1. Michael E. Williams, MD, ScM
Debate - Optimal management of low-tumor burden advanced-stage, asymptomatic follicular lymphoma? Rituximab weekly x 4 with Maintenance
Michael E. Williams, MD, ScM
Byrd S. Leavell Professor of Medicine
Chief, Hematology/Oncology Division
University of Virginia Cancer Center
Charlottesville, VA

2. Disclosures Michael E. Williams, MD
Research support: Allos, Celgene, Gilead, Genentech, Janssen, Millennium, Novartis, Onyx, Pharmacyclics
Data Safety Monitoring Committees: Celgene, Millennium
Consultant: Celgene, Millennium, TG Therapeutics
ECOG-ACRIN Lymphoma Committee Vice-chair
ABIM Hematology Subspecialty Board Chair

3. Recommended approach for a 62 yo with low tumor burden FL?
Watch and Wait??
Rituximab induction  R maintenance??
R-chemo??
Fortunately, we have recent Phase III trials that inform the answer!

4. SAKK Trial: Follicular lymphoma Grade I, II, IIIA or IIIB (Taverna et al, ASH 2013)
To investigate if maintenance rituximab every 2 months for 5 years or until relapse/progression, unacceptable toxicity or death is superior to maintenance R every 2 months x 4 doses only
Any of the following disease status
Untreated
Relapsed/progressed
Chemotherapy resistant
Stable disease (last systemic treatment at least 12 weeks before registration)

5. R Study design SAKK 35/03 Short-term maintenance Induction
375 mg/m² every 2 months x 4
375 mg/m²
weekly x 4
PR,CR
375 mg/m² every 2 months for a maximum of 5 years or until progression, relapse or unacceptable toxicity
PD, SD
off study
Long-term maintenance 5
Christian Taverna _

6. Short-term maintenance (n=82) Long-term maintenance (n=83)
SAKK - Adverse events
Short-term maintenance (n=82)
Long-term maintenance (n=83)
At least 1 AE
41 (50%)
63 (76%)
Highest grade 1 2 3 4
25 (31%)
15 (18%)
1 (1%)
0 (0%)
18 (22%)
31 (37%)
12 (15%)
2 (2%)
Infection ≥ grade 3
hypogammaglobulinemia
22%
5 (6%)
44%
Secondary malignancy
6 (7%)
8 (10%)

7. SAKK - Event-free survival ITT (primary study endpoint)
Median EFS 3.4 years vs 5.3 years, p=0.14

8. SAKK - Overall survival ITT

9. SAKK - Conclusions
EFS, the primary endpoint, was not met mainly due to unexplained early separation of the EFS curves favoring arm A, at a time when the treatment in both arms was the same
A retrospectively defined analysis considering only EFS events from the time when treatment was different in the 2 arms, shows a statistically significant increase in EFS with long-term maintenance
Long-term R maintenance doubles the median PFS

10. SAKK - Event-free survival
Only patients at risk after 8 months from randomization
Median EFS 2.9 years vs 7.1 years p=0.004

11. Rituximab +/- Maintenance R versus Watch & Wait in Non-bulky FL
UK Intergroup trial
Stage II-IV, asymptomatic, no prior therapy
3 arms:
Watch/Wait
R weekly x 4 (closed early)
R x 4  R q 2 months x 2 years
Primary endpoints: Time to next Rx & QOL
Indications for additional line of therapy:
Symptomatic increase in nodes or spleen
B symptoms or pruritis
Mass > 7 cm if > 25% increase
> 3 nodal masses > 5 cm
Ardeshna K et al. ASH 2010 (Plenary); Lancet Oncol 2014; 15:424

12. Rituximab  Maintenance R versus Watch & Wait in Non-bulky FL: Results
Ardeshna K et al. ASH 2010 (Plenary); Lancet Oncol 2014; 15:424-35

13. Rituximab +/- Maintenance R versus Watch & Wait in Non-bulky FL: Results
Ardeshna, Lancet Oncol 2014

14. Summary: Ardeshna et al, Lancet Oncol 2014
R x 4  Maint R > R x 4 > W&W
Significantly improves PFS and TTNT
But more SAE: infection, allergic rxn, neutropenia
Maint R improved QOL scores vs W&W
No OS advantage for maintenance R
No difference in histologic transformation
Not tested in this trial: How would rituximab retreatment at progression compare with maintenance rituximab??

