Traitement des LCM en rechute et perspectives

Prof Le Gouill Steven

CHU de Nantes

DES hématologie 26 avril 2019

Autograft

R-Maintenance

R-CHOP(R-Bendamustine)

R-Maintenance

R-BendamustineR-CVPR-Cbl

Other?

? Maintenance

- Nature of previous chemotherapy lines- Duration of response- Comorbidities, Age

3

ESMO

Dreyling et al. Annals of Oncology 28 (Supplement 4) 2017

Poly-chimiothérapies de rechute

• Bendamustine:• RiBVD (Gressin et al)• R-BAC (Visco et al)

• Anthracycline:• R-CHOP• VRCAP• Hyper-CVAD-MTX

• Aracytine• R-DHAP, R-DHAC, RDHAOx• Hyper-CVAD-MTX

• Non intensive• Chl-Ritux• CEP• VLB/CTC

Approved new drugs in R/R MCL

Wang ML, et al. N Engl J Med. Epub Ahead of Print 19 June 2013

0

10

20

30

40

50

60

70

80

90

100

No Prior Treatment withBortezomib

(n = 63)

Prior Treatment withBortezomib

(n = 48)

All Patients(N = 111)

Pati

ents

(%)

68% 67% 68%

PR

CR

19%

49%

23%

44%

21%

47%

IBRUTINIB Efficacy: ORR

Wang ML, et al. N Engl J Med. Epub Ahead of Print 19 June 2013

Efficacy: PFS

Median PFS in Months (95% CI)

No BortezomibExposure

BortezomibExposure

All Patients

7.4 (5.3-19.2)

16.6(8.3-NR)

13.9 (7.0-NR)

The median PFS among subjects with a CR has not yet been reached

Among subjects who achieved a PR, the median PFS was 17.5 months

NR, not reached.

Wang ML, et al. N Engl J Med Epub Ahead of Print 19 June 2013

Efficacy: OS

Median OS in Months (95% CI)

No BortezomibExposure

BortezomibExposure

All Patients

NR (10.0-NR)

NR(11.9-NR)

NR (13.2-NR)

NR, not reached.

The median OS for this study has not been reached

(estimated OS of 58% at 18 months)

Ibrutinib Versus Temsirolimus: ResultsFrom a Phase 3, International, Randomized,

Open-Label, Multicenter Study in Patients With Previously Treated Mantle-Cell Lymphoma

Simon Rule,1* Wojciech Jurczak,2* Mats Jerkeman,3* Rodrigo Santucci Silva,4

Chiara Rusconi,5* Marek Trneny,6* Fritz Offner,7* Dolores Caballero,8*

Cristina Joao,9* Mathias Witzens-Harig,10* Georg Hess,11* Isabelle Bence-Bruckler,12

Seok-Goo Cho,13 John Bothos,14 Jenna D. Goldberg,14 Christopher Enny,14

Shana Traina,14 Sriram Balasubramanian,15 Nibedita Bandyopadhyay,14

Steven Sun,14 Aleksandra Rizo,14 Jessica Vermeulen,16 and Martin Dreyling17*

1Derriford Hospital, Plymouth, UK; 2Jagiellonian University, Krakow, Poland; 3Skånes University Hospital, Lund University, Lund, Sweden; 4Instituto de Ensino e Pesquisa Sao Lucas, Sao Paulo, Brazil; 5Niguarda Cancer Center, Niguarda Hospital, Milan, Italy; 6Charles University General Hospital, Prague, Czech Republic; 7University Hospital Ghent, Ghent, Belgium;

8Hospital Universitario de Salamanca, Salamanca, Spain; 9Champalimaud Centre for the Unknown, Lisbon, Portugal; 10University Hospital Heidelberg, Heidelberg, Germany; 11University Medical School of the Johannes Gutenberg University,

Mainz, Germany; 12The Ottawa Hospital, Ottawa, ON, Canada; 13Seoul St. Mary’s Hospital, Seoul, Korea; 14 Janssen Research & Development, Raritan, NJ, USA; 15Janssen Research & Development, Spring House, PA, USA; 16Janssen Research &

Development, Leiden, The Netherlands; 17Klinikum der Universität München, Munich, Germany

*Member of the European MCL Network.

