO 2008

alloSCT > autoSCT for High-risk AML Low-Risk High-Risk Good K / MRD- Adverse K Int K / MRD- FLT3+ Good K / MRD+ Int K / MRD+ auSCT alloSCT Total L-risk 26 6 32 H-risk 30 17 47 Total 56 23 79 Buccisano et al, Blood 2010

alloSCT > autoSCT for High-risk AML 1,0 AlloSCT (ITT) 85% 0,9 N=21 0,8 0,7 Disease Free Survival 0,6 AlloSCT N=15 0,5 44% 0,4 0,3 AutoSCT 20% 0,2 N=53 0,1 P=0.003 0,0 0 1 2 3 4 5 Time (yrs) Buccisano et al, 2010 unpublished

AML02: A prospective, multicenter study of risk/MRD-directed therapy LR CI CII CIII SR H-ADE (w/o donor) Enrollment, ADE Final Randomization, ± Risk Initial Risk GO Assignment Assignment ADE HR HR SCT SR SR (with donor) (with donor) MRD MRD  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 + GO  Persistent MRD ≥ 0.1% → eligible for HSCT (Rubnitz et al, Lancet Oncology 2010)

AML02: Main conclusions N=230 CR rate 94% MDR+ 37% (Ind1) MDR+ 20% (Ind2) St. Jude AML Trials 1 0.9 0.8 71% ± 4% OS 0.7 0.6 63% ± 4% EFS 0.5 0.4 0.3 19% ± 3% Relapse 0.2 9% ± 2% Death 0.1 0 0 1 2 3 4 5 6 7 Years on Study  Risk- and MRD-adapted therapy resulted in 71% OS  Day 22 MRD >1% significantly associated with worse OS, EFS, CIR

GIMEMA AML1310: a study of risk- adapted and MRD-directed therapy for adult AML MRD marker Risk stratif MRD assess LAIP CG, molecular LAIP Low-risk Consolidation 1 autoSCT (1 or 2 courses) MRD- Induction CR Diagnosis Int-risk MRD+ alloSCT High-risk No CR FLA-I salvage CR Low-risk : CBF/Kit wt ; NPM1+/FLT3- alloSCT: Int-risk : all others MRD, MUD, High-risk : Adverse K; FLT3+ UCB, HRD

GIMEMA AML1310: Aims  Improve outcome by  Refining risk stratification  Using MRD to guide type of transplant in Int-risk AML  Primary endpoint  Overall survival  Secondary endpoints  CIR  DFS  EFS

Issues to address  20-30% relapse rate in MRD negative  Why are we unable to predict it?  Technical reasons  Increase sensitivity/specificity  Define more significant thresholds  Define more relevant checkpoints  Biological reasons  Quantification 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 Acknowledgments Emperor Caesar Augustus Dept. Hematology (63 B.C. – 14 A.D.) Tor Vergata Univ. Hospital Adriano Venditti “Sic Est” Francesco Buccisano Luca Maurillo Maria I. Del Principe Francesco Lo Coco William Arcese GIMEMA Group Marco Vignetti Paola Fazi Giulio D’Alfonso