Treatment of DLBCL Dr. Nicolas Ketterer CHUV, Lausanne SAMO, May 2009
Non-hodgkin lymphomas DLBCL Most common NHL subtype throughout the world many other types of lymphoma with striking geographic variations SLL 8% MCL 6% MZL, MALT 8% FL 22% MZL 3% others 6% DLBCL 35% anaplastic T/null 2% PTCL 7% lymphoblastic 2% Burkitt 1%
Increasing of the rates of NHL, including DLBCL, in the US by 3-4% each year from 1973 to the mid-1990s
DLBCL in the WHO classification: heterogeneous group of diseases WHO Classification, IARC Press: Lyon 2008
Distinct types of DLBCL identified by gene expression profiling 2 major patterns of gene expression which are clinically distinct Alizadeh AA et al. Nature 2000;403:503
International Prognostic Index Unfavorable variables Age > 60 years Poor performance status (ECOG 2) Advanced Ann Arbor stage (III-IV) Extranodal involvement 2 sites High serum LDH (>normal) Risk group Unfavourable variables All patients Patients 60 Low 0 or 1 0 Low/intermediate 2 1 High/intermediate 3 2 High 4 or 5 3 Shipp M. N Engl J Med 329:987,1993
Blood 2007;109:1857-61 PFS IPI and R-IPI for patients treated with R-CHOP OS
Treatment of DLBCL
CHOP versus second generation regimens
HOWEVER! Improvement possible with dose-dense, dose-intense or HDT regimens Salles G, Ed. Program, EHA 2008
MInT trial design CD20+ DLBCL 18-60 years IPI 0, 1 stages II-IV I with bulk * CHOP-21 (n=396) CHOEP-21 (n=362) MACOP-B (n=33) PMitCEBO (n=32) Randomization 6 x CHOP-like* + 30-40 Gy (Bulk, E) 6 x CHOP-like* + rituximab + 30-40 Gy (Bulk, E) Pfreundschuh M et al. Lancet Oncol 2006;7:379
MInT trial EFS PFS OS Pfreundschuh M et al. Lancet Oncol 2006
RECOVER trial 6 x CHOP-14 + 36 Gy (Bulk, E) CD20+ stages I-IV 61-80 years random 2 x 2 factorial design 8 x CHOP-14 + 36 Gy (Bulk, E) 6 x CHOP-14 + 36 Gy (Bulk, E) + 8 x rituximab Pfreundschuh M et al. Lancet Oncol 2008 8 x CHOP-14 + 36 Gy (Bulk, E) + 8 x rituximab
Superiority of R-CHOP: constistency of all studies Pfreudschuh M, Lancet Oncol 2008 ECOG British Columbia Habermann T, JCO 2006 Sehn LH, JCO 2005
Q1: Which place for dose-dense regimens in the area of rituximab? The «story» of CHOP14 Superiority of CHOP14 over CHOP21 Pfreundschuh M et al. Blood 2004 Superiority of R-CHOP21 over CHOP21 MInT trial Pfreundschuh M et al. Lancet Oncol 2006 Superiority of R-CHOP14 over CHOP14 RECOVER trial Pfreundschuh M et al. Lancet Oncol 2008 No proof today that R-CHOP14 is superior to R-CHOP21!
GELA LNH 03-6B 66-80 yrs, aa-ipi = 1, 2 or 3 4 IT MTX Closed 12/2008 600 pts included R-CHOP 21 R 0 3 6 9 12 15 18 21 Wks Prophylactic Darbepoietin alfa Interventional Darbepoietin alfa 0 2 4 6 8 10 12 14 Wks R-CHOP 14 4 IT MTX UK Clinical Research Network: R-CHOP14 vs. R-CHOP21 DLBCL > 18 years
Q2: Which place for dose-intense regimens in the area of rituximab? GELA LNH 03-2B < 60 yrs, aa-ipi = 1 R-ACVBP 14 MTX IFM - VP16 ARA-C R 0 2 4 6 10 14 24 Wks 4 IT MTX 0 3 6 9 12 15 18 21 Wks R-CHOP 21 Closed 12/2008 380 pts included
CALGB/NCI trial Phase III Randomized Study of R-CHOP vs. Dose-Adjusted EPOCH-R With Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas Primary outcome: 5-y EFS Secondary outcome: molecular predictors as measured by cdna microarray 5 years after completion of study treatment No proof today that dose-intense regimens are superior to R-CHOP in the area of rituximab!
Q3: Role of PET in the management of DLBCL? PR according the IWC CR according the IWC+PET No evidence of disease after 29.5 mths Juweid ME et al. JCO 2007;23:4652
Revised response criteria for malignant lymphoma Cheson BD et al. JCO 2007;25:579
Early PET evaluation in DLBCL? Haioun C et al. Blood 2005;106:1376
Primary objective To evaluate if an early positive PET after 2 cycles of R-CHOP-14 can be used to identify a group of patients having a poor prognosis. Primary endpoint Event-free survival at 2 years
GELA LNH 07-3B study
Q4: How to further improve the results of R-CHOP? Optimize use of rituximab? Dose Schedule of administration Maintenance Add something to R-CHOP? RIT? Other agent? Maintenance treatment? New molecules?
