Follicular lymphoma : To treat or not to treat, and if so when ? 11th European Congress on Hematologic Malignancies: From Clinical Science to Clinical Practice  13-15 March 2015 Barcelona, Spain Follicular lymphoma : To treat or not to treat, and if so when ? Gilles SALLES « Pathologie des Cellules Lymphoïdes » UMR 5239 CNRS – UCB – ENS – HCL Université de Lyon

Gilles SALLES DISCLOSURES OF COMMERCIAL SUPPORT Name of Company Research support Employee Consultant Stockholder Speaker’s Bureau Advisory Board Other Amgen YES Celgene Gilead Janssen Mundi-pharma Roche

is an acceptable option in selected patients GELF-86 OVERALL SURVIVAL Watch and wait is an acceptable option in selected patients GELF-86 OVERALL SURVIVAL P = 0.88 At risk 66 51 29 6 64 48 23 5 63 31 3 Low Tumor Burden No Treatment Prednimustine Interferon a 0.0 0.2 0.4 0.6 0.8 1.0 Years 4 8 12 Proportion Brice et al., 1997, JCO

Therapeutic strategies in asymptomatic follicular lymphoma pts Watchful waiting strategy has been validated in randomized studies 1 It was challenged with the use of rituximab as single agent 2-4 Young RC et al. Semin Hematol, 1988 ; Brice et al. , JCO 1997 ; Ardeshna KM et a Lancet 2003 Colombat P, Blood. 2001 Ghielmini M, et al. J Clin Oncol. 2005 Witzig TE, J Clin Oncol. 2005

Rituximab as single agent summary of phase II studies in first line Good efficacy : - about 3 out of 4 patient respond to therapy Some long term (molecular) responses Minimal toxicity Hainsworth 2000 ; Colombat 2001 ; Ghielmini 2004; Witizig 2005

Rituximab as single agent summary of phase II studies in first line Good efficacy : - about 3 out of 4 patient respond to therapy Some long term (molecular) responses Minimal toxicity But: short median PFS: - 20 to 30 months Costs are high ? Hainsworth 2000 ; Colombat 2001 ; Ghielmini 2004; Witizig 2005

Does rituximab (4 infusions) delay the time to next treatment ? OBSERVATION The median time to first systemic treatment was 2·6 years (~ 31 months) for the entire observation group. Ardeshna et al., 2003, Lancet

Does rituximab (4 infusions) delay the time to next treatment ? OBSERVATION 4 RITUXIMAB INFUSIONS YEARS MONTHS Ardeshna et al., 2003, Lancet Colombat et al., 2012, Ann Oncol

Watch and Wait in the Rituximab era Time to initiation of lymphoma therapy (TLT) and OS OS TLT Solal Celigny et al, JCO 2012

Watch and Wait in the Rituximab era Time to initiation of lymphoma therapy (TLT) and OS Freedom From Treatment Failure according to initial management OS W&W TLT Rituximab Solal Celigny et al, JCO 2012

Therapeutic strategies in asymptomatic follicular lymphoma pts Watchful waiting strategy has been validated in randomized studies 1 It was challenged with the use of rituximab as single agent 2-4 Several clinical trials have investigated prolonged rituximab treatment: RWW, RESORT, SAKK Young RC et al. Semin Hematol, 1988 ; Brice et al. , JCO 1997 ; Ardeshna KM et a Lancet 2003 Colombat P, Blood. 2001 Ghielmini M, et al. J Clin Oncol. 2005 Witzig TE, J Clin Oncol. 2005

Rituximab vs. Watch and wait: Study design Primary endpoints: Time to initiation of new therapy (chemotherapy or radiotherapy) Effect on quality of life R A N D O M I S E ARM A Watchful waiting ARM A Watchful waiting ARM B R-mono 375 mg/m2 weekly x 4 X ARM B R-mono 375 mg/m2 weekly x 4 Asymptomatic stage 2, 3 or 4 FL Grades 1, 2 & 3a Adequate bone marrow reserve DISCONTINUED ARM C R-mono 375 mg/m2 weekly x 4 + maintenance q2mo for 2 years ARM C R-mono 375 mg/m2 weekly x 4 + maintenance q2mo for 2 years Total planned enrolment: 360 patients Ardeshna KM, et al. Blood 2010;116:Abstract 6.

Time to Initiation of New Therapy (TTINT) 1.0 0.9 0.8 Proportion of patients with no new treatment initiated 0.7 0.6 0.5 0.4 0.3 % not requiring Rx at 3yr W+W=48% R4=80% R4+RM=91% 0.2 Events Totals W+W 83 187 0.1 R4 19 84 R4 + M 19 192 0.0 1 2 3 4 5 Years from randomisation HR (Rituximab vs W+W) = 0.37, 95%CI = 0.25, 0.56, p<0.001 HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p <0.001 HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p =0.10 Ardeshna KM, et al. Blood 2010;116:Abstract 6.

Overall survival % of patients alive 3yr OS=95% 1.0 0.9 0.8 % of patients alive 0.7 3yr OS=95% 0.6 0.5 0.4 0.3 0.2 Events Totals W+W 9 187 0.1 R4 4 84 R4 + M 8 192 0.0 1 2 3 4 5 Years from randomisation HR (Rituximab vs W+W) = 0.63, 95%CI = 0.21, 1.92, p=0.42 HR (Rituximab + M vs W+W) = 0.84, 95%CI = 0.32, 2.18, p=0.72 HR (Rituximab + M vs Rituximab) = 1.21, 95%CI = 0.37, 3.97, p=0.75 Ardeshna KM, et al. Blood 2010;116:Abstract 6.

Rituximab re-treatment at progression* E4402 (RESORT) Schema R A N D O M I Z E Rituximab Maintenance* 375 mg/m2 q 3 months Rituximab 375 mg/m2 qw  4 CR or PR Rituximab re-treatment at progression* 375 mg/m2 qw  4 *Continue until treatment failure Primary Endpoint: No response to retreatment or PD within 6 months of Rituximab ; Initiation of cytotoxic therapy or inability to complete treatment

RESORT Secondary endpoints PFS Time to chemo Kahl et al, JCO 2014.

RESORT Primary Endpoint: Time to Treatment Failure Kahl et al, JCO 2014.

Asymptomatic FL patients What is the evidence in 2015 ? Delaying treatment initiation remains an acceptable option in 2015 The benefit of using a short treatment with rituximab to delay R-chemo is doubtful The clinical benefit of prolonged rituximab treatment in FL patients is not established

Asymptomatic FL patients What is the evidence in 2015 ? But if treatment needed, when ?

Individuals with > 10-4 IGH-BCL2+ cells in PB have a 23 fold increased risk to develop FL Roulland et aL., JCO 2014

Median time to develop FL according to IGH-BCL2+ cells in PB Roulland et aL., JCO 2014,

For patients on W&W, “EFS12” is associated with prolonged survival Maurer et al., ASH 2014

How do define asymptomatic patients ? GELA criteria BNLI 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 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< 3.0×109/L or Plat.<100×109/L ; related to marrow involvement

Asymptomatic FL patients Do not treat (immediately) in 2015 ! Delaying treatment initiation remains an acceptable option in 2015 The benefit of using a short treatment with rituximab to delay R-chemo is doubtful The clinical benefit of prolonged rituximab treatment in FL patients is not established There is no harm in waiting for clinical progression to start a very efficient treatment - rituximab plus chemotherapy followed by R maintenance

PRIMA 6 years follow-up Progression free survival from randomization HR= 0.57 P<0001 Median follow-up since randomization : 73 months