Presentation on theme: "First-line management of follicular lymphoma: Will induction and maintenance treatment prolong survival? Robert Marcus Department of Haematology, Addenbrooke’s."— Presentation transcript:
1First-line management of follicular lymphoma: Will induction and maintenance treatment prolong survival?Robert Marcus Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK
2Trial 1: R-CVP versus CVP study design Follicular NHL (IWF B, C, D)Stage III−IV 18 yearsNo prior RxMeasurable diseaseCentral histology reviewRANDOMISERESTAGR-CVP x 4 cycles (q3wk)R-CVP x 4 cycles (q3wk)CR, PRCVP x 4 cycles(q3wk)CVP x 4 cycles(q3wk)SD PDoff studyRituximab 375 mg/m2 iv day 1Cyclophosphamide 750 mg/m2 iv day 1Vincristine 1.4 mg/m2 iv day 1Prednisolone 40 mg/m2 po days 1–5Marcus R, et al. Blood 2005; 105:1417–1423.
3Participating sites Australia Belgium Brazil Canada France Israel K Bradstock, J Catalano, R Herrmann, J McKendrick, J Norman, D Rosenfeld, K TaylorBelgiumM Bron, R De Bock, F OffnerBrazilC ChiattoneCanadaA Belch, I Bence-Bruckler, M Crump, D Forrest, K Imrie, KS Robinson, C ShustikFranceS Castaigne, P Solal-CélignyIsraelM ShaklaiPolandA Dmoszynska, K Kuliczkowski, J WalewskiPortugalF Placido, J Raposo, J VeigaSpainJN Batista, M Constenla, E Flores, J Gomez Codina, J Guma, A RuedaSwitzerlandT Cerny, R ZenhausernUKD Cunningham, DJ Dunlop, E Fitzsimons, BW Hancock, C Hatton, P Johnson, R Marcus, G Morgan, A Pagliuca, R Pettengell, M Potter, C Poynton, S Proctor
4Patient characteristics R-CVP (n = 162)CVP (n = 159)Median age, years5253HistologyGrade 3 FL, %98Bulky disease, %3946FLIPI 3−5 (poor prognosis), %4047FLIPI 2 (intermediate prognosis), %4137FLIPI 0−1 (good prognosis), %1915Central review of pathology performed on 90% of patients FL diagnosis confirmed in 95% of patientsMarcus R, et al. Blood 2005; 105:1417–1423.
5Response rates* Response R-CVP (n = 162) CVP (n = 159) p-value CR/CRu (%)4110p <PR (%)4047ORR (%)(CR+CRu+PR)8157* Response up to 42 days after completion of treatmentMarcus R, et al. Blood 2005; 105:1417–1423.
6Conclusions Rituximab plus CVP improved: Overall and complete response ratesTTP, TTNLT, DFSOverall survivalAddition of rituximab did not substantially increase regimen toxicity8 cycles of R-CVP should be considered as standard treatment for previously untreated FL
7Trial 2: R-CHOP versus CHOP study design Patients < 60 years (< 65 years)RANDOMISTRANDOMISTPBSCTCR, PR6–8 cycles x CHOP6–8 cycles x CHOP plusrituximabStandard IFN-maintenancePatients > 60 years (> 65 years)Intensive IFN-maintenanceStandard IFN-maintenanceHiddemann W, et al. Blood 2005; 106:3725–3732.
8TTF is significantly improved with rituximab-based induction therapy Patients aged > 60 years1.00.8R-CHOP (78/112)Median 5 years0.6Probability0.4CHOP (37/109)Median 2.1 years0.2p <0.0123456YearsBuske C, et al. Blood 2006; 108:Abstract 482.
9Patients aged > 60 years Overall survival is significantly improved with rituximab-based induction therapyPatients aged > 60 years1.0R-CHOP (102/112)0.8CHOP (89/109)0.6Probability4-year OSR-CHOP: 90%CHOP: 81%0.40.2p = 0.0390.0123456YearsBuske C, et al. Blood 2006; 108:Abstract 482.
