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What is the optimal management of an asymptomatic 62 year old with low tumor burden, stage IV, grade 1-2 FL? Answer: R-chemotherapy Peter Martin, M.D. The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology Director of Lymphoma Clinical Research Assistant Professor of Medicine
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Phase 3 trial of chlorambucil vs. observation: Overall survival
Ardeshna et al. Lancet. 2003;362:516
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How long do patients on “watch and wait” go before being treated?
Median time to treatment in indolent NHL observation studies (all risk groups) 31 months (Portlock, 1979) 3 years (Horning, 1984) 2.6 years (shorter in age < 70) (Ardeshna, 2003)
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Johnson, et al (St. Barts) – 1995
212 pts, newly diagnosed follicular lymphoma over 20 years Treated generally with chlorambucil, CVP, CHOP Median Response Survival Duration From Response (months) (years) 1st Line nd Line 3rd Line 4th Line Johnson PWM et al. J Clin Oncol. 1995; 13(1):
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OS by era of diagnosis. Tan D et al. Blood 2013;122:
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Rituximab is standard front-line therapy of indolent B-cell non-Hodgkin lymphoma
Study Treatment N 1o outcome 2o outcome Witzig R x 4 36 ORR 72% TTP 2.2 y Herold MCP +/- R 358 ORR 92% vs. 75% 4-y OS 87% vs. 74% Buske CHOP +/- R 552 5-y TTF 65% vs. 32% 5-y OS 90% vs. 84% Marcus CVP +/- R 321 TTF 27 vs. 7 mo. 4-yOS 83% vs. 77% Salles CHVP+I +/-R 360 5-y EFS 53% vs. 37% 5-y OS 84% vs. 79% All p values < 0.05 except OS in the Salles trial Witzig et al. J Clin Oncol 2005;23:1103 Herold et al. J Clin Oncol 2007;25:1986 Buske et al. Blood 2008;112:2599 Marcus et al. J Clin Oncol 2008;26:4579 Salles et al. Blood 2008;112:4824
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EFS after first treatment course by era of diagnosis.
Tan D et al. Blood 2013;122:
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Goals of management of any disease
Cure Prolong survival Improve symptoms
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CHOP ± Rituximab in Previously Untreated FL
Pts ≥ 60 years Intensive IFN maintenance R A N D O M I Z E R A N D O M I Z E Standard IFN maintenance Untreated pts with advanced stage III/IV FL (N=428) R-CHOP × 6-8 Pts < 60 years CHOP × 6-8 PBSCT (n=79) IFN maintenance (n=131) Hiddemann et al. Blood. 2005;106:3725.
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CHOP ± Rituximab in Previously Untreated FL: TTF
1 2 3 4 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P <0.001 CHOP (144/205) R-CHOP (195/223) Probability progression-free Years Hiddemann et al. Blood. 2005;106:3725.
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Prognosis According to FLIPI in Patients With Advanced Stage FL Treated With R-CHOP Frontline: TTF
TTF According to Risk Groups Survival probability 2-y TTF 92%* 90%* 67% 1 2 3 4 5 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 LR IR HR Years FLIPI * P= vs HR. Buske et al. Blood Epub ahead of print.
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A Phase III Intergroup Trial of CHOP + Rituximab vs CHOP Tositumomab/ 131Iodine-Tositumomab for Previously Untreated Follicular Lymphoma SWOG S0016 CALGB 50102
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Progression Free Survival
100% 80% CHOP-RIT 60% Median FU 4.9 yr CHOP-R 40% CHOP -RIT CHOP-R At Risk 265 267 Relapse or Death 86 106 2-Year Estimate 80% 76% 2-sided, multivariate p = .11 20% 0% 2 4 6 8 10 Years from Registration S0016
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PFS: follicular, FLIPI low (0-2) (n=152; 54.5%)
1.0 Median (months) B-R n. y. r. CHOP-R 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Hazard ratio, 0.56 (95% CI ) p = 0.1 0.0 months 2 2
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Prognostic impact of post-induction PET-CT on PFS
Trotman J et al. JCO 2011;29:
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Goals of management of any disease
Cure True cure is unlikely but a functional cure is feasible. Prolong survival Improve symptoms
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Examining the Effectiveness of Watchful Waiting (WW) Among US Patients with Advanced Stage Follicular Lymphoma (FL) Sinha R, Byrtek M, Dejoubner N, Taylor M, Nooka A, Ziemiecki R, Friedberg J, Link B, Cerhan J, Hirata J, Flowers C on behalf of the National LymphoCare Study (NLCS)
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Watchful waiting (WW) vs. active treatment (AT): Patient flow
2,727 patients with newly diagnosed FL enrolled into NLCS 1,822 Stage III/IV 59 patients excluded* 31 patients excluded* AT group n = 1,462 WW group n = 270 R-monotherapy n = 232 R-chemotherapy n = 1,019 Other† n = 211 * Patients having disease progression, death, or discontinuation of the study within 90 days after the diagnosis of follicular NHL were excluded † Investigational treatment (n = 129), chemotherapy (n = 48), radiation/BMT/others (n = 34)
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Endpoints for analysis
WW AT PD1 PFS TTNT AT1 PD2 AT2 PFS2 PFS-Active Primary endpoint Overall survival Secondary endpoints Progression-free survival (PFS) Time to next treatment (TTNT)* Time to first chemotherapy (TTchemo) (Comparing WW and R- monotherapy) PFS-Active PFS2 * For WW strategy, this is time to first active treatment
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No differences in overall survival at 5 years of follow-up
WW (n = 270) R-mono (n = 232) R-chemo (n = 1,019) Other (n = 211) Median follow-up time, months 60 57 59 62 Median OS Not reached Deaths, % 18 25 20 HR 1.00 (0.64–1.56) 0.76 (0.52–1.10) (0.46–1.26)
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Risk of progression after first AT was lower if AT was received directly after diagnosis
PFS after 1st active treatment (PFS-Active): HR* = 0.70 for AT vs WW (p = ) Time (months) Survival probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 12 24 36 48 60 72 84 First active treatment at diagnosis First active treatment after WW * Adjusted for sex, treatment setting (academic/community), histology grade, and FLIPI components (age, # nodal sites, LDH, Hgb) at initiation of active treatment
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Time to second progression was delayed in patients who had initially received AT
Time to PD after 2nd management strategy (PFS2): HR* = 0.66 for AT vs WW (p = ) Active treatments Watchful waiting 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 12 24 36 48 60 72 84 Survival probability Time (months) * Adjusted for sex, treatment setting (academic/community), histology grade, and FLIPI components (age, # nodal sites, LDH, Hgb) at diagnosis Patients were excluded if they had disease progression, death, or discontinued the study within 90 days of diagnosis
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Goals of management of any disease
Cure True cure is unlikely but a functional cure is feasible. Prolong survival ?trend to improved survival Improve symptoms Prolong PFS with 1st and 2nd line therapy
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My conclusion R-chemo at diagnosis may result in durable remissions exceeding 6-8 years R-chemo at diagnosis may impact survival R-chemo at diagnosis may be more effective than R-chemo after W&W
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