Transcript Document 7314133

LATEST CONCEPTS IN LARGE
CELL AND HODGKIN LYMPHOMAS
Morton Coleman, M.D.
Director, Center for Lymphoma and Myeloma
New York-Presbyterian Hospital Weill Cornell Medical Center
Clinical Professor of Medicine
Weill Cornell Medical College
Chairman, Medical Affiliates Board
Lymphoma Research Foundation
Disclosures for Morton Coleman, MD
In compliance with ACCME policy, ASH requires the following disclosures to the session audience:
Employment
None
Consultancy
Celgene, Genzyme, GlaxoSmithKline,
Millenium, Onyx, Spectrum
Equity Ownership
Immunomedics
Research Funding
Glaxo Smith Kline, Onyx
Honoraria
None
Patents & Royalties
None
Disclosures for Morton Coleman, MD, con’t
In compliance with ACCME policy, ASH requires the following disclosures to the session audience:
Speakers Bureau
None
Membership on Board of
Directors/Advisory Committee
Immunomedics, Glaxo Smith Kline
Other
None
Presentation includes a description
of the following off-label use of a
drug or medical device
None
THE THRUST OF CURRENT
DEVELOPMENTS
 Identify subsets of patients with diffuse large
B cell or Hodgkin lymphoma who are either
destined to do well or fare poorly using
techniques beyond the known clinical
predictive factors, particuarly those
techniques using molecular changes and/or
PET scans.
 By applying our better understanding of the
(molecular) biology of these diseases, can we
not only identify these subsets, but also
develop and individualize treatments using
less therapy for those with a good prognosis
and using novel therapies for those destined
to do poorly.
R-CHOP-21/14
OS by IPI score
1.0
0.9
Probability
0.8
0.7
0.6
0.5
0.4
0.3
Events Totals
9
84
28
231
56
306
81
280
54
154
12
25
0
1
2
3
4
5
0.2
0.1
0.0
0
1
2
84
231
306
280
154
25
83
215
275
233
125
19
69
181
228
195
96
16
Patients at Risk
0
1
2
3
4
5
p <0.0001
3
4
Years from randomisation
42
105
144
120
56
9
21
50
73
60
30
3
5
6
4
16
13
16
8
1
0
1
0
1
0
0
Cunningham et al, ASCO 2011
R-CHOP-21/14 cures about 2/3 of
“all comers”: Failure-free survival
1.0
0.9
Probability
0.8
0.7
0.6
0.5
0.4
Events, n (%)
0.3
2-yr FFS
R-CHOP14
155 (29)
153 (28)
75%
75%
Log-rank test
0.2
0.1
R-CHOP21
0.99 (0.79–1.24)
HR (95% CI)
R-CHOP14
R-CHOP21
p=0.94
0.0
0
Patients at Risk
1
2
3
4
Years from randomisation
5
R-CHOP21 534
429
358
216
R-CHOP14 533
438
355
224
25
25
116
102
6
1
1
Cunningham et al, ASCO 2011
DLBCL patients who recur post R-CHOP-21
do not do well
31%
N=228
Gisselbrecht C, et al. J Clin Oncol 2009; 27(15s):
Abstract 8509.
