Transcript Abstract 385 - ANCO On-Line

ASH Highlights, 2007:
Lymphoma
Lawrence D. Kaplan MD
UCSF
ASH 2007 Highlights:
Lymphoma
No.
385
LB-1
387
643
213
787
Topic
R-Bendamustine vs R-CHOP for indolent NHL
Intensive immunochemotherapy for MCL
HyperCVAD for MCL. S0213
90Y-Ibritumomab consolidation for follicular NHL
PET-Guided consolidative RT in advanced HL
Abbreviated chemotherapy for PET-negative
limited stage DLBCL
121 Oral everolimus in relapsed aggressive NHL
122 Oral forodesine in refractory CTCL
Abstract 385
Bendamustine Plus Rituximab Versus CHOP Plus
Rituximab in the First-Line Treatment of Patients
with Indolent and Mantle Cell Lymphomas First
Interim Results of a Randomized Phase III Study
of the StiL (Study Group Indolent Lymphomas,
Germany).
Mathias J. Rummel, U. von Gruenhagen, N. Niederle, F. Rothmann, H. Ballo, E.
Weidmann, M. Welslau, G. Heil, H. Duerk, M. Stauch, C. Losem, A. Matzdorff, C.
Balser, K. Schalk, D. Kofahl-Krause, U. Kaiser, W. Knauf, A. Banat, D. Hoelzer, W.
Brugger, on behalf of the StiL Hematology, University Hospital, Giessen,
Germany; Cottbus; Leverkusen; Potsdam; Offenbach; Nordwest-Krankenhaus,
Frankfurt; Aschaffenburg; Luedenscheid; Hamm; Kronach; Neuss;
Saarbruecken; Marburg; Limburg; MHH, Hannover; Hildesheim; Frankfurt;
University Hospital, Frankfurt; Villingen-Schwenningen; StiL - Study Group
Indolent Lymphomas, Giessen, Germany
Background
• Phase II R-bendamustine for refractory
lymphoma:CR: 71% FL(24), 53% SLL(17), 50%
MCL(16), 67% MZL(6)
Rummel MJ, et al JCO 2005; 23: 3383
R-Bendamustine vs R-CHOP
Untreated
Follicular
Mantle cell
Other indolent
R
a
n
n
o
m
i
z
e
R-bendamustine x 6
Ritux: 375mg/m2 d1
Bendamustine 90mg/m2 d1,2
28 day cycle
R-CHOP-21 x 6
Non-inferiority study, EFS difference < 10% after 3 yrs
463 randomized, 315 eligible for interim analysis
Patient Characteristics
Parameter
N
Stage 4
FLIPI >3
Follicular
MCL
Other
All
52%
19
29
RB
166
70%
50
RCHOP
149
77%
58
Outcomes
Parameter
Alopecia
Gr 3/4 neutrop
Infect complicats
ORR
CR
PD during followup
Deaths
PFS
Med followup
RB
0
16%
23
93%
47%
33
13
39 mo
18 months
RCHOP
94%
41%
41
93%
42%
43
12
39 mo
Significance
• Highly active regimen
• Better tolerated than R-CHOP
• Opportunity to defer use of anthracyclenebased regimen
• Very attractive as first-line therapy
• Anticipated approval for CLL soon
• Median followup very short
• No data on long-term toxicity
Mantle Cell Lymphoma Can Be Cured by
Intensive Immunochemotherapy with In-Vivo
Purged Stem-Cell Support; Final Report of the
Nordic Lymphoma Group MCL2 Study (#LB-1)
Christian H. Geisler, MD, PhD1, Erkki Elonen, MD, PhD2,*, Arne Kolstad, MD,
