Conclusiones ASH 2012 Tratamiento de primera línea del linfoma folicular Miguel A. Canales Hospital Universitario La Paz Universidad Autónoma de Madrid [email protected] The clinical course of patients with follicular lymphoma in the rituximab era: a paradigm shift St Bart’s 1997-2007 100 Cumulative % in remission n=177 (150), FL 1-3a Median age 56 (25-89) 80 60 40 1st n = 179 20 2nd n = 86 rd n = 48 nd rel375% ORR 1st line 91%, 1st rel 83%, 2 th 4 n = 25 0 5-y PFS0 38% (95%CI 31-46) 3 6 5-y OS 78% (95%CI 71-83) 9 12 15 18 21 Time (years) El-Najjar I, et al. Blood 2012; 120: Abstract 1580 First-line treatment of FL: What do we know now? Immunochemotherapy is the new standard as up-front therapy in follicular lymphoma1 – R-CHOP vs R-CVP improves CR rate and PFS2,3,4 – Fludarabine-containing regimens are as effectives as R-CHOP but more toxics3,4 – R-Benda vs R-CHOP improves CR rate and PFS5 Maintenance therapy with Rituximab improves PFS3 and reduces the risk of death (meta-analysis)6 1. 2. 3. 4. 5. 6. Dreyling M et al, Ann Oncol 2011;22(Suppl. 6):vi59–63 Nastoupil L, et al. ASH 2011: Abstract 97 Salles G, et al. Lancet 2011;377:42–51 Federico M, et al. ASCO 2012: abstract 8006 Rummel MJ, et al. ASCO 2012: abstract 3 Vidal L, et al. J Natl Cancer Inst 2011;103:1799–806 Patterns of delivery of chemoimmunotherapy to patients with follicular lymphoma: results of the National Lymphocare Study n=1165; R-CHOP=641, R-CVP=297, R-Flu=222 P = 0.0006 P < 0.0001 P = 0.0082 P = 0.0014 P < 0.0001 P = 0.0185 Martin P, et al. Blood 2012; 120: Abstract 3702 Achievement of CR with BR or CHOP-R results in superior survival compared to PR: subanalysis of the StiL NHL 1-2003 Rummel MJ, et al. Blood 2012; 120: Abstract 2724 BR replaces R-CHOP as “standard of care” in the treatment of indolent NHL (in German Haematology Outpatient Centres) TLN Registry, 106 sites (30-40% outpatient centres) n=645, 52% FL, 14% MCL, 12% LPL, 11% MZL, 3% MALT n % Age Rituximab 606 94 Bendamustine 455 71 R-Bendamustine 428 66 67.2 ± 12.1 R-CHOP 105 16 60.8 ± 12.4 121 patients have received 2nd line treatment; BR 60%, R-CHOP 7% Knauf WU, et al. Blood 2012; 120: Abstract 3666 Bendamustine-containing regimens in untreated patients with FL: summary of phase II studies Regimen Bendamustine, Mitoxantrone, and Rituximab (x4) + Rituximab (x4) Boccomini C, FIL (#2720) Bendamustine and Rituximab (x4) + 90Y-Ibritumomab N Median age Results 76 71 y (65-79) ORR 92% CR 76% 13 ORR 89% CR 78% 39 64 y (30-89) ORR 92% CR 59% 1-y PFS 81% 32 61 y (40-86) ORR 75% CR 50% 3-y PFS 59% Lansigan F, Fol-B-RITE (#3657) Bendamustine, Bortezomib, and Rituximab (x6) Flinn IW, SCRI (#1624) Bortezomib and Rituximab (3 cycles + 4 maintenance doses) Evens AM (#1642) BR compared with R-CVP or R-CHOP in first-line treatment of patients with advanced indolent NHL or mantle cell lymphoma: the BRIGHT study Primary objective - To determine whether BR is non-inferior to standard treatment (R-CHOP or R-CVP) in CR rate Patients with untreated iNHL or MCL requiring therapy, n=447 Preassignment by investigator BR or R-CHOP BR or R-CVP (Randomization) (Randomization) R-CHOP (21-day cycle) Bendamustine Rituximab R-CVP (28-day cycle) (21-day cycle) - Bendamustine 90mg/m2/day (Day and 2: 30-min infusion) - Rituximab 375mg/m2 (Day 1) 6 cycles during the randomized treatment phase (Up to 8 cycles at investigator´s discretion) Flinn IW, et al. Blood 2012; 120: Abstract 902 BR compared with R-CVP or R-CHOP in first-line treatment of patients with advanced indolent NHL or mantle cell lymphoma: the BRIGHT study Primary endpoint: CR rate P Value Evaluable: IRC BR (n=213) R-CHOP/R-CVP (n=206) CR Ratio CR, % (95% CI) 31 (25.3-38.2) 25 (19.5-31.7) 1.26 (0.93-1.73) 65 66 PR, % OR of CR + PR 97 (95% CI) (93.3-98.7) (NI) (Sup) 0.0225 0.1269 91 (86.0-94.4) Flinn IW, et