Overall survival of patients with DLBCL refractory to
0.75
0.50
0.25
0.00
Proportion of Patients
1.00
second line therapy is very poor
0
5
10
15
Time (months)
Elstrom et al , Clin Lymph Myel Leuk, 2010
20
25
R-ACVBP (vs R-CHOP in DLBCL < 60 aaIPI = 1)

R-ACVBP (every two weeks)
–
PDN: 60 mg/m2; d1-d5
–
Ritux: 375 mg/m2 ; d1
–
Doxo :75 mg/m2; d1
–
CPM: 1200 mg/m2; d1
–
Vindesine: 2 mg/m2; d1 & d5
–
Bleomycin 10 mg ; d1 & d5
–
Methotrexate (IT) 15 mg; d1
–
G-CSF 5 µg/kg/d; d6-d13

Methotrexate 3 g/m2; d1-d15

R-Ifosfamide-VP16

 Increased dose-intensity
(mg/m2.wk) compared to R-CHOP
Doxo: 37,5
x 2.25
Doxo: 16.7
CPM: 600
x 2.4
CPM: 250
Rituximab: 187 R-ACVBP
x 1.5
Rituximab: 125
R-CHOP
 Sequential consolidation
using second-line agents
– Ifosfamide, VP16, Ara-C
 CNS prophylaxis
–
Ritux: 375 mg/m2 ; d1
–
Ifosfamide: 1.5g/m2; d1
– High-dose i.v Methotrexate
–
VP16: 300 mg/m2; d1
– Intrathecal Methotrexate
Ara-C 100mg/m2 sc, d1-d4
PFS and OS of randomized DLBCL
patients treated with R-CHOP
Stiff et al,
ASCO 2011
CALGB 50303: R-CHOP vs REPOCH in Newly Diagnosed DLBCL
R-CHOP
every 3 wks for 6 cycles
Untreated
patients with
newly diagnosed
DLBCL
(N = 478)


R-EPOCH
Doxorubicin, etoposide, vincristine Days 1-4;
cyclophosphamide Day 5;
prednisone Days 1-5
Primary endpoints: EFS, molecular predictors of outcome for each regimen
Secondary endpoints: RR, OS, toxicity, use of molecular profiling for
pathological diagnosis
Clinical Trials.gov. NCT00118209. http://www.clinicaltrials.gov
SO WHAT
NEW ‘STUFF’
HAVE WE
LEARNED?
Germinal center vs activated B cell DLBCL
Rosenwald A et al. N Engl J Med. 2002;346:1937-1947
Outcome by GCB vs non-GCB gene signatures in
DLBCL
N=233 patients treated with R-CHOP
PFS
Lenz G, et al, NEJM November 27, 2008
OS
Non-GCB DLBCL is associated with high expression of target genes of
NF-kB transcription factors
Davis, et al, J Exp Med 2001
CHOP-R + bortezomib DLBCL PFS and OS by subtype (n = 40)
Ruan et al, JCO 2010
What about other specific subtypes
defined pathologically/molecularly?
 Gray zone (vs Hodgkin Lymphoma)
 B cell lymphoma intermediate between
DLBCL and BL
 C-MYC +
 “Double hit”
 “Triple hit”
Chromosomal translocations in
lymphoma and MYC
 40% of B cell lymphomas have recurrent
reciprocal translocations
–
–


May be subtype specific
Often oncogene plus Ig loci enhancer
t(8;14)(q24;q32) – lymphoma initiating in BL
MYC breakpoints may be at diagnosis or
may be secondary events with progression
in other lymphomas
 In MYC+ DLBCL and DH lymphoma, often
non Ig-MYC breakpoints
What is a “double hit” lymphoma?
 Recurrent breakpoints activating multiple
oncogenes, one being MYC
 BCL2+/MYC+ most common
 BCL6, CCND1 and BCL3 may also occur
 Can also have “triple hit”
B cell lymphoma, unclassifiable, with
features intermediate between diffuse
large B cell lymphoma and Burkitt
lymphoma
 WHO 2008 classification
 35-50% of cases have a MYC translocation,
15% have a BCL2 translocation
 Increasing incidence with age
 Many are DH
Immunophenotype of “double hit”
lymphoma
 CD10+, GCB phenotype
 Lack MUM1, ABC phenotype
 BCL2 + also present (with Myc) in a
majority of cases
 High proliferative index
– median 90% Ki67+
Aukema et al, Blood 2011
Clinical features of “double hit” lymphoma
N DH/
total N
(%)
DH w
prior
iNHL
%
Med
age
St III/IV