10Survival is significantly improved with R-CHOP in all FLIPI subgroups 1.01.0Median NR0.80.8Median 4.1 yearsMedian NR0.60.6Survival probabilitySurvival probabilityMedian 3.0 yearsMedian 4.0 years0.40.40.20.2Median 2.0 years123456123456Time (years)Time (years)FLIPI 0–1: Low risk p = FLIPI 2: Intermediate prognosis p < FLIPI 3–5: Poor prognosis p =Buske C, et al. Blood 2006; 108:Abstract 482 and unpublished data.
11Trial 3: R-MCP versus MCP study design ESTAGINGRANDOMISEAdvanced FL, IC and MCL18–75 yearsNo prior rituximabCentral histology reviewWritten informed consentR-MCP 6 cycles (q4wk)R-MCP 2 cycles (q4wk)CR, PRMCP 6 cycles (q4wk)MCP 2 cycles (q4wk)IFN-maintenance for FLSDPDoff studyRituximab 375mg/m2 iv d 1Mitoxantrone 8 mg/m² iv d 3 and 4Chlorambucil 3 x 3mg/m² po d 3–7Prednisolone 25 mg/m² po d 3–7Herold M, et al. J Clin Oncol 2007; April 9 (Epub).
12Rituximab-based induction therapy significantly improves survival in patients with FL ITT population: Median follow-up 47 months1.00R-MCP: Median NR0.75MCP: Median NRSurvival distribution function0.504-year OSR-MCP: 87%MCP: 74%0.25p =102030405060Time (months)Herold M, et al. J Clin Oncol 2007; April 9 (Epub).
13PFS is significantly improved with R-MCP in all FLIPI subgroups Median NR 4-year PFS: 82%1.01.0Median 36 months4-year PFS: 43%0.80.8Median NR 4-year PFS: 61%0.60.6Survival probabilitySurvival probability0.40.4Median 26.5 months 4-year PFS: 36%0.20.2102030405060102030405060Time (months)Time (months)FLIPI 2: Intermediate prognosis p = FLIPI 3–5: Poor prognosis p =Herold M, et al. J Clin Oncol 2007; April 9 (Epub) and unpublished data.
14Trial 4: R-CHVP-IFN vs CHVP-IFN study design Arm A6 months12 monthsRStaging including CT-scan and bone marrow biopsyArm Bd1 Cyclophosphamide 600 mg/m2d1 Doxorubicin 25 mg/m2d1 Etoposide 100 mg/m2d1–5 Prednisolone 40 mg/m2αIFN 2b, 4.5 MUtiw for 18 months (3 MU if aged 70 yr)Rituximab: 375 mg/m2every month for 6 months (arm A & B) then every 2 months in arm AFoussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.
15EFS and OS are significantly increased with rituximab-based therapy 100100R-CHVP + IFN- (Arm B)R-CHVP + IFN- (Arm B)91%Event-free survival75Ovarall survival75CHVP + IFN- (Arm A)84%67%505046%CHVP + IFN- (Arm A)2525p <p = 0.0291020304050607010203040506070MonthsMonthsFoussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.
16First-line rituximab-based induction therapy improves overall survival Induction regimenOutcome (median)Overall survivalCHVP R + IFN-1EFSNR vs 3 yrs p <3.5 yr91% vs 84% p = 0.029MCP R2PFSNR vs 29 mo p <4 yr87% vs 74% p =CHOP R3TTFNR vs 31 mo p =2 yr95% vs 90% p = 0.016CVP R4TTP34 mo vs 15 mo p <83% vs 77% p =1. Foussard C, et al. J Clin Oncol 2006; 24:Abstract 7508.2. Herold M, et al. J Clin Oncol 2007; April 9 (Epub).3. Hiddemann W, et al. Blood 2005; 106:3725– Marcus R, et al. Blood 2006; 108:Abstract 481.