Patients with previously treated MCL

Enrollment dates:Dec 2012 – Nov 2013

1:1 → Stratified by number of prior lines of therapy and by sMIPI

Ibrutinib (N = 139)

Oral ibrutinib 560 mg daily starting Cycle 1, Day 1

Treat to PD or unacceptable

toxicity

Temsirolimus (N = 141)

Intravenous temsirolimus175 mg on Cycle 1, Days 1, 8, 15; then 75 mg on Days 1, 8, 15 of all subsequent cycles

RANDOMIZE

Primary end point:

• IRC-assessed PFS

Secondary end points included:

• IRC-assessed ORR (CR + PR)

• Overall survival

• Duration of response

• Time to next treatment

• Safety

• Patient-reported outcomes (FACT-Lym)

Jul 2014

Crossover to ibrutinib (after IRC-confirmed

PD; n = 32)

10

Treat to PD or unacceptable

toxicity

MCL3001 (RAY): Phase 3 Open-Label Study

• At a 2-year landmark, the PFS rate was 41% for ibrutinib versus 7% for temsirolimus

• Investigator-assessed HR for ibrutinib versus temsirolimus was 0.43 (95% CI, 0.32-0.58)

11

Primary End Point: IRC-Assessed PFSITT populationMedian follow-up: 20 months

Ibrutinib Temsirolimus

Median PFS (months) 14.6 6.2Hazard ratio (HR) 0.4395% confidence interval (CI)

0.32-0.58

Log-rank p value < 0.0001

0 3 6 129 15

Months

18 21 24 27 30

0

30

10

20

40

50

60

70

80

90

100

% a

live

wit

ho

ut

pro

gre

ssio

n

Patients at riskIbrutinib 139 114 101 83 77 45 34 8 5 0 0Temsirolimus 141 93 69 45 33 19 11 3 1 0 0

Temsirolimus

Ibrutinib

• 1-year survival rates were 68% for ibrutinib versus 61% for temsirolimus

• OS results are confounded by crossover to receive ibrutinib

• Overall, ibrutinib reduced the risk of death by 24%

12

0 3 6 129 15

Months

18 21 24 27 30

0

30

10

20

40

50

60

70

80

90

100

Patients at riskIbrutinib 139 125 113 103 92 84 64 35 14 2 0Temsirolimus 141 116 100 85 78 71 48 25 10 2 0

Temsirolimus

Ibrutinib

% a

live

Overall SurvivalIbrutinib Temsirolimus

Median OS (months) Not reached 21.3

HR 0.76

95% CI 0.53-1.09

Log-rank p value 0.1324

32 patients (23%) in the temsirolimus arm crossed over to receive ibrutinib

ITT populationMedian follow-up: 20 months

Should Ibrutinib always be used at first relapse ?

• Discontinuation rates due to AEs at time of primary analysis (median follow-up):

• PCYC-1104 (15.3 months): 7%

• SPARK (14.9 months): 7%

• RAY (20 months): 6%

Median 3.5-year follow-up of ibrutinib treatment in patients with relapsed/refractory MCL: A pooled analysis - Patient disposition

Total (Pooled)(N = 370)

Study, n (%)PCYC-1104SPARKRAY

111120139

Patients rolled over to CAN3001, n (%) 87 (23.5)

Median duration of follow-up, months (range) 41.1 (0.2-72.1)

Treatment discontinuation, n (%)AEDisease progressionDeathOther*

316 (85.4)37 (10.0)

218 (58.9)19 (5.1)

42 (11.4)

*Includes: alternative access to ibrutinib (n = 1); physician decision (n = 14); withdrawal of consent (n = 24); other reasons (n = 3).

Rule et al., ASH 2017 (abstract 151, oral presentation)

Median 3.5-Year follow-up of ibrutinib treatment in patients with relapsed/refractory MCL: a pooled analysis

Rule et al., ASH 2017 (abstract 151, oral presentation)

⚫ In this pooled analysis of 370 patients:– Approximately one-third (n = 115, 31.1%) were

treated with ibrutinib for ≥ 2 years

– 54 remained on ibrutinib at time of analysis, with a median exposure of 46.3 months (range 28.8-72.1)

– Maximum treatment exposure was 72 months

Ibrutinib Exposure in Patients With≥ 2 Years of Exposure (N = 115)

2 to < 3 yrs32 (27.8%)≥ 4 yrs

40 (34.8%)

3 to < 4 yrs43 (37.4%)

43,2% 41,4% 43,9%

26,5%36,4%

22,9%

0%

20%

40%

60%

80%

100%

ITT 1 prior line > 1 prior line

Ibrutinib in MCL: Overall response and PFS/OS by best response

N = 370

ORR: 69.7% (n = 258)

N = 99CR PR

N = 271

ORR

ORR: 77.8% (n = 77)

ORR: 66.8% (n = 181)

Kaplan-Meier estimate of median.