%
LDH >
Nl
%
BM
+%
CNS +
%
>1
ENS %
IPI
Hi/HiI
%
Bertrand
2007
10/17
(59%)
10%
58
70%
NA
NA
NA
NA
56%
Johnson
2009
54/54
(100%)
46%
62
76%
50%
71%
NA
35%
70%
Kanungo
2006
14/14
(100%)
None
55
NA
93%
79%
21%
57%
NA
Le Gouill
2007
16/16
(100%)
25%
61
100%
100%
94%
50%
88%
81%
Macpherson
1999
15/39
(38%)
46%
65
92%
80%
69%
NA
62%
90%
Niitsu 2009
19/19
(100%)
None
61
100%
100%
84%
21%
63%
89%
Snuderl
2010
20/20
(100%)
15%
64
95%
100%
59%
45%
30%
85%
Tomita 2009
27/27
(100%)
17%
51
96%
93%
65%
9%
65%
87%
Study
Aukema et al, Blood 2011
R-CHOP and MYC rearranged DLBCL
EFS
35 (14%) with MYC
rearrangements
19 also had t(14;18)
3 also had BCL6
OS
7 “triple hit”
Therefore most
“MYC+” are “double”
or “triple” hit
Barrans et al, JCO 2010
DA-R-EPOCH and MYC+ DLBCL
9 MYC+ DLBCL
EFS
99 MYC- DLBCL
Similar
risk by IPI
OS
High RR/PFS in
BL
Dunleavy et al, Lugano 2011
Approach to “variant” DLBCLs
 GCB vs non-GCB
– R-CHOP is standard
– Various randomized trials underway
 MYC+, DH, TH
–
–
–
–
Consider FISH/IHC for MYC, BCL2, BCL6
Less favorable with R-CHOP
Unclear if other approaches better
Prospective studies underway, including REPOCH
In Hodgkin lymphoma, what role
does PET Scans play in
lessening (toxicity) therapy and
enhancing cure?
May interim PET/CAT scans be of
value or should scans be used
only at the end of treatment?
FDG-PET: After one (two
treatments) versus two cycles
(four treatments) of therapy
Early determination of treatment sensitivity in Hodgkin
lymphoma: FDG-PET/CT after one cycle of therapy
has a higher negative predictive value than after two
cycles of therapy
Hutchings, M., Kostakoglu,L., Coleman, M., et al.
Submitted for publication
Participating Nations
Denmark
United States
Italy
Poland
Patient Population:126 Pts.






Stage I 8%
Stage 2 46%
Stage 3 19%
Stage4 27%
B Sxs
56%
Bulky
37%
Comparison of the prognostic value of
PET 1 and PET 2: Progression Free
Survival at 2 Years
PET 1 PET2





Negative predictive value
Positive predictive value
Sensitivity
Specificity
Concordance
98% 91%
63% 85%
95% 61%
86% 97%
>90%
The RAPID Trial in Patients With
Clinical Stages IA/IIA Hodgkin
Lymphoma and a “Negative” PET Scan
After 3 Cycles ABVD
Abstract 547
Radford J, Barrington S, Counsell N, Pettengell R,
Johnson P, Wimperis J, Coltart S, Culligan D, Lister A, Bessell E,
Kruger A, Popova B, Hancock B, Hoskin P, Illidge T, O’Doherty M
RAPID Trial Design
Initial treatment:
ABVD x 3
Reassessment:
if NR/PD, patient goes off study
if CR/PR, FDG-PET scan performed
PET-positive
4th cycle ABVD then IFRT
PET-negative
Randomization
IFRT
Radford J, et al. Blood. 2012;120: Abstract 547.
No further
treatment
Outcomes After Median Follow-Up of
45.7 Months
PET negative;
PET negative;
PET positive;
randomized to
randomized to
IFRT
NFT
4th cycle ABVD/IFRT
(n = 145)
(n = 209)
(n = 211)
Progressions
9
20
11
Deaths
6
1
8
PFS at 3 years
93.8%
90.7%
85.9%
OS at 3 years
97.0%
99.5%
93.9%
Radford J, et al. Blood. 2012;120: Abstract 547.
Progressions and Deaths in the
Randomized PET-Negative Population
(n = 420)
 IFRT arm; progressions 9, deaths 6
– Pneumonitis, n = 2
– HL, n = 1
– Cardiovascular disease, n = 1
– Intracerebral hemorrhage, n = 1
– AITL, n = 1
 NFT arm; progressions 20, deaths 1
– Bronchopneumonia, n = 1
Radford J, et al. Blood. 2012;120: Abstract 547.
