Checkpoint MRD inhibitors Antibodies

HIGHLIGHTS OF ASH Orlando - 2015

B-ALL MMAMYLOIDOSIS

AML HEMOPHILIA

T-CARCheckpoint inhibitors

MRD Antibodies

D. Bron, MD, PhD (ULB)

B-ALL

• BiTE Ab in B- ALL MRD+

• T-CAR in B-ALL

• Rituximab in B-ALL

Ph neg

B-ALL : GRAAL 2005-R

Maury et al # 1

PhIII RCT in adult B-ALL (<59yo) CD20+ (>20%+) ,209 pts,FU 30mo

B-ALL GRAAL 2005-R

1,00

0,75

0,50

0,25

0

0 12 24 36 48 60 72 84 96

52 % (42-63)

65 % (56-75)

Hazard-ratio : 0,66 (0,45-0,98) ; p = 0,038Suivi médian : 30 mois

Rituximab

Contrôle

1,00

0,75

0,50

0,25

00 12 24 36 48 60 72 84 96

32 % (22-42)

18 % (11-27)

Hazard-ratio : 0,52 (0,31-0,89) ; p = 0,017

Rituximab

Contrôle

MoisNbre à risque

1,00

0,75

0,50

0,25

0

0 12 24 36 48 60 72 84 96

64 % (55-74)

71 % (62-80)

Rituximab

MoisNbre à risque

Contrôle

Hazard-ratio : 0,70 (0,46-1,07) ; p = 0,095

EFS/30Mos

CIR

OS

Après censure à l’autogreffe

en RC1 : HR = 0,55 (0,34-0,91) ;

p = 0,018

Key Message :

Rituximab combined with chemotherapyis now the standard of care

for CD20+ ALL

Maury et al, abst # 1

HIGHLIGHTS OF ASH 2015Orlando Dec 5-9, 2015

MMAMYLOIDOSIS

AML HEMOPHILIA


MDR Antibodies

D. Bron, MD, PhD (IJB-ULB)

• Midostaurine (Multikinase inh including

Anti Flt3, KIT ,PKC ,VEGFR) during and after treatment for AML ?

• MRD : a critical and prognostic marker in all malignant hemopathies including

AM L ?

AML

Correspondances en Onco-Hématologie ASH 2015 - D’après Levis MJ et al., abstr. 6 actualisé

0

10

20

30

40

50

60

70

80

90

100

0 12 24 36 48 60 72

Su

rvie

(%

)

Midostaurine50mg Bid (d8-21 and 12 mo

Placebo

Mois

Greffe chez les RC1HR = 0,61

Greffe en dehors des RC1HR = 0,98

AML (FLT3 m) – Ratify Trial( N = 717)

OS After SCT

Treatment with Midost increases CR (FlT3 ITD+) and OS (75 vs 26 mo)after allo- transplantation

Key Message :

Midostaurin (MultiKinase Inh)should be combined with standard CT

and continued for One year in Flt3 mutated (FLT3-ITD or TKD)

Young (18-60yo ??) AML pts.

Stone RM et al, abst #6

HIGHLIGHTS OF ASH 2015

MMAMYLOIDOSIS

HEMOPHILIA


MDR Antibodies


• Autologous (double ?) SCT rehabilitated• #391 #27

• New Proteasome InhibitorsCarfilzomib #731, Ixazomib #727

• New Monoclonal AntibodiesDaratumomab #507 - Elotuzumab #508

• 4 drugs > 3 drugs > 2 drugs in Fit Patients ?

MULTIPLE MYELOMA(25% of ASH abstr !!! )

MM : VRD + ASCT vs VRDm

M Attal et al,Abst # 361

Progn Factors(Multivariateanalysis)

PFS

Risk HR adjusted p

Treatment arm (B/A) 0,80 0,02

ISS II vs. IISS III vs. I

1,331,45

0,020,01

FISH (high risk/standard) 2,22 <0,001

CR 0,58 <0,001

MRD - (cytometriy) 0,39 <0,001

Key Message :

In “FIT” Myeloma pts,

Auto SC Transplantation

is superior to

Maintenance with biological/ targeted therapies


HEMOPHILIA


MDR Antibodies


HEMOPHILIA

• Factor VIII is required to prevent/treat bleeding in Patients with hemophilia A

• Recombinant FVIII was developed to reduce the risk of inhibitors

• The risk to develop inhibitors is not similar in all pts but correlated with FVIII polymorphisms, HLA exp , intensity of the treamentt, duration of treat, infections, inflammatory status, etc…

• The SIPPET multicentric trial (14 countries) compared prospectively Plasmatic and recombinant FVIII in 251 children with hemophilia

• 44,5 (28,4)% vs 26,8 (18,6 )% developped inhibitors (High level >5BU) in the recombinant and plasmatic arm respectively : an increased rik of 87% !

