Acute Myeloid Leukemia

Allo HSCT after Low Toxicity CDT A step toward individualized allogeneic

immunotherapy?

Didier Blaise, MDInstitut Paoli Calmettes,

CRCM and Aix Marseille University

Marseille, France

What do we know about allo

HSCT?

2

Koreth J, Jama, 2009

Are these data reflecting present time?

– 1982 to 2006

– Median age: 35-39 years

– HLA –ID siblings

– CYTBI / BUCY

Evidence based medicine

= Not always real life

Donor

T Cell

Donor

mononuclear cell

Host cells

Conditioning regimenDiseaseEndotoxin

IL2

IFN G

IL1

TNF@

IL1

TNF@

CDT is a major factor for

Mortality

Reduced Toxicity Strategies

and challenges

• Young: Lower NRM?

– Similar GVL

• Older: HSCT access?

– Acceptable NRM

– Efficient GVL

The less intensive, the less

toxic?

Flu-Bu-ATG

N=69

Flu-TBI

N=70

Age 54 (21-65) 52 (34-65)

- AML/HMY

- HLY

37%

63%

27%

73%

- Advanced 63% 65%

Blaise, D , cancer 2012

Flu-Bu-

ATG

Flu-TBI

NRM 38% 22%

Relapse 27% 54%

5

HLA-Matched, Related Allo PBSCT

The less intensive, the less

toxic?

Flu-Bu-ATG

N=69

Flu-TBI

N=70

Age 54 (21-65) 52 (34-65)

- AML/HMY

- HLY

37%

63%

27%

73%

- Advanced 63% 65%

Blaise, D , cancer 2012

Flu-Bu-

ATG

Flu-TBI

NRM 38% 22%

Relapse 27% 54%

2-4 aGVHD 47% 28%

Ext cGVHD 61% 46%

6

HLA-Matched, Related Allo PBSCT

GVHD remains a major cause of

death after RIC

No

n R

ela

pse M

ort

ali

ty

7

p=0.003

17%

31%

41%

12%

Saillard C, Leuk & Lymphoma, 2014

Dose Intensity and Toxicity

• DI is not the only cause of toxicity

The increase from 2.5 to 5 mg/kg of r-ATG dose

in RIC is beneficial

Devillier, R , BMT 20129

Study NMAC1

N 274

Age 60 (5-74)

AML 100%

CR1 / CR>1 /adv 58% / 36% / 6%

CDT

TBI2

BU2

BU4

100%

R-ATG 0%

MRD / UD 43% / 57%

10

Feasibility of Dose Intensity in older pts

1. Gyurkockza B, J Clin Oncol 2010

Study NMAC1 RIC2 MA-LTC3

N 274 102 79

Age 60 (5-74) 58 (20-70) 58 (55-76)

AML 100% 100% 80%

CR1 / CR>1 /adv 58% / 36% / 6% 76% /20% / 4% 32% / 23% / 47%

CDT

TBI2

BU2

BU4

100%

100%

100%

R-ATG 0% 100% 1 AG mm / UD

MRD / UD 43% / 57% 56% / 44% 52% / 48%

11

Feasibility of Dose Intensity in older pts

1. Gyurkockza B, J Clin Oncol 2010

2. Oudin C, haematologica 2014

3. Alatrash G, BBMT 2011

Study NMAC1 RIC2 MA-LTC3

N 274 102 79

Graft Failure 12 0 0

100 days NRM 4% 5% 5%

Overall NRM 26% 24% 26%

12

Feasibility of Dose Intensity in older pts

1. Gyurkockza B, J Clin Oncol 2010

2. Oudin C, haematologica 2014

3. Alatrash G, BBMT 2011

Dose Intensity and Toxicity

• DI is not the only cause of toxicity

• DI is not always associated with toxicity

CR1 AML

NMAC

N=160

RIC

N=78

MA-RTC

N= 25

14

Importance of Dose Intensity in Disease

Control?

The less intensive, the less

toxic?

Flu-Bu-ATG

N=69

Flu-TBI

N=70

Age 54 (21-65) 52 (34-65)

- AML/HMY

- HLY

37%

63%

27%

73%

- Advanced 63% 65%

Blaise, D , cancer 2012

Flu-Bu-

ATG

Flu-TBI

NRM 38% 22%

Relapse 27% 54%

2-4 aGVHD 47% 28%

Ext cGVHD 61% 46%

15

HLA-Matched, Related Allo PBSCT

Dose Intensity and Toxicity

• DI is not the only cause of toxicity

• DI is not always associated with toxicity

• DI may contribute controlling disease

17

• 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

Dose Intensity studyNCT: 01985061

Conclusions• Toxicity was (is) a major issue

– Low post-transplant toxicity is achievable• It is critical for some populations: Older/unfit patients

• CDT is an important adjustment variable

– Low toxicity does not mean only reduced intensity

• Disease control is the major issue– Low toxicity is not NO toxicity

• Still some work to do...

