Follicular Lymphoma Michele Ghielmini Oncology Institute of Southern Switzerland Bellinzona
Conflicts of interest Astra Zeneca Roche Cellgene Mundipharma Janssen Gilead Bayer Abbvie
FL remains an incurable disease, but new therapies improved survival Swedish registry, n = 2641 IOSI, Novara, Barcelona, London database, n = 1002 Junlén et al. Leukemia 2015 Conconi A, et al. Leuk Lymphoma. 2010
Patients progressing within 2 years have a bad prognosis Lymphocare study data (USA) 90% 50% (at 5 years) 588 patients: RCHOP no maintenance Prevalence early POD (2 years): 19% Casulo et al. J Clin Oncol 2015
FLIPI = Follicular Lymphoma International Prognostic Index 0-1 factor 2 factors AGE < 60 vs. 60 HEMOGLOBIN 12g/dL vs. < 12g/dL SERUM LDH LEVEL ULN vs. > ULN ANN ARBOR STAGE I II vs. III IV NUMBER OF NODAL SITES INVOLVED 4 vs. > 4 3-5 factors Solal-Celigny, Blood 2004
The clinicogenetic risk model m7-flipi m7flipi High-risk FLIPI High-risk m7flipi High-risk FLIPI High-risk Pastore et al., Lancet Oncol., 2015
ESMO guidelines 2016 (simplified) Low tumor burden High tumor burden Stage I-II Stage III-IV Stage III-IV (age > 65) Stage III-IV (age < 65) Front line IF-RT W+W R- chemo + R- maintenance (W+W) (R-mono) (R-mono) Relapse W + W R-monotherapy R-chemo + maintenance Idelalisib Radioimmunotherapy Palliative RT SAME as >65 + HDCT with ASCT Allo-transplant Dreyling et al, Ann. Oncol. 2016
Relapse after RT: NCCN centres Stage Size of bulk Stage Size of bulk Charpentier et al., Abstr. 62, ICML-12, 2013
How to define high tumour burden patients? GELA criteria High tumor bulk defined by either: - a tumor > 7 cm - 3 nodes in 3 distinct areas each > 3 cm - symptomatic splenic enlargement - organ compression - ascites or pleural effusion Presence of systemic symptoms Serum LDH or β2-microglobulin above normal values BNLI criteria Rapid disease progression in the preceding 3 months Life threatening organ involvement Renal or liver infiltration Bone lesions Systemic symptoms or pruritus Hb<10 g/dl or WBC<3.0 10 9 /L or Plat.<100 10 9 /L ; related to marrow involvement
W+W does not compromise patients survival W+W vs. ProMACE-MOPP 89 pts Young, 1988 Overall survival W+W vs. Prednimustine 130 pts Brice, 1997 W+W vs. Chlorambucil 309 pts Ardeshna, 2003 With permission from The Lancet, Ardeshna K M et al., The Lancet, August 2003, Vol. 362 9383):516-522
Probability RT and CT have long-term life threatening side-effects HL: Competing Causes of Mortality 0.20 0.15 Hodgkin s s Disease Second Malignancy Infection Cardiac/Pulmonary Other 0.10 0.05 0.0 0 5 10 15 20 25 30 Years Diehl et al. Lancet Oncol 2004
Today 90% of FL aged <40 are alive at 10 years The median survival of FL patients aged < 40 is expected to be > 30 years! N= 155/1002, 4 EU centres N= 164/2652, Lymphocare Conconi et al. Ann Oncol 2015 Casulo et al. Ann Oncol 2015
Does waiting increase the chance of transformation? Al Tourah et al., JCO, 2008
Meta-analysis of chemo vs R-chemo: Overall survival Schulz H, et al. J Natl Cancer Inst 2007; 99:706 714.
Chemotherapy for FL: «is more better»? Ardeshna et al, The Lancet 2003 Peterson et al., JCO 2003 Sebban et al, Blood, 2006 Ladetto, M. et al. Blood 2008
Italian randomised study (N = 504) Is R-CHOP standard? No difference in OS! R-CHOP vs R-CVP 0.003 R-FM vs R-CVP 0.006 R-CHOP vs R-FM 0.763 Federico M, et al. J Clin Oncol 2013 Mar 25. Epub ahead of print.
FL: STIL vs BRIGHT study (PFS) 0 12 24 36 48 60 72 84 96 Time (months) Rummel MJ, et al. Lancet 2013. Flinn IW et al. ASH 2012; abstract 902.
