salvage treatment in hodgkin's lymphoma: targeted … · salvage treatment in hodgkin's...

Charles University General Hospital

www.ebmt.org #EBMT2014

Salvage Treatment in Hodgkin's Lymphoma: Targeted therapy - competing or complementary to transplantation?

Marek Trneny

Charles University General Hospital, Prague

16 - 17 October 2014, Nicosia, Cyprus



Disclosure

• Takeda, Celgene, Mundipharma, BMS

– consultancy

– research support

2



Outline

• Treatment strategy

• New drugs

• „Old“ drugs

• The place of new drugs

• Conclusions

3



Outline


• New drugs

• „Old“ drugs


• Conclusions

4


Treatment strategy

Chemotherapy +/- RT

cure 75-95%

Progressive dis. Relapse

eligible Salvage + ASCT

non-eligible 2nd line, new drugs, RT,

palliative tx

eligible alloSCT

Prog/Relapse non-eligible

2nd line, new drugs, RT, palliative tx

Diagnosis


Treatment strategy

Chemotherapy +/- RT which one?

cure 75-95%




palliative tx

eligible alloSCT



15 %

5-10 %



Salvage Tx for R/R HL

7

Collins GP et al, Br J Haematol 2014



Outcome of HL after relapse Early relapses after first-line chemotherapy (n 138) Late relapses after first-line chemotherapy (n 168)

Josting A et al, JCO 2002, Schmitz N eg al, Lance 2002 Josting A et al, JCO 2010


Treatment strategy


cure 70-95%




palliative tx

eligible alloSCT



15 %

5-10 %

~ 7.5 %


Treatment strategy


cure 70-95%




palliative tx

eligible alloSCT


2nd line, new drugs, RT, palliative tx <1 %

~ 5%

~ 7.5 %

15 %

5-10 %


Outcome after ASCT failure

11

Martinez C et al, Ann Oncol 2013

Factors: early relapse, stage IV, bulky dis, worse PS, age≥50y at relapse



Outline


• New drugs

• „Old“ drugs


• Conclusions

12


New drugs - rationale

13

Acording to Diefenbach C & Advani R, Hem Onc Clin N Am 2013



New drugs

• Histon deacetylase inhibitors – panobinostat – vorinostat – mocetinostat

• Proteasome – bortezomib • mTor inhibitor – everolimus • Microenvironment – lenalidomide • antibodies

– antiCD30 - SGN 35 – anti CD40 – lucatumumab – anti CD25 – radioimmunotherapy

• anti PD1 - nivolumab

Sureda A et al, ASH 2010 Younes et al, ASH 2010

Fanale et al, Br J Haematol, 2011 Johnston et al ASCO 2010 Feniger et al, Blood 2011

Younes et al ICML 2011 Freedman et al, ASH 2010

Dancey et al, Clin Canc Res, 2010 Moskowitz et al, ASH 2009

Younes et al JCO 2012 Younes et al JCO 2012

Hamid O et al, Exp Opinion Biol Th 2013



New drugs

• Histon deacetylase inhibitors – panobinostat – vorinostat – mocetinostat

• Proteasome – bortezomib • mTor inhibitor – everolimus • Microenvironment – lenalidomide • antibodies

– antiCD30 - SGN 35 – anti CD40 – lucatumumab – anti CD25 – radioimmunotherapy








Buglio D et al. Blood 2008

HDAC inhibitors in HL



Histon deacetylase inhibitors

17



Panobinostat • n 129, age m 32y, failed ASCT, primary refractory 57%, failed alloSCT 10%,

• panobinostat 40 mg 3 times w,

• reduction of the tumor volume 74%

• ORR 27%, CR 5 (%), PR 30 (23%), SD 71 (55%)

• ongoing 19 (15%), dis. progression 65 (50%),

Sureda A et al, ASH 2010 Younes et al JCO 2012



Vorinostat

• n 25

• ASCT 44%

• refractory 48%

• 200 mg TID,

• ORR 4% (1 PR), SD 48% (12)

Kirschbaum M et al, Leuk Lymphoma 2012



Mocetinostat

• n 51

• 110/85 mg po 3tW

• Dis Control rate 35% and 25%

85 mg

110 mg

58% of subjects experienced tumor

reduction

Younes et al Lancet Oncology 2011

Baseline 2 months

CT (– 52% = PR)

