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ASH Highlights, 2007:Lymphoma
Lawrence D. Kaplan MD
UCSF
ASH 2007 Highlights: Lymphoma
No. Topic385 R-Bendamustine vs R-CHOP for indolent NHLLB-1 Intensive immunochemotherapy for MCL387 HyperCVAD for MCL. S0213643 90Y-Ibritumomab consolidation for follicular NHL644 PET-Guided consolidative RT in advanced HL787 Abbreviated chemotherapy for PET-negative
limited stage DLBCL121 Oral everolimus in relapsed aggressive NHL122 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
UntreatedFollicularMantle cellOther indolent
Rannomize
R-bendamustine x 6Ritux: 375mg/m2 d1Bendamustine 90mg/m2 d1,228 day cycle
R-CHOP-21 x 6
Non-inferiority study, EFS difference < 10% after 3 yrs463 randomized, 315 eligible for interim analysis
Patient Characteristics
Parameter All RB RCHOP
N 166 149
Stage 4 70% 77%
FLIPI >3 50 58
Follicular 52%
MCL 19
Other 29
Outcomes
Parameter RB RCHOPAlopecia 0 94%Gr 3/4 neutrop 16% 41%Infect complicats 23 41ORR 93% 93%CR 47% 42%PD during followup 33 43Deaths 13 12PFS 39 mo 39 moMed followup 18 months
Significance
• Highly active regimen• Better tolerated than R-CHOP• Opportunity to defer use of anthracyclene-
based 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/m2Doxo 75mg/m2VCR 2mgPrednisone 100mg D1-5
Cytarabine
3Gm/m2 x 4
Maxi-CHOP
R-cytarabine
R-Maxi-CHOP
RR-cytarabine
BEAM-ASCT
Untreated MCL, cyclin D1+Central path reviewPrimary endpoint PFS
Patient Characteristics
• N 160• Median age 56 (32-65)• Male 71%• Stage IV 84%• Histology
– Classical 128– Blastoid 31
• CR/CRu (pre-transplant) 55%• PR 41%• TRM 3.8%
Molecular Remission Post-Transplant
MRD-negativeMCL-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 analysis5 year EFS: 63%Multivariate analysis: Only Ki67 independently predicts EFS
Lenz, G. et al. J Clin Oncol; 23:1984-1992 2005
Progression-free survival after CHOP and R- CHOP
Significance• Stem cell product can be rendered MRD-negative in high-
proportion (demonstrated in 2 previous studies)• Survival curves appear flat after 3 years, but follow-up still too
short
Years from Study Entry
Proportion
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
Progression-Free Survival
N= 70 Events= 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-upMedian PFS: 24mo
90Y-Ibritumomab Tiuxetan (Zevalin) Consolidation of First Remission in Advanced Stage Follicular Non-
Hodgkins 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
Abstract 643
90Y-Ibritumomab Tiuxetan (Zevalin) Consolidation: Schema
Follicular NHLGr 1,2Stage III/IV<25% BM
CVP, CHOP-likeFludara, chlorambRitux-chemo
Off study
CR/PR
90Y-IbritumomabN=208
ObservationN=206
77 study centers13 countries
90Y-Ibritumomab Tiuxetan Consolidation
Characteristic Ibritumomab Observation
N 208 206Age 55 53Stage IV 64% 66%FLIPI 3-5 24% 20%CVP 26% 25%CHOP(-like) 43% 46% Fludara-comb 6% 5%Chlorambucil 9% 10%Ritux-chemo 16% 14%Post-chemo response
CR 51% 53%PR 49% 47%
Endpoints: Results
Endpoint Ibritumomab Observ p
CR/CRu 87% 53%
PFS 37mo 13.5<.0001
If PR 29.7 6.3 <.0001
If CR 54.6 29.9 .01
PR to CR 17.5% 77.2% <.001Median followup 3.5 yrMolecular remission in 90%
Ibritumomab toxicities
• Median platelet nadir: 45 x109/L (8-404) tx wk 5 • Median ANC nadir: 1 x109/L (.02-6.6) tx wk 6• Gr 3/4 infection: 8%
• Deaths: 11– Control 5 (4 progression)– Ibritumomab 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 CHOP-tositumomab) 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
Stage III / IVBulky stage IIOr B-sxs
ABVD x 6 CT
NegativeNo further tx
>2cm mass
PET+RT
PET -No tx
Standard of care in BC since July, 2005:
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+ patientsRT in 10 6 relapses, 3 in-field
2 yr PFS: 38%
40 PET- patients 3 relapses2 yr PFS: 92%NPV: .925
No RT
60% reduction in use of RT in PET era
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%) 1 relapse, 2yr PFS: 97%RT in 35
PET+:n=13 (26%) 2 relapse, 2yr PFS: 75%RT in 13
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