PhD3,*, Anna Laurell, MD, PhD4,*, Niels Andersen, MD, PhD1,*, Lone B. Pedersen,
B.Sc1,*, Anne Marie Boesen, MD, Phd5, Mikael Eriksson, MD, PhD6,*, Mats
Jerkeman, MD, PhD6,*, Eva Kimby, MD, PhD7, Outi Kuittinen, MD, PhD8,*, Grethe
F. Lauritzen, MD, PhD3,*, Herman Nilsson-Ehle, MD, PhD9, Marie Nordstrom, MD,
PhD7,*, Elisabeth Ralfkiaer, MD, PhD1, Mans Akerman, MD, PhD6,*, Mats Ehinger,
MD, PhD6,*, Christer Sundstrom, MD, PhD4, Ruth Langholm, MD, PhD3,*, Jan
Delabie, MD, PhD3,*, Marja-Liisa Karjalainen-Lindsberg, MD, PhD2,* and Peter
Brown, MD, PhD1,*
Study Design
Maxi-CHOP
CTX 1.2Gm/m2
Doxo 75mg/m2
VCR 2mg
Prednisone 100mg D1-5
Cytarabine
Maxi-CHOP
3Gm/m2 x 4
R-cytarabine
R-Maxi-CHOP
Untreated MCL, cyclin D1+
Central path review
Primary endpoint PFS
RR-cytarabine
BEAM-ASCT
Patient Characteristics
•
•
•
•
•
N
Median age
Male
Stage IV
Histology
– Classical
– Blastoid
• CR/CRu (pre-transplant)
• PR
• TRM
160
56 (32-65)
71%
84%
128
31
55%
41%
3.8%
Molecular Remission Post-Transplant
MRD-negative
MCL-1
MCL-2
Product
12%
85% (n=42)
Patients
38%
90% (n=77)
Nordic MCL Trial: Survival
Median follow-up 3 years.
Intent-to-treat analysis
5 year EFS: 63%
Multivariate analysis: Only Ki67 independently predicts EFS
Progression-free survival after CHOP and R- CHOP
Lenz, G. et al. J Clin Oncol; 23:1984-1992 2005
Significance
• Stem cell product can be rendered MRD-negative in highproportion (demonstrated in 2 previous studies)
• Survival curves appear flat after 3 years, but follow-up still too
short
0.6
0.4
0.0
0.2
Proportion
0.8
Progression-Free Survival
0
1
2
3
4
5
Years from Study Entry
N = 70
Ev ents = 29
Median= 5.4
Gianni et al 1998
CALGB 59909,Damon et al 2007
Abstract 387: R-HyperCVAD for MCL
SWOG S0213
•
•
•
•
•
•
•
•
Stage III/IV or bulky II MCL up to age 70
Target accrual 50, 56 registered
Eligible patients: 49, 37 eval for response
Median age 57.4 (35-69)
Off study for toxicity: 42%
Grand 4 heme toxicities in most patients
CR+CRu: 58%
Median follow-up: 1.6yr. PFS: 2 yrs 69%
Also presented E1499: RCHOP-ibritumomab with 24mo med follow-up
Median PFS: 24mo
Abstract 643
90Y-Ibritumomab Tiuxetan (Zevalin) Consolidation of
First Remission in Advanced Stage Follicular NonHodgkins Lymphoma: First Results of the International
Randomized Phase 3 First-Line Indolent Trial (FIT) in
414 Patients.
Anton Hagenbeek, Angelika Bischof-Delaloye, John A. Radford, Ama Rohatiner,
Gilles Salles, Achiel Van Hoof, Barbara Putz, Michael Kunz, Franck Morschhauser
UMC Utrecht/HOVON, Netherlands; Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland; Christie Hospital, Manchester, United Kingdom; St.
