Follicular lymphoma Every patient should be treated at diagnosis Michele Ghielmini Medical Oncology Dept Oncology Institute of Southern Switzerland Bellinzona

W + W vs. immediate chemotherapy: only old and underpowered studies W+W vs. ProMACE-MOPP 89 pts Young, 1988 W+W vs. Prednimustine 130 pts Brice, 1997 W+W vs. Chlorambucil 309 pts Ardeshna, 2003 Overall survival With permission from The Lancet, Ardeshna K M et al., The Lancet, August 2003, Vol. 362 9383):516-522

What is the point of delayng treatment of 3 years? W+W lasts a median of 3 years What is the point of delayng treatment of 3 years?

New treatments have improved survival 1002 FL patients 3 decades Barcelona London Bellinzona Novara Conconi et al. 2015; in press

Meta-analysis of chemo vs. R-chemo: overall survival Schulz H, et al. J Natl Cancer Inst 2007; 99:706–714.

Risk of follicular lymphoma transformation by initial therapy Link B K et al. J Clin Oncol 2013;31:3272-3278

FL: STIL vs. BRIGHT study (PFS) 12 24 36 48 60 72 84 96 Time (months) Rummel MJ, et al. Lancet 2013. Flinn IW et al. ASH 2012; abstract 902. 2 2

BRIGHT-Phase III Study R-Benda vs. R-CHOP/R-CVP Quality of life In all pts, GHS/QOL score significantly improved from baseline to final visit with BR vs R-CHOP/R-CVP GHS/QOL iNHL pts: BR: +2.1 R-CHOP/R-CVP: -6.3 (p=0.0021) MCL pts: BR: +10.9 R-CHOP/R-CVP: +1.6 (p=0.0654) Mean (SEM) changefrom baseline in QLQ-C30 functioning scales Adapted from Burke JM et al. ASH 2012; abstract 155.

UK intergroup trial (n=600) Asymptomatic non-bulky FL N D O M I S A T I O N ARM A Watch and Wait R R R R R R R R R R R R Rx4 1 3 5 7 9 11 13 15 17 19 21 23 25 months Clinic visits Continued follow up ARM B Rituximab Induction ARM C Rituximab Induction & maintenance

UK study on W+W patients: Time to Initiation of New Therapy (TINT) Proportion of patients with no new treatment initiated W+W R4 R4 + M 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 Years from randomisation ICML update: R + M reduces anxiety compared to W+W Ardeshna et al., Abstr. 19, ICML-11, 2011

Risk of Transformation Ardeshna et al, Lancet Oncol 15:424, 2014

Rituximab maintenance for how long? SAKK 35/03 study design SAKK 35/03 trial Short maintenance Rituximab 375 mg/m² q2 months x 4 Randomization PR + CR Rituximab 375 mg/m² qwk x 4 restage week 12 SD + PD off study Rituximab 375 mg/m² q2 months until progression (max. 5 years) Long maintenance Taverna CJ, et al. ASH 2013 12

SAKK 35/03: 1 vs. 5 years maintenance EFS PFS Long-term maintenance Median 5.3 y Short-term maintenance Median 3.4 y P=0.14 Long-term maintenance Median 7.4 y Short-term maintenance Median 3.5 y P=0.04 Taverna C. et al. ASH 2013

Conclusion: is R2 as active as R-chemo? R2 in first line FL MDACC CALGB n= 50 66 Lenalidomide 20 mg d1-21 x 6 20 g d1-21 x 12 Rituximab 375 mg/m2 qd 4 wks x 6 375 mg/m2 weekly x 4 + cycle 4, 6, 8, 10 Median age 58 53 FLIPI ≥ 2 78% 69% RR 98% 93% CR 87% 72% 2y. PFS 89% - Ref Fowler et al. Abstr. 901, ASH 2012 Martin et al. Abstr. 63, ICML-12, 2013 Conclusion: is R2 as active as R-chemo?

Radio-Immunotherapy as Initial Therapy for Indolent NHL I-131 Tositumomab n = 76 patients, 97% RR, 76% CR 90-Y Ibritumomab n = 50 patients, 94% RR, 86% CR Kaminski MS, et al. N Engl J Med. 2005;352(5):441-449. Ibatici A, et al. Br J Haematol. 2014;164(5):710-716.

Which one do you consider to be the loser? I am in remission since 7 years! I have cancer and they don’t want to treat me!

Conclusions Patients are happier when they are free of disease Treatment of FL is today well tolerated and achieves long PFS Patient-friendly options are single agent, long term rituximab, R2 or R-bendamustine Treatment reduces the risk of transformation