Recurrent Follicular Lymphoma With a Short First Remission: How Aggressive Should We Be?

1. Recurrent Follicular Lymphoma With a Short First Remission:How Aggressive Should We Be? Carla Casulo, MD Wilmot Cancer Institute University of Rochester Medical Center Rochester, New York Lymphoma & Myeloma 2014: An International Congress on Hematologic Malignancies October 25th, 2014

2. No Disclosures

3. Case Presentation • 63 year old woman with grade 2-3 FL, stage IV • No other significant PMH • Treated with R-CHOP • 18 months later developed enlarged 3 cm neck mass • PET scan showed widespread disease • Otherwise feels well • What is her prognosis? • How aggressive should you be?

4. Introduction • Follicular lymphoma (FL) represents the most common indolent non-Hodgkin lymphoma (NHL) in the world • Gains in overall (OS) and progression-free survival (PFS) have been made in FL with aggressive treatment strategies and maintenance rituximab • Most patients live many years with minimal impact of disease, but a subset will have aggressive course and short survival Zelenetz et al. J NatlComprCancNetw. 2011 Swenson et al. J Clin Oncol, 2005

5. Recurrent FL and Risk of Death • Contributors to relapse: • Biologic risk factors: • BCL6 rearrangement, MYC abnormalities, modification of histones • Changes in microenvironment; gene expression profiling • Clinical risk factors • FLIPI score – predicts PFS • Time to progression? Smith, Hematology, 2013

6. 20% of Patients With FL Experience Disease Progression Within 24 Months of First Line Chemoimmunotherapy 1.0 100 0.8 80 R-CHOP B-R 0.6 60 Progression-free survival (%) Probability 0.4 40 R-CHOP Press et al. J ClinOncol. 2013. (SWOG S0016) 20 0.2 Rummel el al. Lancet. 2013. 0 0.0 0 6 12 18 2 4 30 36 42 4 8 54 60 0 6 12 18 24 30 36 42 48 54 60 Time (months) Time (months) 1.0 Rituximab maintenance 0.8 0.6 This suggests a high-risk group of patients who will relapse early despite different treatment approaches; maintenance Event-free rate 0.4 0.2 Salles et al. Lancet. 2011. (PRIMA) 0.0 0 6 12 18 24 30 36 42 48 54 60 Time (months)

7. Does Short 1st Remission Predict for Poor Overall Survival in FL? • Given that 20% of FL patients have early relapse, The National LymphoCare Study (NLCS) conducted study to determine whether early PD defines patients at high risk for death • What is the clinical significance of early progression after treatment in FL? • Is early progression a marker of short OS in FL? Casulo et al, Proc ASH 2013, Abstract 510

8. National LymphoCare Study Sites and Enrollment • The National LymphoCare Study (NLCS) is a multicenter, prospective observational study of 2,727 newly diagnosed patients with FL from 2004 to 2007 at 265 sites in the US • Evaluable patients for this subset analysis: • No mixed/transformedFL • Stage II-IV • Treatment with 1st line R-CHOP Friedberg et al. J ClinOncol. 2009.

9. NLCS Participant Selection and Classification Evaluable patients in the NLCS with newly diagnosed FL (N=2,655) Stage I or unknown (n=487) Stage II, III, lV (n=2,168) Watchful waiting or other treatment (n=1,579) First-line R-CHOP (n=588) Early progressor: Relapse or death within 2 years of R-CHOP n=122 Reference group: NO relapse or death within 2 years of R-CHOP n=420

10. Distribution of Characteristics by Group *X2

11. Poor Survival in FL Relapsing Within 2 Years of 1st line R-CHOP (“Early PD”) • 122 patients with early progression • (n=110 PD and n=12 non-PD death within 2 years) 1.0 • 5 year OS 95% 0.8 Reference Group 0.6 Early Progressor Survival probability 0.4 • Two-year OS (95% CI) was 71% (61.5–78.0) • Five-year OS (95% CI) was 50% (40.3–58.8) 0.2 0.0 0 1 2 3 4 5 6 7 8 9 10 Patients at risk: Early = 122 101 78 69 58 49 45 33 14 6 0 Reference= 420 420 420 407 387 363 344 252 144 33 0 Time (years)

12. NLCS: Outcomes for Early Progressors • Similar to other studies: • 21% of patients relapsed early after treatment • Early PD associated with significantly poor OS: • Hazard ratio (HR)=13.3 (95% CI: 7.94–22.4) • After adjusting for FLIPI score, early PD associated with an increased risk of death: • HR=15.4 (95% CI: 9.6–24.7)

13. Replication/Validation Study • NLCS outcomes replicated at the University of Iowa/Mayo Clinic • Cohort: 103 patients with FL treated with R-CHOP in first line setting • Characteristics well matched, except more grade 3 FL in UI/Mayo cohort than NLCS (62% vs 38%; p<0.01) • 20% (N=21) had early progression/death, similar to NLCS

14. UI/Mayo Validation Set: Poor Outcomes in Early Relapsed FLAfter 1st Line R-CHOP (“Early PD”) • Median follow up: 6 years • Two-year OS (95% CI) was 57% (40–83) • Five-year OS (95% CI) was 32% (17–60) 1.0 0.8 • Unadjusted HR=24.2 (95% CI: 8.6–67.8) • FLIPI adjusted HR=23 (95% CI: 7.9–64.3) 0.6 Survival probability 0.4 0.2 0.0 0 1 2 3 4 5 6 7 8 9 10 Years from diagnosis

