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Allogeneic HSCT in AML Where are we in 2016?
Didier Blaise, MD Institut Paoli Calmettes,
CRCM and Aix Marseille University
Marseille, France
Whom to be considered for HSCT?
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Koreth J, Jama, 2009 Evidence based medicine
and real life?
Hübel et al, 2011
What to expect from allo HSCT?
“The theoretical principle of treatment of acute leukemia
by adoptive immunotherapy is to permit allogenic,
immunologically competent cells to act against the host's
leukemic cells and the basic leukemogenic factors
present in the host.” G Mathe, 1965
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Infusion of HLA-mismatched PBSC improves
the outcome of chemotherapy for AML in
elderly patients
M Guo, Blood, 2012
Allogeneic HSCT
Recent breakthroughs
• Reduced toxicity
• Donor availability
• Post transplant treatments
Reduced Intensity?
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• Eligibility • Poor prognosis AML/MDS • HLA identical RD or UD
• Primary endpoint : 2 year PFS • Sample size: 177 patients
• Quality of life study • Economics • Non interventional PK • BX Pharmacogenomics
Prospective Clinical Trial
Dose Intensity study NCT: 01985061
Not AML… but AMLs!
Patel JP, NEJM, 2012
Pre
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E J
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loo
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01
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Intermediate Risk Low Risk
Patients beyond 60 years
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HLA-Identical Donor Availability
is a major limitation
A donor for every patient?
CB T replete Haplo MM UD
Cost Very High 20-40 000 US $
Low High 20-25 000 US $
Probability finding donor
Intermediate High Intermediate High if caucasian
Timing Fast Very Fast From fast to long
aGVHD Intermediate Low High
Severe Infections High Low Intermediate
Relapse Low ? Low
TRM High Low High
Immunotherapy No Yes Yes
Elderlies: good area for proof of concept
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0 12 24 36 480
50
100
Months Post-Transplant
Perc
en
t su
rviv
al
PFS
Haplo MRD UD
0 12 24 36 480
50
100
Months Post-Transplant
Perc
en
t su
rviv
al
Haplo MRD UD
PFS w/o ext cGVHD
Blaise, BBMT, 2015
Comparison of 2 allo HSCT strategies for
patients older than 55 years and lacking MRD
• Primary Question – One year DFS w/o ext cGVHD
• Population – High risk hematologic
malignancies
• Numbers: 54 patients per arm
• Starting time: – Day of no MRD
• Secondary questions – other
– QOL
– Economic evaluation
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• Prospective Study
– HAPLO • F5Bx2
• Thiothepa: 5mg
• HD Cy post HSCT
• CyA+MMF
– MUD 10/10 and 9/10 • F5Bx2
• ATGx2
• CyA+MMF
• Graft – PBSC
Allo-HSCT for Refractory AML
Patients Age CR at allo Cond NRM CIR OS PFS
Michallet
BMT 2000379 28y 149 MAC 45% - 22% 20%
Duval
JCO 20101673 38y 0 MAC - - 19% -
Craddock
Leuk 2011168 41y 0 MAC - 45% 26% 23%
Todisco
Leuk 2013523 48 0 MAC 16% 55% 16% 21%
Schmid JCO
200575 52y 16 SEQ 33% - 42% 40%
Schmid
Blood 2006103 52y 1 SEQ 22% 37% 40% 39%
Pfeiffer
Haem 2013141 51y 11 SEQ 18% 34% 53% 48%
Allogeneic Immunotherapy platform
Conditioning Donor
Age Comorbidity
Relapse CR Mol CR Ref
AML
Pre Allo-HSCT Treatments
NRM GVHD
Allogeneic Immunotherapy platform
Conditioning Donor
Age Comorbidity