PET

Charles University General Hospital Charles University General Hospital

AKT

Receptor

tyrosine kinase

mTORC1

PIP2 PIP3

PI 3-kinase

p85

p110

PTEN

S6K1 4EBP1

Protein translation/synthesis

AKT

Receptor

tyrosine kinase

mTORC1

PIP2 PIP3

PI 3-kinase

p85

p110

PTEN

S6K1 4EBP1

Protein translation/synthesis

Targeting Oncogenic Pathways

Physiologic signaling Activated oncogenic signaling



Clinical Results of PI3k/Akt/mTOR Pathway-Specific Inhibitors in Unselected Patients

with Relapsed Lymphoma

Target % Response rate in different histologies

DLBCL FL MCL SLL/CLL T-Cell HL

Everolimus mTOR 30% 50% 32% 18% 63% 47%

Temsirolimus mTOR 36% 56% 38% 10% - -

MK-2206 AKT - - - - - -

CALI-101 PI3K 0% 55% 67% 30% - -

BEZ-235 PI3K +

mTOR

- - - - - -



Everolimus

• n 19, ASCT 84%, lines 6

• Everolimus 10 mg/d

• ORR 47% (1 CR, 8 PR)

Johnston P et al Am J Hematol 2011



Activity of the mTOR Inhibitor Sirolimus and HDAC Inhibitor Vorinostat

24

Janku F et al ASCO 2014

DAY 1-7 DAY 8-14 DAY 15-21 DAY 22-28 DAY 1-7 DAY 8-14 DAY 15-21 DAY 22-28

DAY 7-14 DAY 15-21 DAY 22-28 DAY 1-7 DAY 8-14 DAY 15-21 DAY 22-28

Sirolimus PO daily

Vorinostat PO daily

CYCLE 1 CYCLE 2

Tumor Bx Tumor Bx

PK PK PK

PD PD PD

CT (PET/CT) PET/CT CT (PET/CT)



Hodgkin lymphoma: Waterfall plot (maximum reduction per Cheson 2007 criteria)

25

Patient without progression at the time of analysis

Clinical progression arbitrarily marked +50%. The patient was treated with lower dose than R2PD

Ch

ange

in %

pe

r C

HES

ON

20

07

TTF (months)

-100

-80

-60

-40

-20

0

20

40

60

1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627

CR+PR rate: 57% (Investigator Assessed)

3.7

1.5

3

0.2

5.4+

4.5

3.3+

2.4

5.8

1.6+

5.7+

3.4

12+

8.3+

1.9

3.7+

6.4+

2.5+

6.6+

3.6

3.7+

2.7+

3.2+

1.9

5.9+

1.9+ 4+

One patient, who did not have restaging scans at the time of analysis is not included

Janku F et al ASCO 2014



New drugs

• Histon deacetylase inhibitors – panobinostat

– mocetinostat

• Proteasome – bortezomib

• mTor inhibitor – everolimus

• Microenvironment – lenalidomide

• antibodies – antiCD30 - SGN 35

– anti CD40 – lucatumumab

– anti CD25 – radioimmunotherapy









Lenalidomide – mechanism of action

LENALIDOMIDE

INCREASED apoptosis Caspase activation

TNF α

IL-6/IL-8

VGDF

DECREASE proliferation p21

SPARC

pAkt

pErk

Tumor cell cytoskeleton rearangement

CD20 localization F actin

Increased expression of costimulatory Ag

T-cell Immune synapse formation

Activation

IL-2, IFNγ

NK cell Immune synapse formation

Perforin accumulation

Proliferation Chanan-Khan AA, Cheson BD. J Clin Oncol. 2008;26:1544-52;

Gaidarova S, et al. Blood (ASH). 2008;112:[abstract 2616];

Gorgun G, et al. Proc Natl Acad Sci USA. 2009;106:6250-5;

Ramsay AG, et al. Blood. 2009;114:4713-20;

Zhang LH, et al. Blood (ASH). 2008;112:[abstract 2612];

Zhang LH, et al. Am J Hematol.2009;84:553-9



Lenalidomide

• n 38

• age 34, ASCT 79% aloSCT 8%, lines 4

• ORR 19.4% , CR 2.8%, SD 13.9%

Fehniger T et al Blood 2011



New drugs

• Histon deacetylase inhibitors – panobinostat

– mocetinostat

• Proteasome – bortezomib

• mTor inhibitor – everolimus

• Microenvironment – lenalidomide

• antibodies – antiCD30 - SGN 35

– anti CD40 – lucatumumab

– anti CD25 – radioimmunotherapy








Structure of selected tumor necrosis factor family receptors.