Summary
 602 pts registered between 2003 and 2010
 75% PET-negative at central review after ABVD x 3
 In the randomized PET-negative population, 3 yr PFS is 93.8% IFRT
and 90.7% NFT
 Risk difference -3% is within the maximum allowable difference of -7%
Radford J, et al. Blood. 2012;120: Abstract 547.
Conclusion
Patients with a negative PET scan
after 3 cycles ABVD have an
excellent prognosis without further
treatment, and for these patients RT
can be avoided
Radford J, et al. Blood. 2012;120: Abstract 547.
Commentary
 These data are similar to those reported from Argentina
several years ago.
 Would the slightly higher rate of false negative PET
scans at cycle 3 seen in those patients not receiving
adjuvant radiotherapy been avoided had the PET been
performed at cycle 2, or better yet, cycle 1
 Response-adapted therapy based on qualitycontrolled/assured PET imaging may become the future
standard of care in early-stage HL
Radford J, et al. Blood. 2012;120: Abstract 547.
An Individual Patient-Data Comparison
of German Hodgkin Study Group HD10
and HD11 Combined Modality Therapy
and NCIC Clinical Trials Group HD.6
ABVD Alone
Abstract 549
Hay AE, Klimm B, Chen BE, Goergen H, Shepherd LE, Fuchs M,
Gospodarowicz M, Borchmann P, Connors JM, Markova J, Crump M, Lohri A,
Winter JN, Dorken B, Pearcey RG, Volker D, Horning SJ, Eich HT, Engert A,
Meyer RM
Comparison of NCIC CTG HD.6 and GHSG
HD10 and HD11 Staging, Eligibility and
Preferred Arms
2 ABVD + 20 Gy IFRT
Early,
favorable
HD10
4 ABVD + 30 Gy IFRT
Early,
unfavorable
HD11
Advanced
GHSG
4 – 6 ABVD alone
NCIC CTG
HD.6
Favorable
Unfavorable
Not necessarily to scale
Hay AE, et al. Blood. 2012;120: Abstract 549.
Advanced
Comparison of NCIC CTG HD.6 and GHSG
HD10 and HD11 Staging, Eligibility and
Preferred Arms
Very good prognosis
Early,
favorable
HD10
B or Bulk
Early,
unfavorable
HD11
Advanced
GHSG
NCIC CTG
HD.6
Favorable
Unfavorable
Advanced
Not necessarily to scale
Hay AE, et al. Blood. 2012;120: Abstract 549.
Attribution of Death: All Patients
Cause of Death
GHSG HD10/11
NCIG CTG HD.6
Number
406
182
Med. F/U
7.6 Years
11.2 Years
Hodgkin lymphoma
5
4
Immediate toxicity
2
1
Second cancer
2
3
Cardiac
4
2
Other
6*
0
Total
19
10
*Other deaths were: 1 suicide, 1 respiratory failure, 1 cerebral hemorrhage, 1 progression
of NHL, 2 unknown
Hay AE, et al. Blood. 2012;120: Abstract 549.
Outcomes: All Patients
NCIG CTG
Endpoint
Number
Med. F/U
GHSG HD10/11
HD.6
HR
GHSG
NCIC CTG
182
(95% CI)
PD/OS
PD/OS
406
7.6 Years
11.2 Years
8-yr TTP
93%
87%
0.44 (0.24, 0.78)
25/0
23/0
8-yr PFS
89%
86%
0.71 (0.42, 1.18)
25/13
23/4
8-yr OS
95%
95%
1.09 (0.49, 2.40)
19
10
Hay AE, et al. Blood. 2012;120: Abstract 549.
Overall Summary
 Combined modality therapy (CMT)
improves disease control by 4%-7%
 Superior long-term overall survival with
CMT is highly unlikely
 The relatively long term outcomes
associated with IFRT remain to be
clarified
Hay AE, et al. Blood. 2012;120: Abstract 549.
What’s new for
refractory/relalpsing disease?
