R-CHOP Stem Cell Transplantation for Follicular Lymphoma John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Associate Dean for Clinical Research Vice Chairman, Department of Medicine

Disclosures Consulting advice: Seattle Genetics, Genentech, Pharmacyclics, Biotest, Celgene, Medimmune, Gilead

What do we expect going forward? Case 43 year-old male, follicular, grade 1-2 NHL, high risk FLIPI receives 6 cycles of chemoimmunotherapy Does not achieve a CR What do we expect going forward? What do we do?

Overall survival high-risk FLIPI 5 year OS 52% 10 year OS 35% Solal-Celigny et al, Blood 2004

PET negative (CR) vs PET positive (no CR) after induction therapy for FL - PFS PRIMA Observation Group Maintenance Trotman et al JCO 2011

PET negative (CR) vs PET positive (no CR) after induction therapy for FL - OS Combined observation and Maintenance groups 45% of PET + are high risk FLIPI Trotman et al JCO 2011

Issues to consider in this patient’s status (no CR after chemoimmunotherapy) Median PFS with observation is probably about 2 years Median PFS with maintenance rituximab is difficult to define but 40% progress in 2-3 year range Lack of CR correlates with worsened overall survival

Radioimmunotherapy impact on PET positive (no CR) status after induction therapy for FL – PFS after Y-90 RIT Median 2 year PFS in PR Treated w/ RIT FIT study Morschhauser et al JCO 2013

PFS and OS after R-CHOP or CHOP-I-131 tositumomab by FLIPI Note: Includes both CR and PR pts S0016 Press et al Clin Can Res 2013

Issues to consider in this patient’s status (no CR after chemoimmunotherapy) RIT appears to associate with some durable remissions in this population but most patients relapse in 2+ year time frame No clear benefit of RIT vs maintenance R but possible OS status unclear after RIT in this specific population (our case) High risk FLIPI + PET positive/no CR after induction may be an adverse “double whammy” that maintenance R and RIT modestly impact

What other options will be out there for this patient when he has his expected relapse? Chemoimmunotherapy (B-R, R-CHOP) Lenalidomide Novel anti-CD20s Anti-apoptotic agents PI3K inhibitors BTK inhibitors

Regarding the other options….. Regarding the other options…. What fraction of patients, if any, can have durable remissions with these agents? If comparable, how does QOL (short-term vs chronic) compare? SCT data limited in modern era with respect to use in first PR (must extrapolate from relapsed setting)

CUP trial in of AuSCT in relapsed FL Schouten, et al, JCO 2003, 21(21): 3918-3927

CUP trial - PFS Schouten, et al, JCO 2003, 21(21): 3918-3927

CUP trial - OS Schouten, et al, JCO 2003, 21(21): 3918-3927

Remission Duration of Patients Receiving AuSCT for FL in Second or Later Remission St. Barts and DFCI Rohatiner et al. J Clin Oncol. 2007;25:2554-9.

280 enrolled and randomized (purged/non-purged) Rituximab purging and/or maintenance in R-naive patients with chemosensitive relapsed FL. 280 enrolled and randomized (purged/non-purged) Approximately 200 transplanted (100 purged/100 non purged) Approximately 50 maintenance R in each arm Rituximab naïve, 80% 2 prior regimens, 30% CR, 70% VGPR Pettengell R et al. JCO 2013;31:1624-1630

Progression-free survival by treatment arm Pettengell R et al. JCO 2013;31:1624-1630

AuSCT at first relapse after R-CHVP-IFN PFS and OS After ASCT vs no ASCT 175 relapsers after FL2000 study (R-CHVP-I vs CHVP-I) 70 relapsers after R-CHVP-I Various second line rx (65% included R) 13 with ASCT ASCT associated with improved PFS and OS Le Gouill S, et al, Haematologica 2011

Allo vs. Auto SCT IBMTR Registry data OS DFS N = 904 patients with FL Transplants between 1990-1999 Probability of improved long-term OS not improved by allo ASCT Significant heterogeneity in subjects DFS OS van Besien K, et al, Blood 102:2003;3521-3529

Allo vs. non-myeloablative SCT in FL Retrospective, 88 pts (48 allo, 40 miniallo) Characteristics Miniallo pts were older and more often had prior autoSCT Outcomes Relapse rate 13% (allo) vs 28% (miniallo) 1 year TRM 33% (allo) vs 28% (miniallo) 2 year OS and PFS (allo) 52% and 46% 2 year OS and PFS (miniallo) 53% and 40% Chemosensitive disease and no prior AutoSCT correlated with outcome Rodriguez R, et al, Biol Blood Marrow Transplant, 2006;12(12): 1326-34.

Conclusions High risk FLIPI at diagnosis and lack of CR with front line therapy correlate with less favorable PFS and OS Still, maintenance R and RIT can associate with good outcomes in a subset of patients Novel agents warrant study in this setting AuSCT is associated with high PFS and OS rates in this group in non-comparative trials and should be strongly considered