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First-line management of follicular lymphoma: Will induction and maintenance treatment prolong survival? Robert Marcus Department of Haematology, Addenbrooke’s.

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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:

1 First-line management of follicular lymphoma: Will induction and maintenance treatment prolong survival? Robert Marcus Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK

2 Trial 1: R-CVP versus CVP study design Follicular NHL (IWF B, C, D) Stage III−IV  18 years No prior Rx Measurable disease Central histology review RANDOMISERANDOMISE CVP x 4 cycles (q3wk) R-CVP x 4 cycles (q3wk) CVP x 4 cycles (q3wk) R-CVP x 4 cycles (q3wk) SD PD off study CR, PR Rituximab 375 mg/m 2 iv day 1 Cyclophosphamide 750 mg/m 2 iv day 1 Vincristine 1.4 mg/m 2 iv day 1 Prednisolone 40 mg/m 2 po days 1–5 RESTAGERESTAGE Marcus R, et al. Blood 2005; 105:1417–1423.

3 Participating sites Australia K Bradstock, J Catalano, R Herrmann, J McKendrick, J Norman, D Rosenfeld, K Taylor Belgium M Bron, R De Bock, F Offner Brazil C Chiattone Canada A Belch, I Bence-Bruckler, M Crump, D Forrest, K Imrie, KS Robinson, C Shustik France S Castaigne, P Solal-Céligny Israel M Shaklai Poland A Dmoszynska, K Kuliczkowski, J Walewski Portugal F Placido, J Raposo, J Veiga Spain JN Batista, M Constenla, E Flores, J Gomez Codina, J Guma, A Rueda Switzerland T Cerny, R Zenhausern UK D 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

4 Patient characteristics Characteristic R-CVP (n = 162) CVP (n = 159) Median age, years52 53 Histology Grade 3 FL, %9 8 Bulky disease, %39 46 FLIPI 3−5 (poor prognosis), %40 47 FLIPI 2 (intermediate prognosis), %41 37 FLIPI 0−1 (good prognosis), %19 15 Central review of pathology performed on 90% of patients FL diagnosis confirmed in 95% of patients Marcus R, et al. Blood 2005; 105:1417–1423.

5 Response rates* * Response up to 42 days after completion of treatment Response R-CVP (n = 162) CVP (n = 159) p-value CR/CRu (%)4110p < PR (%)40 47 ORR (%) (CR+CRu+PR) 81 57p < Marcus R, et al. Blood 2005; 105:1417–1423.

6 Conclusions Rituximab plus CVP improved: ─ Overall and complete response rates ─ TTP, TTNLT, DFS ─ Overall survival Addition of rituximab did not substantially increase regimen toxicity 8 cycles of R-CVP should be considered as standard treatment for previously untreated FL

7 Trial 2: R-CHOP versus CHOP study design RANDOMISATIONRANDOMISATION 6–8 cycles x CHOP 6–8 cycles x CHOP plus rituximab RANDOMISATIONRANDOMISATION PBSCT Standard IFN-maintenance Intensive IFN-maintenance Standard IFN-maintenance Hiddemann W, et al. Blood 2005; 106:3725–3732. Patients > 60 years (> 65 years) Patients < 60 years (< 65 years) CR, PR

8 TTF is significantly improved with rituximab-based induction therapy Buske C, et al. Blood 2006; 108:Abstract 482. CHOP (37/109) Median 2.1 years R-CHOP (78/112) Median 5 years p < Patients aged > 60 years Years Probability

9 Overall survival is significantly improved with rituximab-based induction therapy CHOP (89/109) R-CHOP (102/112) 4-year OS R-CHOP: 90% CHOP: 81% Years Probability p = Buske C, et al. Blood 2006; 108:Abstract 482.

10 Survival is significantly improved with R-CHOP in all FLIPI subgroups FLIPI 0–1: Low risk p = FLIPI 2: Intermediate prognosis p < FLIPI 3–5: Poor prognosis p = Median NR Time (years) Survival probability R-CHOP Median NR CHOP Time (years) Survival probability Median 4.1 years Median 3.0 years Median 4.0 years Median 2.0 years Buske C, et al. Blood 2006; 108:Abstract 482 and unpublished data.

11 Rituximab 375mg/m 2 iv d 1 Mitoxantrone 8 mg/m² iv d 3 and 4 Chlorambucil 3 x 3mg/m² po d 3–7 Prednisolone 25 mg/m² po d 3–7 Advanced FL, IC and MCL 18–75 years No prior rituximab Central histology review Written informed consent RANDOMISEDRANDOMISED R-MCP 6 cycles (q4wk) MCP 6 cycles (q4wk) R E S T A GI N G SD PD off study CR, PR IFN-maintenance for FL Trial 3: R-MCP versus MCP study design R-MCP 2 cycles (q4wk) MCP 2 cycles (q4wk) Herold M, et al. J Clin Oncol 2007; April 9 (Epub).

12 Rituximab-based induction therapy significantly improves survival in patients with FL p = R-MCP: Median NR MCP: Median NR Survival distribution function Time (months) ITT population: Median follow-up 47 months 4-year OS R-MCP: 87% MCP: 74% Herold M, et al. J Clin Oncol 2007; April 9 (Epub).

13 PFS is significantly improved with R-MCP in all FLIPI subgroups FLIPI 2: Intermediate prognosis p = FLIPI 3–5: Poor prognosis p = Time (months) Survival probability Median NR 4-year PFS: 82% Median NR 4-year PFS: 61% Time (months) Survival probability Median 36 months 4-year PFS: 43% Median 26.5 months 4-year PFS: 36% R-MCP MCP Herold M, et al. J Clin Oncol 2007; April 9 (Epub) and unpublished data.