Evolving Data on Brentuximab Vedotin
Brentuximab Vedotin Mechanism of
Action
Brentuximab vedotin (SGN-35) ADC
monomethyl auristatin E (MMAE), potent antitubulin agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
ADC-CD30 complex
traffics to lysosome
MMAE is released
MMAE disrupts
microtubule network
G2/M cell
cycle arrest
Apoptosis
Long-Term Survival Analyses of an
Ongoing Phase 2 Study of
Brentuximab Vedotin in Patients with Relapsed or
Refractory Hodgkin Lymphoma
Abstract 3689
R Chen, AK Gopal, SE Smith, SM Ansell, JD Rosenblatt, KJ Savage,
JM Connors, A Engert, EK Larsen, EL Sievers, A Younes
Overall survival after treatment with Brentuximab
vedotin
•
Median observation time
from 1st dose:
– All patients = 29.5 months
(range, 1.8 to 36.9)
– CR patients = 29.1 months
(range, 2.6 to 34.3)
• 60/102 patients (59%) remain
alive; median OS has not
been reached (95% CI: 28.7,
NE)
• Estimated 24-month survival
rate* = 65% (95% CI: 55, 74)
Overall Survival by Best Clinical Response
•
Estimated 24-month
survival rate* by best
response:
– CR: 91% (95% CI: 81,
100)
– PR: 61% (95% CI: 45,
76)
– SD: 38% (95% CI: 17,
59)
– PD: 33% (95% CI: 0,
87)
Overall Survival by Cycle 4 PET Status
Conclusions
 After a median observation time of ~2.5 years from first brentuximab
vedotin dose, 60 of 102 patients (59%) remain alive at last follow up
 Median OS has not yet been reached; the estimated 24-mo survival
rate was 65%
– Improved OS strongly correlated with both:
 Achievement of CR
 Negative PET scan at Cycle 4
– Prolonged OS was observed in patients with both long
and short progression-free intervals after auto-SCT
What are we doing new for
Advanced-Stage HL
How can we improve the cure rate and reduce the toxicity for
advanced stage disease?
Frontline Therapy With Brentuximab
Vedotin Combined with ABVD or
AVD in Patients with Newly
Diagnosed Advanced-Stage Hodgkin
Lymphoma
Abstract 798
Ansell SM, Connors JM, Park SI, O’Meara M, Younes A
Study Design
 Phase I, multicenter, dose-escalation study
 Major eligibility criteria
– Treatment-naïve HL patients
– Age ≥18 to ≤60 years
– Stage IIA bulky disease or Stage IIB-IV disease
 Treatment design
– 28-day cycles (up to 6 cycles) with dosing on Days 1 and 15
– Dose escalation cohorts – I-6, II-13, III-6, IV-6, expansion-20
Cycle 1
Cycle 3
Cycle 2
Brentuximab Vedotin
A(B)VD
6 Cycles +/- XRT
0
2
4
6
Weeks
Ansell SM, et al. Blood. 2012;120: Abstract 798.
8
10
12
Response Results at End of Front-Line
Therapy
• Response results at end of front-line therapy:
◦ ABVD cohorts: 21 of 22 CR (95%)
◦ AVD cohorts: 24 of 25 CR (96%)
• In addition, 1 patient withdrew consent and 3
patients were lost to follow-up prior to
completion of front-line therapy and were not
evaluable for response
Ansell SM, et al. Blood. 2012;120: Abstract 798.
Conclusions
• Recommended regimen is 1.2 mg/kg brentuximab
vedotin every 2 weeks combined with AVD
• AVD combined with brentuximab vedotin appears to
be well tolerated with manageable AEs
• Concomitant administration of brentuximab vedotin
and bleomycin is contraindicated due to pulmonary
toxicity
• CR rate of 96% observed at the end of front-line
therapy with brentuximab vedotin combined with AVD
Ansell SM, et al. Blood. 2012;120: Abstract 798.
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)
Study Design HL Stages III-IV IPS ≥ 3
Randomized Phase III Trial
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)
Progression-Free Survival
(Not a predefined study endpoint)
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)
Treatment Discontinuations for Toxicity
ABVD
n = 272
BEACOPP
n = 269
Toxicity
10
28
Respiratory related (not including
7
5
infections)
Hematological
4
Infection / meningitis / septicemia
10
Septic / toxic shock
1
4
Hepatic
2
2
Cardiac
1
Neurological
1
Allergy to etoposide
1
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)
Event-Free Survival
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)
Overall Survival
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)
Conclusions
 EFS (primary endpoint) is similar between treatment arms.
