Prognostic value of PET-CT after frontline therapy in follicular lymphoma: a pooled analysis of central review in three multicenter studies. J Trotman, S Luminari, S Boussetta, A Versari, J Dupuis, C Tychyj-Pinel, L Marcheselli, A Berriolo-Riedinger, A Franceschetto, A Julian, F Ricard, L Guerra, C Haioun, I Biasoli, H Tilly, M Federico, G Salles, M Meignan. FOLLCOLL: a collaboration of the LYSA, FIL and ALLG

Follicular Lymphoma: Response assessment Indolent histology yet ~15% of patients will die within 5 years. High risk FLIPI / FLIPI-2 scores alone fail to identify these patients. Solal-Celigny P, Blood 2004, Federico M, JCO 2009 Limitations of CT response assessment (PR/CRu/CR) in predicting OS. Bachy E, JCO 2010 Despite recommendation against routine use of PET-CT for FL in the 2007 IHP criteria it is commonly used in response assessment. Cheson B, JCO 2007 The predictive value of PET assessment after first-line rituximab- chemotherapy for high tumor burden FL recently reported in three trials …

Postinduction response assessment with PET-CT: limitations to these studies… PRIMA 122 patients Trotman J, JCO 2011 Hypothesis generating. Retrospective analysis of local PET interpretation within a prospective study with independent CT assessment. Results confirmed by independent scan review of 61 patients. Tychyj-Pinel C, EJNMMI 2014 FOLL patients Luminari S, Ann Oncol 2013 Retrospective analysis of local PET reports within a prospective study with local CT assessment. PET Folliculaire 106 patients Dupuis J, JCO 2012 Prospective standardised PET acquisition / assessment in accordance to the 5 Point Scale (5PS), with local CT assessment. Shorter follow-up.

Aim To conduct a pooled analysis of data from patients with independently reviewed PET-CT scans in these 3 studies to provide more precise survival estimates from a larger patient cohort with longer follow-up identify the best cut-off for survival when applying the increasingly adopted 5PS for response assessment of FDG-avid lymphoma Barrington S, in press JCO 2014

Methods Postinduction PET-CT scans submitted for central review were assessed independently by three reviewers using the 5PS. 1.no uptake 2.uptake ≤ mediastinum 3.uptake > mediastinum but ≤ liver 4.uptake moderately higher than liver 5.uptake markedly higher than liver and/or new lesions Meignan M, 2009 Only scans of sufficient quality for central review were accepted PET status with score ≥3 and ≥4 were compared with: - baseline disease & patient characteristics, - CT response assessment (IWC 1999), Cheson B, PFS & OS

Study Population: 246 patients with reviewed postinduction PET-CT 37 (15%) received Rituximab maintenance PET performed a median 30 days after last chemotherapy

Patient characteristics Parametern = 246 (%) AgeMedian (range)56 (26-78) <60 years151 (61) Grade (80) 3a 26 (11) Unknown 21 (9) Stage I-II 24 (10) III-IV 222 (90) ECOG (94) Number of nodal areas>4142 (58) Number of extranodal sites>193 (38) Bone marrow involvement134 (57) LDH> normal51 (20) FLIPI score3-5 (Int-High)92 (37)

CT & BM based response (IWC 1999 criteria) ResponsePatients (n = 240) % CR CRu PR SD/PD104.2 } Median follow-up 55 months from individual study registration (range 7-90) 96%

PFS according to CT response SD/PD vs. PR, HR 4.2 CRu, HR 5.6 CR, HR 7.8, p<.0001 PR vs. CR/CRu, HR 1.7 ( ) p=0.02 CRu/PR vs. CR, HR 1.6 ( ), p=0.02

Postinduction PET review concordance (3 independent reviewers) Concordance (κ) Cut-off ≥3 Concordance (κ) Cut-off ≥4 PRIMA FOLL PET Folliculaire Moderate agreement Substantial agreement

Postinduction PET status (n = 246) 68 (28%) PET+ with cut-off ≥3 (uptake > mediastinum) 41 (17%) PET+ with cut-off ≥4 (uptake moderately > liver)

PET Review Results No difference in individual baseline characteristics of PET+ & PET- patients with either cut-off FLIPI 3-5 associated with PET+ status: 23% vs. 13% FLIPI 1-2, p=0.05 (cut-off≥4) Excellent concordance between postinduction CT and PET status IWC 1999 Response Patients (n = 240) PET+ Cut-off ≥3 (%) PET+ Cut-off ≥4 (%) CR11313 (11.5)5 (4.4) CRu5521 (38.2)12 (21.8) PR6222 (35.5)16 (25.8) SD/PD107 (70.0)6 (60.0)

Both PET cut-offs predictive of PFS Score ≥3Score ≥4 HR 3.9 (95% CI , p<.0001) Median PFS: 16.9 ( ) vs mo (54.7-NR) 63% 23%

Postinduction PET status (cut-off ≥4) and Overall Survival 87% 97% HR 6.7, 95% CI , p= Median OS: 79 months vs. NR

Multivariate Analyses PFS P-valueHazard Ratio95% CI PET-positive ≥4 vs. <4< SD/PD vs. CR/CRu PR vs. CR/CRu FLIPI score 3-5 vs OS P-valueHazard Ratio95% CI PET-positive ≥4 vs. < SD/PD vs. CR/CRu PR vs. CR/CRu FLIPI score 3-5 vs

Conclusions Independent review of 246 scans and median 4.6 years follow-up after first-line rituximab-chemotherapy for follicular lymphoma confirms: Postinduction PET-CT status is strongly predictive of PFS/OS - 4yr PFS 23% and OS 87% in PET+ When performing PET-CT conventional CT assessment provides limited additional value PET-CT applying the 5PS (cut-off ≥4) should be the new gold standard for therapeutic response assessment

Postinduction PET-CT: a platform to study response-adapted therapy Achieving PET- status can better reassure patients… especially those otherwise in CRu or PR The inferior survival of patients remaining PET+ compels us to study PET-response adapted approaches

M Meignan (France), A Gallamini (Italy), C Haioun (France), S Barrington (UK), E Itti (France), S Luminari (Italy), E Zucca (Switzerland) 5 th International Workshop on PET in Lymphoma Menton, France September 19-20, 2014 Information on Dead line for abstracts: May 31 st 2014

How to further optimise PET-response assessment in Follicular Lymphoma? Will the 5PS suffice in this heterogeneous lymphoma? What defines “moderately increased” uptake beyond that of the liver anyway? Will ΔSUV or Metabolic Tumour Volume provide additional information? Will PET assessment have the same predictive power for newer biotherapies? Is there any role for interim PET assessment in this lymphoma ?

Postinduction PET in the R-CHOP population n = 180 (74%) PFS (cut off ≥4) OS HR 4.3 ( ) p< Median PFS: 15.7 ( ) vs mo (54.7-NR) 66% 25% HR 6.7 ( ) p= % 98% OS (cut off ≥4)

6% 48% 65% 60% PFS according to PET status (cut-off ≥4) and CT response CR/CRu vs Other

PET status and OS Score ≥3Score ≥4 HR 4.8, 95% CI , p<.003 HR 6.7, 95% CI , p= Median OS: 78.7 months vs. NR

15 deaths 8/41 (19.5%) of PET+ (score ≥4) –4 from lymphoma –2 toxicity of further therapy –1 cirrhosis –1 lung carcinoma 7/205 (3.4%) of PET- patients –6 from lymphoma –1 from infection

PFS & OS according to PET status in all PRIMA and FOLL05 patients PFSOS