Relapse CR Mol CR Ref
AML
Pre Allo-HSCT Treatments
QOL NRM GVHD
Post Allo-HSCT Treatments MRD, Chimerism
Patient-adapted Allogeneic Immunotherapy
HLA KIR Age
Drug combination for conditioning
Valdez exp hem 2015
Valdez env mol mut 2010
Conditioning for Refractory AML / MDS / ALL
Fludarabine
Bu Bu
D -5 D -6 D -4 D -3 D -2 D -1 D 0
PK PK guided dose
Cladribine Dose Escalation
CSA +/- MMF
PT-Cy
D +3 D +4
Cladribine dose Evaluation for REfractory Acute Leukemia (CEREAL Trial)
Devillier on going study
PBSC
N=29 Age 18-70 All donors
Overview
Age Comorbidity
AML / ALL / MDS
Chemo
Epidrugs Immunotherapy
TKI
Epidrugs
Pre Post
Sorafenib post Allo for AML with FLT3-ITD
Chen BBMT 2014
Prospective Phase I trial
D0 D45 - D120
Sorafenib 12 cycles (28 days) Escalated dose, Twice daily
• 200 – 200 mg n=3 0 DLT • 400 – 200 mg n=3 0 DLT • 400 – 400 mg n=6 1 DLT
MTD 400 mg x 2/d
Additional 10 patients at MTD
N = 22 AML FLT3-ITD CR after Allo
2-y OS 78% 2-y PFS 72%
5/22 Sorafenib discontinuation 12/16 dose reduction
Relapse n=3 (2 ref) NRM n=2
24 R Devillier, Marseille transplant Program
Sorafenib post Allo for AML with FLT3-ITD
Brunner BJH 2016
Retrospective study
26 Sorafenib vs. 43 Control
• 200 – 200 mg n=6 • 400 – 200 mg n=3 • 400 – 400 mg n=17
Decitabine post Allo for AML / MDS
Pusic BBMT 2015
D0 D50 - D100
N = 22 - Escalated doses
• 5 mg/m² n=9 1 DLT • 7.5 mg/m² n=4 0 DLT • 10 mg/m² n=4 0 DLT • 15 mg/m² n=5 0 DLT
MTD unestablished
Prospective Phase I trial
8 Cycles 6 weeks 6 weeks
Azacytidine post Allo for AML / MDS
De Lima Cancer 2010
MAC + Haplo + Early Prophylactic DLI
Prophylactic DLI for AML
N = 22 CR AML Full Chimerism No MRD
Legrand BMT 2016 Single center experience
CSA
Prophylactic DLI: Randomized trial
Comparative phase II trial of Early prophylactic donor Lymphocyte Infusion after allogeneic hematopoietic stem cell
Transplantation for patients with Acute Myeloid Leukemia
R
Observational Arm
D+90 D+135 D+60
Prophylactic DLI x 3
Lettre d’intention PHRC-K
N = 124
Overview
Age Comorbidity
AML / ALL / MDS
Chemo
Epidrugs Immunotherapy
TKI
Epidrugs
Pre Post
Perspectives +++
T-cell adoptive immunotherapy
Batlevi Nat Rev Clin Onc 2015
NK-cell adoptive immunotherapy
Childs Nat Rev 2015
NK-cell adoptive immunotherapy
Allogeneic immunotherapy
Modulation?
SR CR1 HR CR1 Advanced
Immunotherapy bridge + +++
CDT MAC/MA-RTC vs. RIC
+++ ++ +
Donor HLA id vs. alternative
+ +++ ++++
GVHD Prophylaxis No ATG vs. ATG
short vs. long term CSA
++++ ++ +
Post Graft immunotherapy No vs. Yes
+ +++ ++++
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Conclusions
• Allogeneic Immunotherapy is an effective
therapy for AML
• What is essential ?
– Not what has been done so far…
– But what you yet have to do!
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Ollie,
So much to do… Keep going!
Stan
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– Transplant Program
• S Furst
• C Faucher
• J El Cheikh
• L Castagna
• A Granata
• S Harbi
• R Crocchiolo
• R Devillier
– Nursing Staff
• L Caymaris
– Cellular Therapy Unit
• C Chabannon
– Hematology department
• N Vey
• R Bouabdallah
• Tumor Immunology Lab
• D Olive
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R. Crocchiolo R. Devillier
C Saillard
S Furst L Castagna
C Chabannon
J El Cheikh C Faucher
A Granata B Mohty
S Harbi L Caymaris
Collaborations
– FB Petersen, Intermountain HC, SLC
– M Mohty, St Antoine, Paris
– B Andersson, MD Anderson, Houston