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
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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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Disclosure
• Takeda, Celgene, Mundipharma, BMS
– consultancy
– research support
2
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Outline
• Treatment strategy
• New drugs
• „Old“ drugs
• The place of new drugs
• Conclusions
3
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Outline
• Treatment strategy
• New drugs
• „Old“ drugs
• The place of new drugs
• Conclusions
4
Charles University General Hospital
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
Charles University General Hospital
Treatment strategy
Chemotherapy +/- RT which one?
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
15 %
5-10 %
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Salvage Tx for R/R HL
7
Collins GP et al, Br J Haematol 2014
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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
Charles University General Hospital
Treatment strategy
Chemotherapy +/- RT which one?
cure 70-95%
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
15 %
5-10 %
~ 7.5 %
Charles University General Hospital
Treatment strategy
Chemotherapy +/- RT which one?
cure 70-95%
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 <1 %
~ 5%
~ 7.5 %
15 %
5-10 %
Charles University General Hospital
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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Outline
• Treatment strategy
• New drugs
• „Old“ drugs
• The place of new drugs
• Conclusions
12
Charles University General Hospital
New drugs - rationale
13
Acording to Diefenbach C & Advani R, Hem Onc Clin N Am 2013
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
Charles University General Hospital
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
Younes A et al, JCO 2012
Charles University General Hospital
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
Younes A et al, JCO 2012
Charles University General Hospital
Survival – PFS and OS
Younes A et al, JCO 2012
Charles University General Hospital
PFS comparison with the last therapy
Younes A et al, JCO 2012
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
BV in routine practice
41
Zinzani P et al, Haematologica 2013
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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
Charles University General Hospital
Different agents - monotherapy
0
20
40
60
80
100
CR PR
But – PFS 4-6 months
Charles University General Hospital
PD-L1
Greaves P , and Gribben J G Blood 2013;121:734-744
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Outline
• Treatment strategy
• New drugs
• „Old“ drugs
• The place of new drugs
• Conclusions
46
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
„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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
„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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Outline
• Treatment strategy
• New drugs
• „Old“ drugs
• The place of new drugs
• Conclusions
51
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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?
53
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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 – ???F 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?
54
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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?
55
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Case report
• Man, 1966, • dg HL 3/2006, IVB, IPS 5
– 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?
56
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Case report
• Man, 1966, • dg HL 3/2006, IVB, IPS 5
– 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 8 cycles – 4th CR PET negative
• 5th relapse – 9/2014 – what next???
57
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
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
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Other drugs
• monotherapy in relaps
• combination therapy with chemotherapy
– BV, HDAC, mTOR inhibitors – with salvage
• combination of diferent drugs
– HDAC + mTOR
– ......
59
Charles University General Hospital
16 - 17 October 2014, Nicosia, Cyprus
Conclusion
• HL – excellent results of 1st line Tx, very good results of ASCT salvage