Key Message :

Children treated with recombinant Fact VIIIhave a 87% increaded risk

To develop FVIII inhibitors.There is room for improvement !!!!



MDR Antibodies


Autologous in ALL # 681, #682, #683 CLL # 184 NHL (DLBCL, MCL, BL, …) # 183 # 184

HL # 185 (No toxicity in Ph I) MM … LBA # 6 ->16/20 OR

Allogeneic T CAR in DLI #99 … coming # 2046

T-CAR

W. Qasim #2046

T-CAR Allogeneic

CAR anti-CD19

• Disruption du gène TRAC

– Prévient la GVH

• Disruption du gène CD52

– Immunosuppression spécifique du patient par anti-CD52

• Gène suicide

– Épitopes CD34/CD20

Key Message :

The T-CAR technology is one of the major achievement in the field of

immunotherapy and genetic engeneering

Major promises are expectedin different malignant diseases

using auto (or allo?) T cells


Checkpoint inhibitors

MDR Antibodies


CHECKPOINT INHIBITORS

in Hodgkin Lymphoma

• HL frequently harbors 9q24.1 Amplification leading to overexpression of PDL1 and PDL2 ! Blood 2010 (17) 3268-77

• Tumor with intense lymphocytes infiltration, macrophages infiltration has a poorer prognosis ! JCO 2011(29)1812-26

• NIVOLUMAB (Anti PD1 3mg/kg IV q2wk)

in HL # 583

( 20/23 pts with OR after 104 Weeks FU, 5 in CCR without treatment)

• IPILMUMAB (anti CTLA4) & BV IN HL # 585

• PEMBROLUZUMAB (anti PDL1) & LenDex in

MM # 505

CHECKPOINT INHL and other LPD

CHECKPOINT INH.In HL # 583

Median DOR (95% CI): NA (15.5–NA)

Time, MonthsPro

bab

ility

of

Pat

ien

ts in

Re

spo

nse

0.00.10.20.30.40.50.60.70.80.91.0

0 3 6 9 12 15 21 2418

18 15 12 10 9 7 2 04No. Patients at Risk

• Median follow-up: 101 wks• Median DOR not reached

OS N=23

1 year

OS rate % (95%CI) 91 569-97)

1.5 years

OS rate % (95%CI) 83 (60_93)

Duration of response

Responding Patients

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112

17

15

20

19

18

16

14

13

12

11

9

7

6

5

4

3

2

1

10

8

Pat

ien

ts

First CR

First PR

Death

Ongoing response

On treatment, ongoing responses

13 patients off treatment without disease progression

6 with maximum clinical benefit

5 proceeded to transplant

2 discontinued for toxicity

Disease progression following initial response

PFS Responders Time, Weeks

• NIVOLUMAB (Anti PD1 3mg/kg) IN HL # 583

( 10/23 pt en CCR, even after discontinuation of treatment)

• IPILIMUMAB (anti CTLA4) & BV IN HL # 585

• PEMBROLUZUMAB (anti PDL1) & LenDex: 76% OR in R/R MM # 505

CHECKPOINT INHL and other LPD

18 Evaluable pts:ORR 72%, CR 50%, RP 22%, SD 17%, PD 11%

Best response

Median FFP: 1,02 y (Médian FU : 0,7 y)Median OS : NA

Key Message :

Checkpoint Inhibitors (Anti PD1, Anti PDL1, Anti CTLA4) : a new approach of

immunotherapywith strong promises in tumors expressing

PDL1 and infiltrated by TIL(Tumor infiltrating lympocytes)


MRD Antibodies


MRD

Evaluated by PET/CT HL #577

Evaluated by Flow Cytometry AML

Evaluated by PCR AML /NHL #225

Evaluated by NGS MM # 191

HL #577• Prot AHL2011 : Lysa trial in HL (n=782, ST IIB-IV)

After 2 BEACOPP, ABVD and BEACOPP in PET 2 negpts have similar FFP/2 yrs with less SAE (HL Pts with a PET 4 + have a very poor prog !!!)