Summary Results of Naked Antibodies Studies in Patients with Relapsed HL and ALCL

Drug Disease Antibody

type

Phase Number of

evaluable patients

PR CR %ORR

MDX-060

HL, ALCL

Humanized

I

HL = 63

ALCL = 9

2

2 2

0

6%

22%

SGN-30

HL, ALCL

Chimeric

I

24

0

0

0

SGN-30

HL, ALCL

Chimeric

II

HL = 38

ALCL = 41

0

5 0

2

0

17%

Xmab2513

HL

Humanized

I

13

1

0

7%



anti CD40 lucatumumab

32

Fenale M et al, Br J Haematol 2014

HL n 37, ORR 13.5%



SGN 35

SGN-35 Antibody-Drug

Conjugate

SGN-35

binds

CD30

Endocytosis

ADC traffics to

lysosome

Enzymatic

linker cleavage

releases MMAE

from ADC

MMAE binds

tubulin

G2/M cell

cycle arrest

& apoptosis

CD30

SGN-35 Antibody-Drug

Conjugate

SGN-35

binds

CD30

Endocytosis

ADC traffics to

lysosome

Enzymatic

linker cleavage

releases MMAE

from ADC

MMAE binds

tubulin

G2/M cell

cycle arrest

& apoptosis

CD30

SGN-35 antibody-drug conjugate

• CD30-targeted antibody (cAC10) conjugated to an auristatin (MMAE), an anti-tubulin agent

• Selectively induces apoptosis in HL and ALCL cells:

• Not influenced by inflammatory cells



Brentuximab vedotin – phase I study

Investigator Assessment IRF Assessment

* Significant correlation observed between investigator and IRF assessment (Pearson correlation coefficient = 0.674; P<.001)

86% of patients achieved tumor reductions 83% of patients achieved tumor reductions

Younes A, et al. N Engl J Med 2010



Brentuximab vedotin - case

• 21-year-old female – ABVD + RT to mediastinum – ICE – BEAMASCT • SGN-35 2.7 mg/kg x 8 cycles – Best clinical response: CR – CT 90% reduction, PET- – Complete remission


Brentuximab vedotin: pivotal Phase II trial characteristics

Number of patients 102

Age, median (range) 31 (1577) years

Gender 48 M/54 F

ECOG performance status

0 42 (41%)

1 60 (59%)

Refractory to front-line therapy 72 (71%)

Refractory to most recent treatment 43 (42%)

Prior chemotherapy regimens (range)* 3.5 (113)

Prior radiation 67 (66%)

Prior ASCT 102 (100%)

Time from ASCT to first post-transplantation relapse (range)* 6.7 (0131) months *median range

Younes A et al, JCO 2012


Brentuximab vedotin: pivotal Phase II trial maximum tumour reduction per IRF

*Four patients were not included in the analysis; three patients had no measurable lesions per IRF; one patient had no post-baseline scans. PET, positron emission tomography. Chen R et al. Presented at American Society of Clinical Oncology annual meeting, Chicago, USA; 4–6 June 2011: Poster presentation: Abstract #8031.

Complete remission by PET



Brentuximab vedotin: pivotal Phase II trial response (% of patients)

Parameter No. of Patients (N = 102) %

Objective response 76 75

Complete remission 35 34

Partial remission 41 40

Stable disease 22 22

Progressive disease 3 3

Not evaluable 1 1



Survival – PFS and OS



PFS comparison with the last therapy




BV in routine practice

41

Zinzani P et al, Haematologica 2013



BV in nontransplant pts

42

Pts

n 14

refractory 4

early relapse 4

late relapse 6

med lines 3 (2-6)

refractory to the last Tx 11 (79%)

cycles of BV 4.5 (2-12)

SCT post 4/1

Efficacy n %

ORR 10 71

CR 5 36

PFS 9 m

OS not reached

Sasse S et al, Leuk Lymph 2013



Brentuximab Vedotin in the HL management

Front-line

Pretransplant

Post transplant

BV + salvage - ICE

BV monotherapy (Aethera trial)