15. NLCS Conclusions • Relapsed FL is a heterogeneous entity • Variable outcomes • PD within 2 years of R-CHOP uniquely defines a group of patients at a substantially greater risk of death • Patients with short remission following chemo-immunotherapy are a high-risk group warranting further exploration in clinical trials

16. How Aggressive Should We Be With Early Relapse after Treatment in FL? • Can we reverse the poor outcomes associated with early relapse in FL? • What are outcomes with second line treatments? • Standard chemotherapies vs. targeted therapies • Role of stem cell transplant • Is there hope for long term disease control? • No consensus on risk stratification, prognostic tools at relapse

17. Conventional Treatment Options in Relapsed FL Davis et al. J ClinOncol2000; Rummel et al. J ClinOncol2005; Robinson et al. J ClinOncol2008; vanOers et al.

18. Intensification of Treatment in Relapsed FL:Role for ASCT • SHOULD you refer and WHEN? • no OS benefit in first remission • high response rates, ? plateau in survival • Toxicity considerations; secondary risks • Myelodysplasia following ASCT (up to 20% at 10 years, especially with TBI regimens) Laport. Hematology 2013; Khabori et al. JNCI 2011; RohatinerJ ClinOncol2007

19. The CUP Trial: ASCT in Relapsed FL • CHOP x 3  if response, randomization: • ASCT with/without purged marrow OR • 3 more cycles CHOP • 89 patients randomized: • Trial closed prematurely due to poor accrual • Median follow-up 69 months • No rituximab in induction or maintenance Schouten et al, J ClinOncol, 2003

20. CUP Trial Outcomes: ASCT vs. Chemo in Relapsed FL ASCT arms Standard chemo PFS: Superior for ASCT 4 yr OS: 46%; 71%; 77% (p=0.071): Schouten et al, J ClinOncol2003

21. Timing of ASCT in Relapsed FL? Survival impacted by number prior regimens Vose et al. BiolBld Mar Trans, 2008; RohatinerJ ClinOncol2007

22. Remission Duration following ASCT in Relapsed FL Can be Durable: Median fu 13 years 5 yr OS 71% 10 yr OS 54% Median fu 8 years 10 yr OS 66, 75% Rohatiner et al J ClinOncol2007 Pettengel et al. J ClinOncol. 2013

23. ASCT vs. allo for Relapsed FL in the Rituximab Era: NCCN analysis • 184 patients with relapsed/refractory FL following rituximab containing treatment • ASCT, N=136 • alloSCT, N= 48 • Median 3 prior treatments • Most chemo-sensitive at transplant ASCT 3 yr OS 87% alloSCT 3 yr OS 63% No difference FFS • Higher toxicity, NRM allo Evens et al, Cancer 2013

24. NCCN Risk Factors: ASCT for Relapsed FL • Multivariate Analysis • Older age, more treatment: adverse predictors • At 3 years OS • 0 factors: 96% • 1 factor: 82% • 2 factors 62% Prognostic Score: Age > 60; > 3 Prior Therapies No Factors 1 Factor 2 Factors Evens et al, Cancer 2013

25. Non myeloablativealloSCTfor Relapsed FL: MD Anderson Experience • 47 patients • 9 year follow up Khouri et al. Blood 2012

26. Conclusions: NCCN Study on ASCT vs. allo in Relapsed FL • ASCT has excellent outcome in the rituximab era • 5 yr OS > 80% • ASCT, alloSCT have equivalent FFS in relapsed FL • Late deaths in allo group (several > 5 yrs after transplant) limit OS • mainly from complications • ASCT should be considered the transplant option for relapsed follicular lymphoma

27. What about Novel Agents? • Idelalisib • Phase II, 72 FL • Combinations • + lenalidomide • + bendamustine + rituximab • Ibrutinib • Phase I, 16 FL • Combinations • + lenalidomide • Lenalidomide • Phase II, 16 FL • Combinations • + rituximab • GDC-0199 • Phase I, 11 FL • Combinations • + bendamustine + rituximab Gopal et al. NEJM 2014; Fowler et al. Proc ASH 2012, abstract 156; Advani et al J ClinOncol2012; Witzig et al. J ClinOncol2009; Wang et al. Leukemia 2013; DavidsProc ASCO 2014

28. Back to our patient…. • 63 year old woman with FL, stage IV, relapsed 18 months from R-CHOP • What is her prognosis? 5 yr OS 30-50% • How aggressive should you be? • Standard treatments: median PFS ~18-24 months • Investigational treatments: median PFS ~ 12 months • ASCT: 3 year OS ~ 85% • Earlier may be better, non TBI regimen • For an otherwise healthy patient, good PS, may consider aggressive strategies

29. Conclusions • FL with short first remission has a poor prognosis • Consider intensive second line treatments • ASCT associated with durable long term remissions, possible cure? • Combinatorial, novel targeted agents may pave the way for improved outcomes

30. Acknowledgments Mentor Jonathan Friedberg Funding Sources -ASH Clinical Research Training Institute -University of Rochester SPORE Career Development Award in Lymphoma Research