FL Grading < 15 Cb/HPF 1 3a 3b 2 > 15 Cb/HPF All Cb/follicular LBCL/follicular 1-2 3a 3b LBCL = large B-cell lymphoma Images courtesy of Stefano A Pileri, MD
Overall Survival (%) Overall survival (%) Grade IS a predictive factor: Nebraska 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 100 90 80 70 60 50 40 30 20 10 0 Follicular lymphoma mean counts No adriamycin p < 0.001 Grade 1 Grade 2 Grade 3 0 1 2 3 4 5 6 7 8 Years Follicular lymphoma mean counts Adriamycin p = 0.87 Grade 1 Grade 3 Grade 2 0 1 2 3 4 5 6 7 8 Years Grade 3 FL must be treated with an anthracyclinecontaining regimen Nathwani BN, et al. Follicular lymphoma. In World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissue. Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds). IARC Press: Lyon 2001.
Overall survival Overall survival Grade 3A vs 3B is a predictive factor: Nordic group Overall survival 1.00 1.00 0.75 0.50 0.25 0 Grade 3B Grade 3A 0 5 10 15 Time (years) Grade 1 2 0.75 0.50 0.25 0 Grade 3A with anthra Grade 3B no anthra Time (years) Grade 3B with anthra 0 5 10 15 Grade 1 2 no anthra Grade 1 2 with anthra Grade 3A no anthra Wahlin BE, et al. Br J Haemtaol 2012; 156:225 233.
Single agent R is a possible option RR of prolonged rituximab in first-line FL Colombat 2001 (n= 50) 73% Hainsworth 2002 (n= 60) 73% Witzig 2005 (n= 37) 72% Ghielmini 2005 (n= 202) 75% Kimby 2008 (n= 123) 78% Ardeshna 2010 (n= 192) 85%
Probability The response to upfront R can be longlasting EFS PFS 1.0 1.0 0.8 Median EFS = 4.4 years 0.8 Median PFS = 7.4 years 0.6 1 year 0.6 5 years 1 year 0.4 1 month 0.4 0.2 0.0 Median EFS = 2.5 years Prolonged Standard p = 0.045 0.2 0.0 Median PFS = 3.5 years P=0.04 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 Years since start of treatment Time from randomisation (years) Martinelli, J Clin Oncol 2010 Taverna C, J Clin Oncol 2015
R-maintanance: the PRIMA trial 3 years FU 6 years FU 1.0 0.8 Rituximab maintenance 75% 59% 1.0 0.8 Rituximab maintenance Observation 89% 87% 0.6 0.4 0.2 0.0 0 Observation Stratified HR = 0.55 95% CI: 0.44 0.68 p < 0.0001 58% 43% 6 12 18 24 30 36 42 48 54 60 Time (months) 0.6 0.4 0.2 Patients at risk p = 0.60 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) Salles G, et al. Lancet 2011; 377:42 51.
Relapse after R-CHOP: fludarabine or bendamustine? PFS STIL trial in relapsed patients OS 1.0 1.0 0.8 R-bendamustine R-fludarabine 0.8 R-bendamustine R-fludarabine 0.6 0.6 BR 0.4 0.4 0.2 0.2 0.0 p = 0.000064 0.0 p = 0.012 0 12 24 36 48 60 72 84 96 108 120 months Rummel et al, ASH 2014 0 12 24 36 48 60 72 84 96 108 120 months
Low-dose involved field RT gives a good palliation 24 Gy Randomised trial N = 614 4 Gy Indolent NHL (86% follicular) PFS 40% early stage with curative intent 24 Gy 4 Gy Response rate: 91% 81% Local progression at 2y: 7% 22% Toxicity: 4% 2% OS Hoskin et al., Lancet Oncol, 2014
ABMT in relapsed FL: Bart s historical comparison EFS OS Rohatiner, A. et al. J Clin Oncol; 2007
FL: autologous transplant in first-line GELF: n = 402 PFS OS True also for high FLIPI patients!! Sebban et al, Blood, 2006
Can transplant cure? Autologous: no Allogeneic: yes Hosing et al., Ann Onc 2003
Mini-allo transplant (RIC) for relapsed FL MDACC: OS and PFS Multicenter French study 60% chronic GvHD (36% extensive) Khouri, I. F. et al. Blood 2008 43% chronic GvHD (20% extensive) Vigouroux, S. et al. Haematologica 2007
Idelalisib approved for R/R inhl 126 indolent lymphomas ORR 57% Gopal AK, NEJM, 2014
Conclusions Advanced FL is incurable: the choice of the treatment is based on cost-benefit assessment There is not a standard treatment, except grade 3(B) which certainly need R-CHOP Rituximab single agent is a good alternative to R-chemo in indolent lymphomas Transplantation is for high-risk relapse New non-chemotherapy options are coming