Post on 18-Jun-2022
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
T-CARCheckpoint inhibitors
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
T-CARCheckpoint inhibitors
MDR Antibodies
D. Bron, MD, PhD (IJB-ULB)
• 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
HIGHLIGHTS OF ASH 2015
HEMOPHILIA
T-CARCheckpoint inhibitors
MDR Antibodies
D. Bron, MD, PhD (IJB-ULB)
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 !!!!
HIGHLIGHTS OF ASH 2015
T-CARCheckpoint inhibitors
MDR Antibodies
D. Bron, MD, PhD (ULB)
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
HIGHLIGHTS OF ASH 2015
Checkpoint inhibitors
MDR Antibodies
D. Bron, MD, PhD (ULB)
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)
HIGHLIGHTS OF ASH 2015
MRD Antibodies
D. Bron, MD, PhD (IJB-ULB)
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
HIGHLIGHTS OF ASH 2015
Antibodies
D. Bron, MD, PhD (ULB)
HIGHLIGHTS OF ASH 2015
• 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
HIGHLIGHTS OF ASH 2015
B-ALL MMAMYLOIDOSIS
AML HEMOPHILIA
T-CARCheckpoint inhibitors
MDR Antibodies
D. Bron, MD, PhD (ULB)
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