MCL #• MRD in MCL (Lyma trial) : R-DHAP + ASCT -> high CR

MRD evaluation has a better prognostic significance before ASCT !!! And Better PFS with or without R maintenance

FOLLIC L #• MRD after (Benda vs BO) : BO>B with more MRD neg post

induction that correlated with better PFS . Rm improves PFS also in MRD neg pts !!

MRD in lymphomas

Sensibility

10-3 10-4 10-5 10-6

Flow cytometry

RQ-PCR Transcrit (CBF, PML-RARA)

RQ-PCR mutations NPM1 DNMT3A

NGS

PCR digital

Sur-expression WT1

« drivers »

0

0

1

1

All ?

All ?

#173

#228

#226, 227

#225

MRD

MRD in MM

• Digital PCR (DDPCR) # 225

Échantillon fractionné en gouttelettes

contenant une seule molécule d’ADN

Quantificationabsolue

SensibilitéJusqu’à 10-6

MM

Prog Fact (NGS, DDPCR )

NGS > Cytometry ->10E-6

83% CR/3 yrs with MRD neg # 191

MRD in MM

PFS accoding to MRD post maintenanceAll patients Patients in CR

• Key Message :

MRD is correlated with PFS and OS

in ALL, NHLs, MM, AML,…

NGS is superior to flowcytometry

and will soon enter in routine practice

L’évaluation de la maladie résiduelle par NSG facteur

hautement prédictif de la SSP dans l’étude IFM/DFCI 2009

SSP selon la MRD avant la phase de maintenance

SSP selon la MRD en post-maintenance

Tous patients Patients en RC

Tous patients Patients en RC


Antibodies



• Nake Antibodies (anti CD20, anti- CD38, anti CS1,

• Combined Antibodies (CD19, CD22, CD30 + Tox, …

• BiTE Antibodies(Blinatumomab= CD19-CD3)

MM : Daratumumab (Hu Anti CD38)

• CD38 is Highly expressed on MM Cells andlow expression on lymph & myeloid cells

Abst # 507 :Dara + Len + DexN=32 R/R MMUntil progression of MM

MM : Elotuzomab (Hu Anti SLAMF7*)

• CS1 (= SLAMF7) is Highly expressed on MM and NK Cells

• Binding of SLAMF7 activates NK cell with selective killing of MM cells

Abst # 28 :Elotu + Len + DexN= 600+ R/R MMUntil progression of MMORR : 74% vs 56%

* SLAMF7 = Signaling Lymphocytes Activation molecule F7

CD19 antigen recognition

TCR independent

HLA class I independent

Induces CMR in

Ph - and Ph + ALL

B-ALL : BiTE antibodies

(Blinatumomab)

Ab # 679, #680

• Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to

BR Alone in Patients with R/R CLL increasing PFS and OS, and with a safetyprofile. Addition of IDELA to BR was also beneficial in pts withdel(17p)/TP53mut. LBA #5

Late Breaking Abstracts***

• Venetoclax (an oral selective BCL-2 inhibitor) Induces deep

Remissions, Including CR (>10%) and undetectable MRD (>20%), in highRisk R/R CLL with 17p Del: ORR = 77%. with acceptable toxicity. LBA#6

• Neutralization of IFNγ with antibodies offers an innovative targeted

and potentially less toxic approach to treat Primary HemophagocyticLymphohistiocytosi (pHLH) , a rare immune disorder which ultimately maycause multi-organ failure and death, Assessment of NI-0501 as first linetreatment for pHLH is ongoing. LBA #3

• Eltrombopag Added to Standard Immunosuppression forAplastic Anemia Accelerates Count Recovery and Increases overall and

complete hematologic response rates in treatment-naive SAA. LBA#2


B-ALL MMAMYLOIDOSIS

AML HEMOPHILIA


MDR Antibodies


To achieve CURE in malignant diseases ,you have to:

understand pathogenesis, stimulate innate/adaptive immunity

reach minimal residual disease- as deeper as possible ! –

I don’t know “how to treat”

but I know how to tweet ….

THANK YOU

for your

attention

Acknowledgment

• M. Attal• N. Boisel• M Delforge• M. Mohty• P. Brice• T. De Foer• A. Vandenbroecke• P. Graas

Highlights of ASH

Documents

Checkpoint MRD inhibitors Antibodies