Dose-Dense rituximab in elderly patients with poor-prognosis DLBCL The Dense-R-CHOP14 trial Pfreundschuh M et al. ASH 2007, abstr. 789
Rituximab pharmacokinetics Serum Levels Pfreundschuh M et al. ASH 2007, abstr. 789
Dense-R-CHOP14 (n=47) Vs. R-CHOP14 (n=306) Pfreundschuh M et al. ASH 2007, abstr. 789
RIT in DLBCL 90Y-ibritumomab tiuxetan: interesting efficacy if no prior rituximab but of limited value as a single agent in patients previously treated with R-chemo Morschhauser F et al. Blood 2007 Role for RIT instead of radiotherapy in localized disease? Role of RIT in consolidation after chemo-immunottt?
Studies combining chemotherapy and RIT for untreated DLBCL Patients Study SWOG Phase II Stage II bulky, III-IV R-CHOP x 6 Bexxar SWOG Phase II Early stage Unfav.,no bulk CHOP x 3 IFXRT Zevalin ZEAL Phase III > 60 years R-CHOP x 6 If CR/uCR Zevalin vs. Obs. MSKCC/NCI Phase II > 60 years IPI 2 R-CHOP x 6 Zevalin
Avastin in combination with R-CHOP (RA-CHOP) in patients with DLBCL 4 x R-CHOP21 + placebo 4 x R-CHOP21 + placebo 3 x R-CHOP14 + placebo R 4 x R-CHOP21 + Avastin (15mg/kg/3w) or 3 x R-CHOP14 + Avastin (10mg/kg/2w) PR MR CR or 3 x R-CHOP14 + 2R + placebo CR PR MR 4 x R-CHOP21 + Avastin (15mg/kg/3w) or 3 x R-CHOP14 + 2R + Avastin (10mg/kg/2w) Interim staging or Interim staging CR CR Observation Avastin (15mg/kg/3w) up to 1 y
Bortezomib combined with R-CHOP - a randomized phase 2 trial - 49 pts included 40/48 pts: CR/CRu (15/16 DLBCL) Grade 3/4 neurotoxicity in 10 pts N. Mounier et al., Lugano 2008
REMARC - RANDOMIZED PHASE III STUDY OF LENALIDOMIDE (REVLIMID ) MAINTENANCE IN RESPONDING ELDERLY PATIENTS WITH DLBCL AND TREATED WITH R-CHOP IN FIRST LINE
Phase III Study of RAD001 Adjuvant Therapy in Poor Risk Patients With Diffuse Large BCell Lymphoma (DLBCL) of RAD001 Versus Matching Placebo After Patients Have Achieved Complete Response With FirstLine Rituximab-Chemotherapy (PILLAR-2) Stage III-IV, or stage II bulky Poor risk patients (IPI 3) 18 years In CR after R-CHOP
New molecules New monoclonal antibodies Same antigen (ofatumumab, GA-101 ) Different antigens: CD19, CD22, CD40, CD80 Bispecific Histone deacetylase inhibitors SAHA (vorinostat) MGCD0103 (Younes A, ASH 2007) SYK inhibitors (Young RM, Blood 2009) ABT-263 (Ackler S, Mol Cancer Ther 2008) Enzastaurin (Robertson MJ, JCO 2007) Pralatrexate (O Connor OA, BJH 2007)
Thank you!
Q5: Which treatment for localized low-risk DLBCL? Miller et al. NEJM 1998;339:21 Superiority of 3 CHOP + RXT compared to CHOP alone BUT: Med. f-up 44 months 50% patients > 60 years 14% «drop out» in chemo arm 20% patients with LDH > N Only 75% DLBCL Updated results (med. f-up 8.2 years) Miller et al. ASH 2001: abstr. 3024 No more superiority of combined CT+RXT (cross-over of the curves) excess of the number of deaths due to lymphoma after 5 years in the CT-RT arm
Reyes F et al. NEJM 2005;352:1197-205 Med. F-up 7.7 years 5-y EFS : 82% vs. 74% 5-y OS : 90% vs. 81% Independent benefit according to stage (I/II) and to tumor burden (+/- bulk)
MINT TRIAL Pfreundschuh et al., Lancet Oncol 2006;7:379
FLYER TRIAL 18-60 years, IPI=0, no bulk 6 x rituximab + 6 x CHOP-21 n = 622 R 6 x rituximab + 4 x CHOP-21
Retrospective analysis of 365 patients treated with R-CHOP Med f-up: 33 months 10% of the patients: «very good risk» (IPI=0) 4-y PFS: 94% 4-y OS: 94% Sehn LH et al. Blood 2007;109:1857