15. Rituximab Maintenance vs Re-treatment at Time of Progression
Previously-treated patients
45 pts/arm (FL~30/arm)
Maintenance improved PFS (32 mo vs 7 mo)
At a median follow up of 41 months, overall R “benefit” similar to re-Rx at time of progression (31 mo vs 27 mo)
Hainsworth JD, et al.
J Clin Oncol; 23:

16. Results of E4402 (RESORT): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma
Brad Kahl, Fangxin Hong, Michael Williams, Randy Gascoyne, Lynne Wagner, John Krauss, Sandra Horning

17. E4402: RESORT Rationale Hypothesis:
After initial rituximab therapy, extended scheduled dosing (maintenance rituximab - MR) will prolong disease control compared to retreatment dosing administered upon disease progression (rituximab retreatment - RR)
Previously untreated, low tumor burden, FL an ideal patient population to test this hypothesis

18. 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
No response to retreatment or PD within 6 months of R
Initiation of cytotoxic therapy or Inability to complete rx

19. E4402 Major Eligibility Indolent NHL No prior lymphoma therapy
Follicular grade 1 or 2
Small Lymphocytic
MALT
Marginal Zone nodal
Marginal Zone splenic
No prior lymphoma therapy
Stage III or IV disease
Measurable disease
Low tumor burden as defined by GELF
No tumor mass > 7cm
Fewer than 3 nodal masses > 3 cm
No system symptoms or B symptoms
No splenomegaly greater than 16 cm by CT scan
No risk of organ compression
No leukemic phase
No cytopenias

20. E4402 (RESORT) Objectives Primary Secondary
To compare the TTTF between the MR and the RR arms
Secondary
To compare time to first cytotoxic therapy between the MR and the RR arms
To compare QOL between the arms
To compare toxicities between arms

21. E4402 (RESORT) Results Activated Nov 2003 – Closed Sept 2008
Enrolled 545 patients
161 non-FL patients will be analyzed and reported separately
384 (71%) FL histology
274 (71%) responded to Induction rituximab
134 assigned to retreatment rituximab (RR)
140 assigned to maintenance rituximab (MR)

22. Disease status at randomization
RR (N=134)
MR (N=140)
CR/CRu
14%
18% PR
81%
78%
Missing data 5% 4%
Median follow up for time to event data: 3.8 years

23. Primary Endpoint: Time to Treatment Failure

24. Breakdown of Treatment Failure by Type
Failure Type RR MR
Total
No response (RR) 18
TTP < 6 mos 11 25 36
Alternative Rx 8 1 9
Adverse event 7
Complicating Dz 6 12
Death 2
Patient withdrawal 16 26 42
Other/unknown 4 3 65 69
134

25. Time to First Cytotoxic Therapy

26. Toxicity RR Grade 3 Grade 4 MR Neutrophils -- 2 Platelets 1
Fever w/o neutropenia
Infection
Fatigue 3
LV dysfunction
Hypertension
Syncope
Insomnia
Hearing loss
Larynx pain
TOTALS 4 10

27. Treatment Information
Analysis of # doses rituximab received, including 4 induction doses
Min
Max
Median
Mean
RR (n = 120) 4 16
4.5
MR (n = 130) 5 31
15.5
15.8

28. Conclusions In this study of previously untreated low tumor burden FL:
Rituximab retreatment was as effective as maintenance rituximab for time to treatment failure
MR was superior to RR for time to cytotoxic therapy
At a cost of 3.5x more R
No benefit in QOL or anxiety at 12 months with MR

29. Summary: Kahl et al, ASH 2011 R x 4  Maint R > Retreatment R
Significantly improves time to first cytotoxic Rx
Both strategies appear to delay time to chemotherapy compared to historical controls
Could Retreatment be considered an alternative form of “Maintenance”??
86% chemo-free at 3 yr on Retreatment
Lack of QOL difference
Fewer AE failures than Maintenance
Fewer R doses required than Maintenance

30. For asymptomatic, stage IV, grade 1-2 FL….. The Goldilocks Paradigm
Just Right! Rituximab weekly x 4  “Maintenance” R
Too Cold! Watch and Wait
“Follicular Lymphoma: W&W is Watch and Worry” (S. Ansell, Lancet Oncol 2014; 15:368-9)
Too Hot! R-Chemotherapy