Post on 16-Feb-2019
LINFOMA DI HODGKINTARGET BIOMOLECOLARI
Enrico Derenzini
Istituto di Ematologia ed Oncologia Medica L.A. Seragnoli, Bologna
Firenze, 29 Marzo 2012
1433 pazienti affetti da HL trattati presso l’Istituto Seragnoli
OS (Years)
50403020100
Pro
ba
bili
ty
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
PFS (Years)
403020100
Pro
ba
bili
ty
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
ABVD/BEACOPP
MOPP/ABVD
MONOCHEMIO
ABVD/BEACOPP
MOPP/ABVD
MOPP
MONOCHEMIO
20%
ChemotherapySingle Center Experience
Bologna
Kuppers R, Nature Rev Cancer 2009
JAK inhibitors
CD20 + B cellsRITUXIMAB
SGN-35
Daclizumab
HDAc inhibitors
mTOR inhibitors
Background
TARGETING CD20Rationale
-CD 20 + HRS CELLS - NLPHL (CD20+)
-DEPLETION OF SURROUNDING CD 20 + B CELLS
-KILLING OF CIRCULATING CD 20 + PUTATIVE HRS STEM CELLS
TARGETING CD20
RITUXIMAB SINGLE AGENT
33m
NRNR
7.8 m(PR+CR)
PFS RefPhaseRRN PTS
Shultz et al. Blood2008
Eichenauer et al.Blood 2011Advani et al. ASH2011
II
IIII
94%
100%100%
15
2819
NLPHLRelapsed-RefractoryFirst line Stage IA Stage I-III
Younes et al.Cancer 2003
II23%22(6 CD20+)
cHLRelapsedRefractory
Younes et al. Cancer 2003
Results
RITUXIMAB-ABVD x 6 cycles in cHL
RefPhaseEFSN PTS
Kasamon etal Blood2012
II83% (3 y)49cHLStage II-IV
Younes etal. Blood2012
II 83% (5 y)85cHLStage III-IV
Randomized phase III ABVD vs ABVD + RITUXIMAB ongoing
Combination
TARGETING HDACs
Cell death, inhibition of proliferation
Immune regulation
Younes-Lemoine Discovery Medicine 2010
Rationale
Buglio et al. Blood 2008
Buglio et al. Blood 2008
MOCETINOSTAT (MGCD0103)
110 mg / 85 mg orally 3 times per week
28 pts 85 mg23 pts 110 mg
Younes et al Lancet Oncol 2011
Results
MOCETINOSTAT
110 mg
85 mg
ORR 26% (85mg) 30% (110mg)DISEASE CONTROL 81%
PANOBINOSTAT
28 pts30 to 60 mg MWF qwk45 to 60 mg MWF qowkMedian n° prior tp 5ORR 64% by PET (5% CR)ORR 42% by CT (4% CR)
Phase IA/II trial
Dickinson et al BJH 2009
Final Analysis: Phase II Study of Oral Panobinostat In Relapsed/Refractory Hodgkin Lymphoma Patients Following Autologous Hematopoietic Stem Cell Transplant
129 pts Panobinostat 40 mg 3 times per week
Prior regimens n=4
77% (99 pts) reduction in tumor sizeORR 27% (5 CR,30 PR)
DCR 82%DOR 6.9 m
Sureda et al. ASH 2010
5.7m--10m3.8 m---
82%81%61%16%54%55%
27%23%16%4%-33%
IIIIIIIIIIII
1295149 (38)251333
PanobinostatMocetinostatEntinostatVorinostatITF2357Resminostat
RefPFSRTSRRPhaseN PTSHDACi
Similar PFS PR vs SDReductions in tumor volume vs metabolic responses
Down-regulation of glucose transporters in HRS cells andin cells from HL microenvironment
Sureda et al. ASH 2010
Younes et al.Lancet Oncol 2011Younes et al.ASH 2011
Younes et al.ASH 2008
Viviani et al.ASCO 2008
Walewsky et al.ASH 2011
12 pts
25 mg daily 1-21
Best response1CR5 PR6 SD
Boll BJH 2009
LENALIDOMIDE
38 pts
25 mg daily1-21
1 CR6 PR5 sustained SD
ORR 33%Fehniger et al. Blood 2011
TARGETING mTOR
Cell GrowthImmune Regulation
Rationale
Georgakis et al. 2006
Younes et al.Oncologist 2011
EVEROLIMUS
Everolimus 10 mg/d
ORR 47%
RTS 89%
19 pts
Results
Johnston et al. Am J Hematology 2010
Ongoing trials - Future strategies
AVD + Lenalidomide
Panobinostat + Everolimus
Lenalidomide post ASCT
Bendamustine + Lenalidomide
Maintenance Therapy
Combination Therapy
Brentuximab Vedotin post ASCT
AVD + Brentuximab Vedotin
Derenzini et al. BCJ 2011
AZD1480 1 µM -
-
++
+PD98059 25 µM
-
- +
0
50
100
150
% c
ell v
iabi
lity **
**
RESISTANT SENSITIVE
Treatment with MEK inhibitors enhances the efficacy of AZD1480 in HD-LM2 and L-428cells by inhibiting sustained ERK hyper-activation caused by JAK inhibition
Derenzini et al. BCJ 2011
Ringraziamenti
Prof. SANTE TURA
Prof. Michele BaccaraniProf. Pier Luigi Zinzani
Gruppo Linfomi
Vittorio StefoniCinzia PellegriniAlessandro BroccoliBeatrice CasadeiLetizia GandolfiFederica QuiriniLisa ArgnaniMarta Tschon
Prof. Anas YounesDr. Richard Eric DavisDr. Hiroshi Katayama
Manuela LemoineDaniela Buglio