17Rituximab-based induction therapy: Conclusions R-Chemo yields superior results to chemotherapy in four prospective randomised trialsThe FLIPI predicts outcome in all studiesPrognosis was worse with a high FLIPI scoreMajority of patients with poor prognosis will relapse within 4–5 yearsThere does not seem to be a TTP/PFS ‘plateau’ of any subgroup in any trial yet
18Overall survival improvement with rituximab in FL 1.0GLSG study NHL 20000.80.6GLSG study NHL 1996Survival probability0.40.2p <0.01224364860728496108120Time (months)Number of patients at risk:NHL 199653848545741938633224212546NHL 20007946214402501088Hiddemann W, et al. Blood 2006; 108:Abstract 483.
19Phase III trial of CVP ± rituximab maintenance Rituximab maintenance after CVP in untreated indolent NHL: ECOG 1496 study designPhase III trial of CVP ± rituximab maintenance401 patients with previously untreated indolent NHL, 322 randomisedRANDOMISERituximab maintenance375 mg/m2 q1wk 4q6mo 4CVP 6–8 cyclesPR, CR or SDObservation
20Rituximab maintenance therapy significantly prolongs PFS in FL Median PFS from randomisation: 15 mo vs 61 mo1.00.8Rituximab maintenance (n = 120)0.6Probability0.40.2Observation (n = 117)p =0.0123456Years from maintenance randomisationHochster H, et al. Blood 2005; 106:Abstract 349.
21Median PFS/EFS (months) Rituximab monotherapy induction and maintenance in first-line treatment of FLPatients (n)Median FU (months)Induction regimenMaintenance scheduleMedian PFS/EFS (months)Minnie Pearl Phase II138†55R-Mono*q6mo x 4*PFS: 52SAKK 35/9826436q2mo x 4EFS: 19 vs 36 p = 0.009* 375 mg/m2 rituximab once weekly x 4 † Follicular lymphoma patients only FU = follow-up1. Hainsworth JD, et al. Blood 2003; 102:Abstract 1496.2. Ghielmini M, et al. Blood 2004; 103:4416–4423.
22SAKK 35/03 study: Efficacy of extended rituximab maintenance therapy in FL Short maintenanceRituximab maintenance q2mo x 4RRituximab375 mg/m²weekly x 4PR, CRRituximab maintenance q2mo until relapse (maximum 5 years)PD, SD off studyLong maintenance
23Rituximab maintenance therapy PRIMA study: Efficacy of rituximab-based induction and maintenance in first-line indolent NHLRituximab maintenance therapy1 x q8wkfor 24 monthsRANDOMISE8 x rituximab+8 x CVPor 6 x CHOP or 6 x FCMIndolent NHLstages III–IV,untreatedCR, PRObservationSDPDoff study
24RiCHOP trial: Efficacy of ASCT followed by rituximab maintenance in indolent NHL HDT ASCTRANDOMISERituximabmaintenance 1 x q8wkfor 24 monthsCR, PRR-CHOP x 6 + R x 2SDPDoff studyN > 600 patients with indolent FL (< 65 years old). Study start 2007
25A note of caution! Incidence of hepatitis B reactivation with rituximab Out of 456 patients, 32 were Hep B positive14 received rituximab monotherapy18 received rituximab plus chemotherapyGroupPatients (n)HBsAgHBsAbHBcAbLiver event (%)A12–+3 (25)B62 (33)C8Not available2 (25)DVariable4 (66)A total of 5 patients developed liver failure (15%)Hanbali A, et al. Blood 2006; 108:Abstract 2766.
26But…prophylactic lamivudine can reduce the incidence of hepatitis during chemotherapy Non-randomised comparison of lymphoma patients treated with prophylactic lamivudine during chemotherapy with historical controls100 mg was administered daily for up to 64 weeks% Control(n = 116)% Lamivudine(n = 40)p-valueHepatitis incidence during chemo52180.000Disruption in chemo administration37100.001Lamivudine prophylaxis reduced the incidence of hepatitisLi Y, et al. Cancer 2006; 106:1320–1325.
27Outstanding questions in first-line therapy for FL Do more intensive therapies yield superior results than R-CVP?If so do ALL patients require such therapy, or only poor prognosis patients?Which component provides superior results?Anthracycline, interferon or both?Does maintenance have a role in first-line FL?PRIMA trial to provide evidenceDo PBSCT or other approaches have a role in first-line therapy?