Median, Months

(95% CI)

Best Response

CR

(n = 98)

PR

(n = 160)

PFS 46.2

(42.1-NE)

14.3

(10.4-17.5)

OS NE

(59.9-NE)

26.2

(21.6-34.7)

ITT, intent-to treat; ORR, overall response rate; PR, partial response.

CR rate was 36% in patients with 1 prior line of therapy

Median PFS was nearly 4 years in patients who achieved a CR

Rule et al., ASH 2017 (abstract 151, oral presentation)

Ibrutinib in MCL: DOR by best response and line of therapy

Median DOR, Months (Range)

Overall(n = 258)

Prior Lines of Therapy

1(n = 77)

> 1(n = 181)

Overall(n = 258)

22.2 (16.5-28.8)

34.4(23.1-NE)

16.0(12.9-23.5)

CR(n = 98)

55.7 (55.7-NE)

55.7(33.1-NE)

NE(40.7-NE)

PR(n = 160)

10.4(7.7-14.9)

22.1(10.6-34.4)

8.5(6.2-12.1)

Median DOR was 4.5 years in patients achieving a CR

Patients with 1 prior line had 2× longer DOR than patients with > 1 prior line

DOR, duration of response.

Rule et al., ASH 2017 (abstract 151, oral presentation)

Ibrutinib in MCL: PFS and OS by prior line of therapy

Median PFS was nearly 3 years in patients with 1 prior line of therapy

PFS

Median 33.6 mo(19.4-42.1)

Median 8.4 mo (7.1-12.8)

Median PFS overall (95% CI): 13.0 (8.4-16.8) months

Median OS overall (95% CI): 26.7 (22.5-38.4) months

Patients censored from OS analysis upon study discontinuation. CI, confidence interval; NE, not estimable.

OS

Median NR (36.0-NE)

Median 22.5 mo(16.2-26.7)

Rule et al., ASH 2017 (abstract 151, oral presentation)

Ibrutinib in MCL: Independent predictors of PFS and OS with ibrutinib: multivariate analysis

PFS OS

HR, hazard ratio.Rule et al., ASH 2017 (abstract 151, oral presentation)

Secondary malignancies: 9.7% (mostly nonmelanoma skin cancers)

Ibrutinib in MCL: Most common grade ≥ 3 treatment-emergent AEs* and secondary malignancies

% PatientsOverall (ITT)

(N = 370)1 Prior Line

(N = 99)> 1 Prior Line

(N = 271)

Neutropenia 17.0 7.1 20.7

Thrombocytopenia 12.2 7.1 14.0

Pneumonia 11.9 7.1 13.7

Anemia 9.5 5.1 11.1

Atrial fibrillation 5.9 5.1 6.3

Hypertension 5.1 6.1 4.8

*Occurring in ≥ 5% patients in ITT population.

Generally, grade 3/4 AEs were less common in patients with 1 prior line of therapy

Rule et al., ASH 2017 (abstract 151, oral presentation)

Can other BTKi be used at relapse ?

Acalabrutinib (ACP-196)

• Acalabrutinib is more selective for BTK with less off-

target kinase inhibition compared with ibrutinib in

vitro

BLK = B lymphocyte kinase; BMX = bone marrow tyrosine kinase gene in chromosome X; BTK = Bruton tyrosine kinase; EGFR = epidermal growth factor receptor; ERBB2 = erb-b2 receptor tyrosine kinase; ERBB4 = erb-b4 receptor tyrosine kinase; IC50 = inhibitory concentration of 50%; ITK = interleukin-2-inducible T-cell kinase; JAK3 = Janus kinase 3; TEC = tyrosine kinase expressed in hepatocellular carcinoma; TXK = T and X cell expressed kinase.Barf T, et al. J Pharmacol Exp Ther. 2017;363:240-52.