– Intensive CDT with low toxicity is achievable• Individualized CDT may be critical for better disease control

– Optimized CDT may not be sufficient to cure some diseases

• Post transplant therapy?

Why are individualized trt needed?

Patel JP, NEJM, 2012

• Cytogenetics

• Molecular Biology

• Disease Status

• MRD(?)

• Age

• Comorbidities

Not AML… but AMLs!

Risk changes with accurate

assessment

Intermediate Risk?

Patel JP, NEJM, 2012

Risk changes with accurate

assessment

E Jourdan, Blood, 2013 21

MRD

CBF AML

Good Risk?

5-year relative survival rates

with respect to age in patients

with AML1

5-y

ea

r s

urv

iva

l ra

te

0

10

20

30

40

50

60

Age, years

<45 45–54 65+55–64

1. Howlader N, et al (eds). SEER Cancer Statistics Review, 2010

2. Appelbaum FR et al, Hematology Am Soc Hematol Educ,2001

OS in patients aged >55 years

(ECOG data from 1973–1997)2

Outcome of AML in the elderly

Older patients with CBF AML

5-years LFS: 26%

CR rate: 88%

Prebet et al JCO 2010

Not AML… but AMLs…

and different patients…

Patient

-3 -2 -1-4-6 -5 0

Immunotherapy: Allo HSCT + recent developments

25

DiseaseHigh Risk

Allo-HSCT

Bridge to Allo

DiseaseHigh Risk

Refractory

• MoABs ? Bi-specifics

• Car-T cells?

• Checkpoint inhibitors?

DonorIndividualized

Conditioning

PatientAge

Comorbidities

-3 -2 -1-4-6 -5 0

26

GVHD prophylaxis

DiseaseStage

Prognostic

Factors

MRD

Allo-HSCT

HLA match vs Alternative DNMAC/RIC vs. MA-RTC

No Post-Graft IS

Long vs. short term

In-vivo T-cell depletBridge to Allo

Immunotherapy: Allo HSCT + recent developments

DonorIndividualized

Conditioning

PatientAge

Comorbidities

-3 -2 -1-4-6 -5 0

27

GVHD prophylaxis

Allo-HSCT

Chimerism

DiseaseStage

Prognostic

Factors

MRD

Rela

pse

Immunotherapy: Allo HSCT + recent developments

Bridge to Allo

DonorConditioning

PatientAge

Comorbidities

-3 -2 -1-4-6 -5 0

28

GVHD prophylaxis

Allo-HSCT

Chimerism MRD

DiseaseStage

Prognostic

Factors

MRD

Immunotherapy: Allo HSCT + recent developments

Bridge to Allo

Individualized

Conditioning

DonorConditioning

PatientAge

Comorbidities

-3 -2 -1-4-6 -5 0

29

GVHD prophylaxis

Chimerism

Individualized Immunotherapy

• Cellular therapy: DLI, NK-DLI , Treg

• Tumor Antigen vaccination: WT1…

• Post graft drugs: Aza, Lenalidomide,

anti-Kir moab…

• Car? Checkpoint inhibitors?

MRD

Allo-HSCT

DiseaseStage

Prognostic

Factors

MRD

Immunotherapy: Allo HSCT + recent developments

Bridge to Allo

Individualized

Conditioning

Tomorrow

allogeneic immunotherapy?

Immunotherapy bridge

CDTMAC/MA-RTC vs. RIC

DonorHLA id vs. alternative

GVHD ProphylaxisNo ATG vs. ATG

short vs. long term CSA

Post Graft immunotherapyNo vs. Yes

31

SR CR1

Immunotherapy bridge

CDTMAC/MA-RTC vs. RIC

+++

DonorHLA id vs. alternative

+

GVHD ProphylaxisNo ATG vs. ATG

short vs. long term CSA

++++

Post Graft immunotherapyNo vs. Yes

+

32

Tomorrow

allogeneic immunotherapy?

Tomorrow

allogeneic immunotherapy?

SR CR1 HR CR1 Advanced

Immunotherapy bridge + +++

CDTMAC/MA-RTC vs. RIC

+++ ++ +

DonorHLA id vs. alternative

+ +++ ++++

GVHD ProphylaxisNo ATG vs. ATG

short vs. long term CSA

++++ ++ +

Post Graft immunotherapyNo vs. Yes

+ +++ ++++

33

Conclusions

• Allogeneic Immunotherapy is an effective

therapy for AL

• What is essential ?

– Not what has been done so far…

– But what we yet have to do!

34

Ollie,

So much to do…Keep going!

Stan

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