ABVD/ AVD + Brentuximab Vedotin

BV + X

BV monotherapy

BV monotherapy


Different agents - monotherapy

0

20

40

60

80

100

CR PR

But – PFS 4-6 months


PD-L1

Greaves P , and Gribben J G Blood 2013;121:734-744



Outline


• New drugs

• „Old“ drugs


• Conclusions

46



„Old“ drugs

• bendamustin

• doxorubicin – peglycolated liposomal 47

Dr. Ozegowski : First published 1963 First clinical data for indolent NHL, MM, CLL, HL in the 60s/70s



„Old“ drugs

• bendamustin

• doxorubicin – peglycolated liposomal 48

Dr. Ozegowski : First published 1963 First clinical data for indolent NHL, MM, CLL, HL in the 60s/70s



Bendamustine

49

PFS

PFS

all 5.7

responders 9.7

CR/CRu 10.2

relapse ≥ 6 m 25 0.11

relapse < 6 m 5

in CR at last Tx 43 0.0001

not in CR at last Tx 0

OS

n %

CR 8 29

PR 6 21

ORR 14 50

SD 2 7

PD 11 39

not eval 1 3

Ghesquieres H et al, Leukemina Lymph 2013



Pegylated liposomal doxorubicin

• n 47 (23 monotherapy, 24 combo), all failed SCT

• ORR 72%, CR 51%, PET neg CR 60%

50

Clozel T e al BJH 2013



Outline


• New drugs

• „Old“ drugs


• Conclusions

51



Case report

• Man, 1966, • dg HL 3/2006, IVB,

– BEACOPP esc. 8 cycles – 1st CR, PET negative

• 1st relapse 2/2007 ??? – 3 cycles of DHAP – PR, ASCT 4/2007 – CR PET negative – radiotherapy

• 2nd relapse 4/2008 – in non irradiated area, bones, – GDP – PR, AlloSCT 10/2008 – 3rd CR PET negative

• 3rd relaps 10/2009 – IF irradiation, DLI, inconclusive PET • 4rd relapse 3/2012 – PET positive, up to 2x4 cm, observation • progression up to 6 cm 6/2013

– Brentuximab vedotin 4 cycles – 4th CR PET negative

• 5th relapse – 9/2014 – what next?

52



Case report

• Man, 1966, • dg HL 3/2006, IVB,


• 1st relapse 2/2007 – 3 cycles of DHAP – PR, ASCT 4/2007 – CR PET negative – radiotherapy

• 2nd relapse 4/2008 – in non irradiated area, bones, ??? – GDP – PR, AlloSCT 10/2008 – 3rd CR PET negative




53



Case report

• Man, 1966, • dg HL 3/2006, IVB,




• 3rd relaps 10/2009 – ???F irradiation, DLI, inconclusive PET • 4rd relapse 3/2012 – PET positive, up to 2x4 cm, observation • progression up to 6 cm 6/2013



54



Case report

• Man, 1966, • dg HL 3/2006, IVB,




• 3rd relaps 10/2009 – IF irradiation, DLI, inconclusive PET • 4rd relapse 3/2012 ???– PET positive, up to 2x4 cm, observation • progression up to 6 cm 6/2013



55



Case report

• Man, 1966, • dg HL 3/2006, IVB, IPS 5




• 3rd relaps 10/2009 – IF irradiation, DLI, inconclusive PET • 4rd relapse 3/2012 – PET positive, up to 2x4 cm, observation • progression up to 6 cm 6/2013 ???



56



Case report

• Man, 1966, • dg HL 3/2006, IVB, IPS 5






• 5th relapse – 9/2014 – what next???

57



Brentuximab Vedotin in the HL management

Front-line

Pretransplant

Post transplant

BV + salvage - ICE

BV monotherapy (Aethera trial)

ABVD/ AVD + Brentuximab Vedotin

BV + X

BV monotherapy

BV monotherapy



Other drugs

• monotherapy in relaps

• combination therapy with chemotherapy

– BV, HDAC, mTOR inhibitors – with salvage

• combination of diferent drugs

– HDAC + mTOR

– ......

59



Conclusion

• HL – excellent results of 1st line Tx, very good results of ASCT salvage

• Pts failing 1st line and ASCT – poor outcome

• Number of new drugs tested

– after 1st failure – before

– after ASCT, after aloSCT

– maintenance Tx



Thank you

61

salvage treatment in hodgkin's lymphoma: targeted … · salvage treatment in hodgkin's...

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