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?

2

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

4

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?

8

• 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

be

t, JC

O 2

010

E J

ou

rda

n, B

loo

d, 2

01

3

Intermediate Risk Low Risk

Patients beyond 60 years

10

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

13

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

14

• 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

+ +++ ++++

35

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!

36

Ollie,

So much to do… Keep going!

Stan

37

– 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

38

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