Kinase Inhibition Average IC50 (nM)

Kinase Acalabrutinib Ibrutinib

BTK 5.1 1.5

TEC 126.0 10.0

ITK >1000 4.9

BMX 46.0 0.8

TXK 368.0 2.0

EGFR >1000 5.3

ERBB2 ~1000 6.4

ERBB4 16 3.4

BLK >1000 0.1

JAK3 >1000 32

Kinase Selectivity Profiling at 1 M

Larger red circles represent stronger inhibition

IbrutinibAcalabrutinib

ACE-LY-004: Acalabrutinib monotherapy in R/R MCL

• Enrollment: March 12th, 2015, through

January 5th, 2016, at 40 sites across

9 countries

BID = twice daily; DOR = duration of response; MCL = mantle cell lymphoma; ORR = overall response rate; PFS = progression-free survival; PO = orally; R/R = relapsed/refractory.1. Cheson BD, et al. J Clin Oncol. 2014;32:3059-68. 2. Cheson BD, et al. J Clin Oncol. 2007;25:579-86.

Acalabrutinib

100 mg BID PO in 28-day cycles until

disease progression

124 Patients with R/R MCL

1-5 prior therapies

Primary endpoint: • ORR by investigator assessment based on the

Lugano Classification1

Secondary endpoints:• ORR by Independent Review Committee (IRC)

assessment• DOR, PFS, OS• Safety• Pharmacokinetics and pharmacodynamics

Exploratory endpoints:• Time to response• IRC-assessed ORR per the 2007 International

Harmonization Project criteria2

Data cutoff: February 28, 2017

Wang et al., ASH 2017 (abstract 155, oral presentation)

ACE-LY-004: Duration of response

• Median time to response was

1.9 months (range 1.5-4.4)

• 92% of responders had initial

response by end of cycle 2

• Median DOR has not been reached;

the 12-month DOR rate was 72%

(95% CI: 62%, 80%)

CR = complete response; DOR = duration of response; PR = partial response.

Wang et al., ASH 2017 (abstract 155, oral presentation)

ACE-LY-004: PFS and OS

• Median PFS and median OS have not been reached

OS = overall survival; PFS = progression-free survival.

OS

12-month PFS rate: 67% (95% CI: 58%, 75%) 12-month OS rate: 87% (95% CI: 79%, 92%)

PFS

Wang et al., ASH 2017 (abstract 155, oral presentation)

Investigator-assessed response to acalabrutinibDuration of response (A), PFS (B), and OS (C)

⚫ Wang et al., ASH 2018; abstract 2876

Median 26-month follow-up

Acalabrutinib in RR MCL: long-term follow-up

ACE-LY-004: Results• At a median follow-up of 15.2 months, 56% of patients remain on treatment

Wang et al., ASH 2017 (abstract 155, oral presentation)

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17

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0 10 20 30 40 50 60

Pneumonia

Neutropenia

Anemia

Pyrexia

Nausea

Cough

Myalgia

Fatigue

Diarrhea

Headache

Grade 1 Grade 2

Grade 3 Grade 4

100

Grade ≥3 AEs occurring in ≥5% of all patients

AEs occurring in ≥15% of all patients

Safety and Activity of BTK Inhibitor BGB-3111 in patients with DLBCL, MCL, FL and MZL

Tam et al., ASH 2017 (abstract 152, oral presentation)

Dose Enrolled (indolent,

aggressive)

40 mg QD 4 (0,1)

80 mg QD 5 (0,1)

160 mg QD 6 (0,2)

320 mg QD 6 (0,1)

160 mg BID 4 (0,2)

Dose escalation

Eligibility• WHO-defined B-cell malignancy• No available higher priority treatment• ECOG 0-2• ANC > 1000µ L, platelets > 100,000/µL• Adequate renal and hepatic function• No significant cardiac disease

Recommended Phase 2 dose

(RP2D)

320 mg QDor

160 mg BID

Population RP2D Disease Planned

R/R BID, QD MCL, MZL, FL, GCB DLBCL

40

R/R BID Non-GCB DLBCL 40

R/R BID, QD MCL 20

TN BID, QD MCL 20

R/R BID iNHL 40

Dose expansion

Primary endpoints• Safety including AEs and SAEs • Recommended phase 2 dose

Select secondary endpoints• Pharmacokinetics • Efficacy

BGB-3111 in patients with MCL: response

Tam et al., ASH 2017 (abstract 152, oral presentation)

