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