Bartholomews Hospital, London, United Kingdom; Centre Hospitalier Lyon Sud,
Pierre Bnite, France; General Hospital St. Jan, Brugge, Belgium; Bayer Schering
Pharma AG, Berlin, Germany; Hpital Huriez, Lille, France
90Y-Ibritumomab
Tiuxetan (Zevalin)
Consolidation: Schema
90Y-Ibritumomab
N=208
Follicular NHL
Gr 1,2
Stage III/IV
<25% BM
CVP, CHOP-like
Fludara, chloramb
Ritux-chemo
CR/PR
Observation
N=206
Off study
77 study centers
13 countries
90Y-Ibritumomab
Tiuxetan Consolidation
Characteristic
Ibritumomab
Observation
N
Age
Stage IV
FLIPI 3-5
CVP
CHOP(-like)
Fludara-comb
Chlorambucil
Ritux-chemo
Post-chemo response
CR
PR
208
55
64%
24%
26%
43%
6%
9%
16%
206
53
66%
20%
25%
46%
5%
10%
14%
51%
49%
53%
47%
Endpoints: Results
Endpoint
Ibritumomab
Observ
p
CR/CRu
PFS
If PR
If CR
PR to CR
87%
37mo
29.7
54.6
17.5%
53%
13.5
6.3
29.9
77.2%
<.0001
<.0001
.01
<.001
Median followup 3.5 yr
Molecular remission in 90%
Ibritumomab toxicities
• Median platelet nadir:
• Median ANC nadir:
• Gr 3/4 infection:
45 x109/L (8-404) tx wk 5
1 x109/L (.02-6.6) tx wk 6
8%
• Deaths:
11
– Control
– Ibritumomab
5 (4 progression)
6 (3 progression)
Significance
• Ibritumobab is one of the most highly active agents
available for follicular lymphoma
• Most did not receive rituximab-containing induction
regimens. SWOG study (RCHOP vs CHOPtositumomab) should answer
• What is overall survival benefit?
• Are there long term risks (ie MDS/AML), ability to
collect stem cells, etc
• Do we need the chemotherapy?
PET Scanning in Lymphoma
• MANY presentations
• Negative predictive value of PET following
therapy is high in most studies
• Two retrospective studies (Abstracts 213,
787) take advantage of this to reduce use of
radiotherapy in HL and NHL respectively
FDG-PET Guided Consolidative Radiotherapy
in Patients with Advanced Stage Hodgkin
Lymphoma with Residual Abnormalities on Post
Chemotherapy CT Scan (#213)
Savage et al. for BCCA
Standard of care in BC since July, 2005:
PET+
RT
Stage III / IV
Bulky stage II
Or B-sxs
ABVD x 6
CT
>2cm mass
PET No tx
Negative
No further tx
52 patients with post-treatment PET and adequate follow-up
PET-guided RT in HL
•
•
•
•
Median age 30
47% bulky (>10cm).
71% IPS 0-2
56% stage II
70% B-sxs
Median folow-up 23 months
12 PET+ patients
40 PET- patients
RT in 10
No RT
60% reduction in use of RT in PET era
6 relapses, 3 in-field
2 yr PFS: 38%
3 relapses
2 yr PFS: 92%
NPV: .925
Progression-free Survival (Savage et al)
•Small data set
•Short follow-up
•Size of residual mass
larger in those with relapse
•What for PET+patients?
Limited Stage DLBCL Patients with a Negative
PET following Three Cycles of R-CHOP Can be
Effectively Treated with Abbreviated
Chemoimmunotherapy Alone (#787)
• CHOP x 4 adequate treatment for elderly patients with low-risk
early stage DLBCL (Bonnet et al JCO 2007)
• BCCA retrospective evaluation of patients.
• Since 2005 stage I/II / no B-sxs / Mass <10cm have PET after 3
cycles RCHOP.
• If PET-: One additional cycle RCHOP, No RT
• If PET+: IFRT
PET-: n=37 (74%)
PET+:n=13 (26%)
RT in 35
RT in 13
1 relapse, 2yr PFS: 97%
2 relapse, 2yr PFS: 75%
Novel Agents for Lymphoma Reported at ASH
• Everolimus (#121) oral mTOR inhibitor Phase 2
–
–
–
–
–
–
Population: Aggressive relapsed NHL
N=37 with median of 4 prior therapies (1-15)
Med age 72, 54% DLBCL, 38% MCL
10 mg daily dose
ORR: 32%
5.5 mo response duration
Toxcicities: Gr 3 heme and increased lipids
• Forodesine (#122) oral PNP inhibitor
–
–
–
–
–
Phase I/2
Population: Refractory CTCL > IB
Optimal biol dose based on pK and PNP inhibition: 80mg/m2
N=36. Med 3 prior txs.
ORR: 39%. Duration: 127 days
For Sezary (N=20): ORR 65% by erythroderma score
• >50% reduction in sezary cells in 45%
– Few > gr 3 toxicities - vertigo, diarrhea, edema, LFTs, lymphopenia