Response (based on CT for majority of patients)

MCL* (n=32)

Median efficacy follow-up, months (range)

9.5 (0.8-31.9)

Best response, n(%)

ORR 28 (88)

CR 8 (25)

PR 20 (63)

SD 1 (3)

PD 1 (3)

NE 2** (6)

*In MCL patients treated with minimum of 320 mg/d ORR is 93% and CR is 28%** Off study for AE before response assessment

PFS

Zanubrutinib (BGB-3111) in relapsed or refractory MCL: Best Overall Response by IRC

aPatients discontinued prior to first disease assessment.bOne subject was assessed at Screening by investigator as having one measurable lesion; however, the IRC was unableto identify any measurable disease at baseline.‡ ResponseCriteria:Lugano2014Data cut: March 27, 2018

⚫ Song et al., ASH 2018; abstract 148

Zanubrutinib (BGB-3111) in relapsed or refractory MCL: PFS

⚫ Song et al., ASH 2018; abstract 148

Ruan et al., ASH 2013; abstract 247 (oral presentation)

Ruan et al., ASH 2013; abstract 247 (oral presentation)

Ruan et al., ASH 2013; abstract 247 (oral presentation)

Allogreffe MCL en rechute

Le Gouill et al -2012Ann of Oncology

Robinson et al -2018BMT 2018

Mortalité cumulée Rechute cumulée

Le Gouill et al -2012Ann of Oncology

Robinson et al -2018BMT 2018

PFS OS

Future directions in MCL treatment:Ongoing clinical trials And« Chemo-free » approches

Future directions in MCL treatment:Ongoing clinical trials And« Chemo-free » approches

Triangleadd on vs head to head comparison

13.01.2014 Dr. Eva Hoster, University Hospital Munich, on behalf of the European MCL Network

ObservationR-CHOP/ R-DHAP x 6

ASCT

2 yrs I-maintenance

2 yrs I-maintenance

R R-CHOP/ R-DHAP x 6 + I

R-CHOP/R-DHAP x 6 + I

ASCT Observation

Observation

A:

A + I:

I:

superiority/non-inferiority: time to treatment failureHR: 0.60; 65% vs. 77% vs. 49% at 5 years

LYMA 101

FIL MCL 0208 trial QuickTime™ and aGIF decompressor

are needed to see this picture.

HD

-CT

X

CH

OP

21

HD

Ara

-C

0 3 6 9 13 17 wks21

BE

AM

+

AS

CT

+IF

RT

36

-40

Gy

29

HD

Ara

-C

CH

OP

21

CH

OP

21

RR R RR R

R

Lenalidomide 15 mg days

1-21 every 28 days /2 yrsObservation

MCL-R2 elderly

45

MCL3002 - study designPhase 3, randomized, double-blind, placebo-controlled study (SHINE study)

Arm Ba

Background therapy (6 cycles): Bendamustine (90 mg/m2 IV Days 1-2) Rituximab (375 mg/m2 Day 1)

CR/PR →Rituximab 375 mg/m2

(every 2 cycles, 2 years)

Study drug:Oral ibrutinib 560 mg (starting on Cycle 1, Day 1) until PD or unacceptable toxicity

Arm Aa

Background therapy (6 cycles): Bendamustine (90 mg/m2 IV Days 1-2) Rituximab (375 mg/m2 Day 1)

CR/PR →Rituximab 375 mg/m2

(every 2 cycles, 2 years)

Study drug:Oral placebo (starting on Cycle 1, Day 1) until PD or unacceptable toxicity

Randomization

520 patients (~260 per arm)

aA cycle is defined as 28 days

ACE-LY-308: Study Schema

47

• Enrolled subjects with previously untreated MCL

Randomization stratification 1:1

Arm1:

Acalabrutinib + BR

Arm2:

Placebo * + BR

Acalabrutinib

Monotherapy

Placebo *

Acalabrutinib +

maintenance Rituximab

(every other cycle)

Acalabrutinib

Monotherapy

Placebo * +

Maintenance Rituximab

(every other cycle)

Placebo *

Survival Follow-up

Cycles 1 to 6

Combination treatment

(each cycle is 28 days)

Cycle 7

(for subjects not

progressing nor PR or

greater)