14 Trial 4: R-CHVP-IFN vs CHVP-IFN study design αIFN 2b, 4.5 MU tiw for 18 months (3 MU if aged  70 yr) d1 Cyclophosphamide600 mg/m 2 d1 Doxorubicin 25 mg/m 2 d1 Etoposide 100 mg/m 2 d1–5 Prednisolone 40 mg/m 2 every month for 6 months (arm A & B) then every 2 months in arm A Rituximab: 375 mg/m 2 R Arm A Arm B Staging including CT-scan and bone marrow biopsy 12 months6 months Foussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.

15 Event-free survival p < Months EFS and OS are significantly increased with rituximab-based therapy 67% 46% R-CHVP + IFN-  (Arm B) 91% 84% CHVP + IFN-  (Arm A) Ovarall survival p = Months CHVP + IFN-  (Arm A) R-CHVP + IFN-  (Arm B) Foussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.

16 First-line rituximab-based induction therapy improves overall survival 1. Foussard C, et al. J Clin Oncol 2006; 24:Abstract 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. Induction regimenOutcome (median)Overall survival CHVP  R + IFN-  1 EFSNR vs 3 yrs p < yr91% vs 84% p = MCP  R 2 PFSNR vs 29 mo p < yr87% vs 74% p = CHOP  R 3 TTFNR vs 31 mo p = yr95% vs 90% p = CVP  R 4 TTP34 mo vs 15 mo p < yr83% vs 77% p =

17 Rituximab-based induction therapy: Conclusions R-Chemo yields superior results to chemotherapy in four prospective randomised trials The FLIPI predicts outcome in all studies ─ Prognosis was worse with a high FLIPI score ─ Majority of patients with poor prognosis will relapse within 4–5 years ─ There does not seem to be a TTP/PFS ‘plateau’ of any subgroup in any trial yet

18 24 Hiddemann W, et al. Blood 2006; 108:Abstract 483. Survival probability Time (months) p < Number of patients at risk: NHL 1996 NHL GLSG study NHL 2000 GLSG study NHL 1996 Overall survival improvement with rituximab in FL

19 Rituximab maintenance after CVP in untreated indolent NHL: ECOG 1496 study design Phase III trial of CVP ± rituximab maintenance 401 patients with previously untreated indolent NHL, 322 randomised Observation Rituximab maintenance 375 mg/m 2 q1wk  4 q6mo  4 RANDOMISEDRANDOMISED PR, CR or SD CVP 6–8 cycles

20 p = Median PFS from randomisation: 15 mo vs 61 mo Years from maintenance randomisation Rituximab maintenance (n = 120) Observation (n = 117) Rituximab maintenance therapy significantly prolongs PFS in FL Probability Hochster H, et al. Blood 2005; 106:Abstract 349.

21 Rituximab monotherapy induction and maintenance in first-line treatment of FL Patients (n) Median FU (months) Induction regimen Maintenance schedule Median PFS/EFS (months) Minnie Pearl Phase II 1 38 † 55R-Mono*q6mo x 4*PFS: 52 SAKK 35/ R-Mono*q2mo x 4 EFS: 19 vs 36 p = Hainsworth JD, et al. Blood 2003; 102:Abstract Ghielmini M, et al. Blood 2004; 103:4416–4423. * 375 mg/m 2 rituximab once weekly x 4 † Follicular lymphoma patients only FU = follow-up

22 Rituximab maintenance q2mo x 4 PD, SD off study Long maintenance Rituximab 375 mg/m² weekly x 4 Short maintenance R PR, CR Rituximab maintenance q2mo until relapse (maximum 5 years) SAKK 35/03 study: Efficacy of extended rituximab maintenance therapy in FL

23 SD PD off study Indolent NHL stages III–IV, untreated Rituximab maintenance therapy 1 x q8wk for 24 months Observation 8 x rituximab + 8 x CVP or 6 x CHOP or 6 x FCM CR, PR PRIMA study: Efficacy of rituximab-based induction and maintenance in first-line indolent NHL RANDOMISERANDOMISE

24 RiCHOP trial: Efficacy of ASCT followed by rituximab maintenance in indolent NHL Rituximab maintenance 1 x q8wk for 24 months CR, PR R-CHOP x 6 + R x 2 HDT ASCT RANDOMISERANDOMISE SD PD off study N > 600 patients with indolent FL (< 65 years old). Study start 2007

25 A note of caution! Incidence of hepatitis B reactivation with rituximab Out of 456 patients, 32 were Hep B positive ─ 14 received rituximab monotherapy ─ 18 received rituximab plus chemotherapy GroupPatients (n)HBsAgHBsAbHBcAb Liver event (%) A12–++3 (25) B6––+2 (33) C8–Not available+2 (25) D6+Variable 4 (66) A total of 5 patients developed liver failure (15%) Hanbali A, et al. Blood 2006; 108:Abstract 2766.

26 But…prophylactic lamivudine can reduce the incidence of hepatitis during chemotherapy Non-randomised comparison of lymphoma patients treated with prophylactic lamivudine during chemotherapy with historical controls ─ 100 mg was administered daily for up to 64 weeks % Control (n = 116) % Lamivudine (n = 40) p-value Hepatitis incidence during chemo Disruption in chemo administration Li Y, et al. Cancer 2006; 106:1320–1325. Lamivudine prophylaxis reduced the incidence of hepatitis

27 Outstanding 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 evidence Do PBSCT or other approaches have a role in first-line therapy?


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