However, more progressions / relapses were observed with ABVD
while early discontinuations were more frequent with BEACOPP
 In this high-risk group, conventional dose escalation with BEACOPP
4+4 provides a better PFS compared to ABVD, yet not good enough
to improve OS
 Additional considerations (treatment burden & cost, fertility issues,
risk of relapse, risk of salvage, immediate & late morbidities) may
guide physician / patient decisions toward ABVD or BEACOPP,
which currently may share the claim for “current standard of care”
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)
BOTTOM LINES
A GENERAL SURVEY OF STUDIES COMPARING BEACOPP TO
ABVD ALMOST ALL CONSISTENTLY SHOW A SUPERIOR
PROGRESSION FREE SURVIVAL FOR BEACOPP BUT LONG
TERM SURVIVAL SEEMS TO BE COMPARABLE DUE TO THE
TOXICITY OF BEACOPP.
AS WITH LIMITED STAGE DISEASE, CAN INTERIM PET SCANS
BE USED TO SELECT OUT THOSE PATIENTS NOTNEEDING
MORE AGGRESSIVE THERAPY AND THEREBY AVOID ALL THE
UNNECESSARY TOXICITY OF BEACOPP? IS GENETIC
INSTABILITY ADVANCED BY DR DIEHL TRULY OPERATIVE
EVEN AS EARLY AS (A PET SCAN AFTER) ONE CYCLE
BOTTOM LINES
 3 cycles of ABVD without IFRT has an excellent outcome for favorable
stage IA/IIA patients who are at the conclusion of treatment.
 Disease control may be slightly better for CMT as compared with CT (3%7%), although a survival difference is unlikely (long-term effects of IF RT
unknown).
 In retrospective analysis, survival of HL patients relapsed after autologous
SCT superior with BV compared with treatments prior to BV availability.
Role of BV in autologous SCT is under investigation.
 BV + AVD results in PET CR after 2 cycles and at completion of treatment
comparable to ABVD for patients with stage III/IV HL. Phase III comparison
has opened (C25003).
Acknowledgment
Clinical Research
Jia Ruan, M.D., Ph.D.
Richard Furman, M.D.
John P. Leonard, M.D.
Peter Martin, M.D.
Maureen Joyce, R.N.
Patricia Glenn, R.N.
Jamie Ketas
Jessica Hansen
Karen Weil
Jennifer O’Loughlin
Rebecca Elstrom
Laboratory Research
Ari Milneck, M.D., Ph.D.(Cornell)
Katherine Hajjar, M.D. (Cornell)
Shahin Rafii, M.D. (Cornell)
Translational Core
Maureen Lane, Ph.D. (Cornell)
Maureen Ward
Biostatistician
Ken Chueng, Ph.D. (Columbia)
Madhu Mazumdar, Ph.D. (Cornell)
Lymphoma Research Foundation
ASCO Foundation (YIA, CDA)
NIH / NHLBI
MANY THANKS TO DRS. DAVID STRAUSS AND
JOHN LEONARD FOR ALLOWING THE USE OF
SLIDES.
PYRAMID study design
DLBCL
diagnosis &
subtyping
Non-GCB
Hans method
GCB
Not
enrolled
R
Vc-R-CHOP
Bortezomib 1.3 mg/m2, d 1, 4
Rituximab 375 mg/m2, d 1
Cyclophosphamide 750 mg/m2, d 1
Doxorubicin 50 mg/m2, d 1
Vincristine 1.4 mg/m2, d 1
Prednisone 100 mg/d, d 1–5
Six treatment cycles q21 days
R-CHOP
Rituximab 375 mg/m2, d 1
Cyclophosphamide 750 mg/m2, d 1
Doxorubicin 50 mg/m2, d 1
Vincristine 1.4 mg/m2, d 1
Prednisone 100 mg/d, d 1–5
Six treatment cycles q21 days
Follow up every 3 months for 2 yrs