Cycles 8 to 30

(for subjects with PR or

greater)

Cycles 31+

(until PD or treatment

discontinuation)

* Subjects in Arm 2 who experience IRC-confirmed PD at any point of the study may be eligible to cross over

to receive acalabrutinib monotherapy until disease progression

n-=546

Future directions in MCL treatment:Ongoing clinical trials And« Chemo-free » approches

ENRICH –Randomised open label phase III trial of rituximab &

ibrutinib vs rituximab & chemotherapy in elderly MCL

IR/R

Intervention

R-CHEMO /

R

Standard

care

Ibrutinib

daily +

Rituximab

(every 21

days) for 8

cycles

R-CHEMO

(every 21

days) for 6-

8 cycles

Rituximab

(every 56

days)

for 2 years

Ibrutinib

daily +

Rituximab

(every 56

days) for 2

years

Ibrutinib to

continue

until

disease

progression

Follow-up

until

disease

progression

R

CI S Rule

Combination Ibrutinib and Venetoclax for the Treatment of Mantle Cell Lymphoma:

Primary Endpoint Assessment of the Phase 2 AIM Study

Constantine S Tam1,2,3, Andrew W Roberts3,4, Mary Ann Anderson3,4, Sarah-Jane Dawson1,3, Rodney J Hicks1, Kate Burbury1, Gillian Turner1, Juliana Di Iulio1,

Mathias Bressel1, David A Westerman1, Rishu Agarwal1, Christiane Pott5, Martin H Dreyling6, Mark A Dawson1,3, John F Seymour1,3,4

1Peter MacCallum Cancer Centre, Melbourne, Australia; 2St Vincent’s Hospital, Melbourne, Australia; 3University of Melbourne, Melbourne, Australia; 4The Royal Melbourne Hospital, Melbourne, Australia; 5University Hospital Schleswig-Holstein, Kiel, Germany; 6 University Hospital of LMU, Munich, Germany.

Plasma DNA

AIM (ABT-199 & Ibrutinib in MCL)Study Schema

Primary Endpoint

OASIS TRIAL

Egress from lymph nodes using a BTKi

(neutralization of BCR and CXCR4 axis)

Mo

FDC

TH

Lymph Nodes

BCLXL high

Venetoclax Resistance

Blood

BCLXL low

Venetoclax Sensitivity

BTK-iCXCR4

Lymphocytosis

Homing

Oasis Trial

2016

NTC#02558816

Clinical Trial

BTK-i (Ibrutinib) // anti-CD20 (GA101) // Venetoclax

PI : Pr. S Le Gouill

Rapid loss of BCLXL

expression in PB

Chiron et al Oncotarget 2015

Obinutuzumab

Le Gouill et al. ASCO 2016 abstract TPS7583Chiron D et al. ASH 2016 oral session

Obinutuzumab

CONCLUSIONS (1)

• Standard of care 1L• young fit patients: Cytarabine and rituximab containing chemotherapy

followed by ASCT and Ritximab maitennance (1 every 2 months for 3yrs)• Elderly or unfit pts: R-CHOP followed by R maintenance or BR (without

maintenance ?) , BR

• Treatment options at first relapse:According to nature of first line therapy, duration of treatment, age and co-morbidities:

• R-chemotherapy (BR ? RiBVD ? RBAC ? RHAP ? ) or BTKi-bsaed therapy for patients who reached prolonged DOR after 1L

• BTKi-based therapy for chemo-refractory patients• Discussed allo-SCT for fit chemo-R (or ealry relapse) pts

CONCLUSIONS (2)

• Pending questions in MCL treatment:• How to use new tools like MRD, PET-CT, NGS in daily practice ?

• Are we ready for MRD/PET/NGS –driven strategies ?

• Are we ready to challenge immuno-chemotherapy frontline ?

• What are the mechanisms of resistance to new drugs ?

• Can we predict targeted therapy resistance ?

• What about CAR-T in MCL ?

• ….

Basic Research M. Amiot (PhD) C. Pellat-Deceunynck (PhD) A. Moreau-Aubry (PhD) D. Chiron (PhD)

C. BellangerC. DoussetS. MaïgaB. TessoulinA. Papin

Translational Research S. Le Gouill (MD PhD)C. Touzeau (MD PhD)

CollaborationsCornell University

Micronit