al. Blood 2012; 120: Abstract 902 BR compared with R-CVP or R-CHOP in first-line treatment of patients with advanced indolent NHL or mantle cell lymphoma: the BRIGHT study Primary endpoint: CR rate ratios Ratio (95% CI) P value NI P value Sup 0.023 0.127 0.008 0.055 0.002 0.005 0.129 ---- 0.017 0.018 1.26 Evaluable: IRC 1.34 Randomized: IRC 1.51 Evaluable: Investigator 1.16 Randomized: IRC Indolent NHL Randomized: IRC Mantle Cell Lymphoma 1.95 I I I I I 0 1 2 3 4 Rate Ratio Flinn IW, et al. Blood 2012; 120: Abstract 902 BR compared with R-CVP or R-CHOP in first-line treatment of patients with advanced indolent NHL or mantle cell lymphoma: the BRIGHT study Primary endpoint: CR rate ratios Ratio (95% CI) P value NI Evaluable: IRC BR vs R-CHOP P value Sup 1.18 0.197 ---- 0.054 --- 0.122 --- 0.030 0.078 0.007 0.033 0.119 --- 1.34 BR vs R-CVP Randomized: IRC BR vs R-CHOP 1.25 1.43 BR vs R-CVP Evaluable: Investigator BR vs R-CHOP 1.55 1.41 BR vs R-CVP I I 0 1 I 2 Rate Ratio I I 3 4 Flinn IW, et al. Blood 2012; 120: Abstract 902 Discordant adverse events in BRIGHT vs StiL Adverse Event Category (%) BR (n=103) R-CHOP (n=98) BR (n=118) R-CVP (n=116) Nausea 63 58 63 39 Vomiting 29 13 25 13 Constipation 32 40 27 44 14 5 8 3 Febrile neutropenia 3 6 3 4 Opportunistic infection 10 7 12 9 Peripheral Neuropathy 4 20 4 26 Paresthesia <1 12 5 10 Peripheral sensory neuropathy <1 6 3 12 Rash 12 7 18 9 Alopecia 4 51 3 21 Gastrointestinal Immune Disorders Drug hypersensitivity Infections Nervous System Disorders Skin Disorders = Higher incidence Flinn IW, et al. Blood 2012; 120: Abstract 902 Lenalidomide and Rituximab for untreated indolent NHL: the R2 combination Eligibility (n = 110) Untreated indolent NHL (FL n=45, SLL n=27, MZL n=27) Stage III or IV Rituximab 375 mg/m2 IV d1 Lenalidomide 20 mg/d* PO d1-21 28-day cycle for 6 cycles or up to 12 cycles Restaging at 4, 6, 9, 12 months • Primary endpoint: ORR • Secondary endpoints: PR and CR rates, PFS, OS, safety and tolerability, effect on tumour and microenvironment * Lenalidomide was increased to 25 mg/d after 3 cycles if stable disease. Patients with SLL/CLL received 10 mg/d cycle 1, 15 mg/d cycle 2, 20 mg/d cycle 3. Fowler NH, et al. Blood 2012; 120: Abstract 901 Lenalidomide and Rituximab for untreated indolent NHL: the R2 combination Response SLL (n=30) MZL (n=27) FL (n=46) ORR, n (%) 24 (80) 24 (89) CR/CRu, n (%) 8 (27) 66 PFS 3-y (%) Response in FL (GELF criteria) All patients Evaluable (n=103) ITT (n=110) 45 (98) 93 (90) 93 (85) 18 (67) 40 (87) 66 (64) 66 (60) 89 81 78 - GELF high tumor burden (n=22) GELF low tumor burden (n=24) ORR, n (%) 22 (100) 23 (96) CR/CRu, n (%) 21 (95) 19 (79) Fowler NH, et al. Blood 2012; 120: Abstract 901 SC administration of Rituximab compared with IV administration as maintenance therapy in patients with FL: the SPARKTHERA study Stage 2: Dose confirmation Induction First-line/relapsed FL, with a CR/PR following induction with rituximab IV ± chemo + ≥ 1 cycle of rituximab IV maintenance • R A N D O M I Z E Maintenance Rituximab for IV use (375 mg/m2), q2mo/q3mo x 2 years Maintenance Rituximab SC (1,400 mg), q2mo/q3mo x 2 years Stage 1 identified a flat dose of 1,400 mg Rituximab SC for non-inferiority testing (Salar A, et al. ASH 2010, Abstract 2858) • Stage 2, n = 154 (IV, n = 77; SC, n = 77) • Stage 2 primary endpoint: Non-inferiority of Ctrough in patients receiving Rituximab subcutaneously compared with by IV infusion - • Protocol-specified non-inferiority limit was an SC:IV Ctrough ratio of 0.8 Secondary endpoints included: PK (area under the curve [AUC]) and safety Salar A, et al. Blood 2012; 120: Abstract 1641 SC administration of Rituximab compared with IV administration as maintenance therapy in patients with FL: the SPARKTHERA study Primary PK endpoint (SC:IV Ctrough ratio) was met – Lower limits of two-sided 90% CI exceeded the non-inferiority threshold (0.8) for q2mo (1.02) and q3mo (0.86) regimens – Secondary PK endpoint (SC:IV AUC ratio > 0.8) was met AUCt Estimated AUC ratio Estimated Ctrough ratio Ctrough Upper 90% CI Ratio Lower 90% CI Salar A, et al. Blood 2012; 120: Abstract 1641 SC administration of Rituximab compared with IV administration as maintenance therapy in patients with FL: the SPARKTHERA study Rituximab IV (n=77) Rituximab SC (n=77) Any-grade AE 61 (79) 61 (79) Grade ≥ 3 AE 13 (17) 14 (18) SAEs 11 (14) 9 (12) 3 (4) 24 (31) Patients, n (%) ARRs * * mostly local reactions; the most common in the Rituximab SC arm were: • Erythema (13%) • Injection-site erythema (5%) • Myalgia (5%) ARR = administration-related reactions Salar A, et al. Blood 2012; 120: Abstract 1641 SC Rituximab in combination with chemotherapy is comparable to IV administration in patients with FL in first-line setting: the SABRINA study First-line FL grade 1, 2, or 3a R A N D O M I Z E Maintenance q2mo x 2 years 8 x R-CHOP*/R-CVP CR/CRu/PR IV (375 mg/m2) SC (1,400 mg) Maintenance, q2mo x 2 years * 8 x R with up to 8 x CHOP • Stage 1, n = 127 (IV, n = 64; SC, n = 63) • Stratified by FLIPI, chemotherapy and region: 40 patients in each arm (63%) received R-CHOP • Stage 1 primary PK endpoint: non-inferiority of the SC:IV Ctrough ratio at cycle 7 of induction (limit for non-inferiority was SC:IV Ctrough ratio > 0.8) • Secondary endpoints: other PK endpoints, safety, efficacy, and pharmacoeconomicrelated parameters Davies A, et al. Blood 2012; 120: Abstract 1629 SC Rituximab in combination with chemotherapy is comparable to IV administration in patients with FL in first-line setting: the SABRINA study Primary PK endpoint was met: SC:IV Ctrough ratio of 1.62 (90% CI: 1.36, 1.94) Rituximab concentration (µg/mL) – SC:IV AUC ratio (1.38 [90% CI: 1.24, 1.53]) is also non-inferior 300 250 134.6 200 Outliers Upper adjacent value Q3 150 Median Q1 100 Lower adjacent value 50 0 IV SC 83.1 * Cycle 7 limited to PK population, all other cycles are study population Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 IV IV IV IV IV SC Q1, quarter 1; Q3, quarter 3; AUC, area under the curve IV SC SC SC IV SC SC SC Davies A, et al. Blood 2012; 120: Abstract 1629 SC Rituximab in combination with chemotherapy is comparable to IV administration in patients with FL in first-line setting: the SABRINA study Patients, n (%) CT + Rituximab IV CT + Rituximab SC Any-grade AE 57 (88) 57 (92) Any-grade treatment-related AE 30 (46) 45 (73) ARRs (>90% grade ½) 21 (32) 31 (50) Grade ≥ 3 AE 30 (46) 29 (47) Grade ¾ neutropenia 14 (22) 16 (26) ORR 54 (84.4) 57 (90.5) CR/CRu 19 (29.7) 29 (46.0) ARR = administration-related reactions Davies A, et al. Blood 2012; 120: Abstract 1629 Ofatumumab in combination with CHOP for previously untreated FL: Follow-up results (n=29) (n=30) • Primary end-point: ORR • Secondary end-points: CR, PFS, AEs, and pharmacokinetics Czuczman MS, et al. Blood 2012; 120: Abstract 1632 Ofatumumab in combination with CHOP for previously untreated FL: Follow-up results Czuczman MS, et al. Blood 2012; 120: Abstract 1632 Obinutuzumab (GA-101) in combination with CHOP or Bendamustine in patients with previously untreated FL: the GAUDI study • Primary objective: safety • Secondary objectives: ORR, CR rate, and pharmacokinetics Dyer MJS, et al. Blood 2012; 120: Abstract 3686 Obinutuzumab (GA-101) in combination with CHOP or Bendamustine in patients with previously untreated FL: the GAUDI study Dyer MJS, et al. Blood 2012; 120: Abstract 3686 Obinutuzumab (GA-101) in combination with CHOP or Bendamustine in patients with previously untreated FL: the GAUDI study Dyer MJS, et al. Blood 2012; 120: Abstract 3686 ¿Qué me llevo yo de ASH?
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