1. 13th Annual Hematology & Breast Cancer Update Update in Lymphoma
Craig Okada, MD, PhD
Assistant Professor, Hematology
January 20, 2010
Governors Hotel, Portland Oregon

2. Initial Treatment of Indolent Lymphoma
Expectant observation
Treatment
Rituximab
Immunochemotherapy
R-CHOP
R-CVP
R-Bendamustine
R-Fludarabine

3. Initial Treatment of Indolent Lymphoma
Expectant observation
Avoids treatment related toxicity
3 RCTs failed to show an overall survival difference between watching and treatment
Young et al, Sem Hematol, 1988
Brice et al, J Clin Oncol 1997
Ardeshna et al, Lancet 2003
Risk and time to transformation similar

4. What Oncologist in US are doing
National LymphoCare Study survey of current practice for FL in the United States
Treatment
Frequency %
Watch and wait 19
Rituximab monotherapy 13
Chemoimmunotherapy 51
R-CHOP 59
R-CVP
R-fludarabine based 11
R-other
Chemotherapy alone 4
Radiation alone 5
Freiberg et al, J Clin Oncol 2006;24:7527

5. Thank Dr. Ardeshna for sharing his slides
ASH Intergroup study of rituximab vs watch and wait (Ardeshna, K et al)
Expectant observation – still relevant today?
Objective
Does initial treatment with rituximab in patients with asymptomatic advanced stage FL result in a significant delay in the initiation of chemotherapy or radiotherapy when compared with a watchful waiting approach?
Participants: National Cancer Research Institute (NCRI), Australasian Leukaemia & Lymphoma Group (ALLG), Istanbul Lenfoma Grubu, Polish Lymphoma Research Group (PLRG), Cancer Research UK, Lymphoma Association, UCL
Asymptomatic: No B symptoms or pruritis
Normal LDH
LN < 7cm
No more than 3 nodal sites with a diamter > 3cm
Hgb >10 g/dl, ANC > 1.5 Plt > 100
< 5000 ciruclating tumor cells
No significant effusions
Spleen ≤ 16 cm by CT
Thank Dr. Ardeshna for sharing his slides

6. R A N D O M I S A T I O N ARM A Watch and Wait Clinic visits Continued
R R R R R R R R R R R R
Rx4
months
Compulsory
CT scan
only if
clinical CR
Bone marrow for histology and MRD only if CT shows CR
Clinic visits
Continued
follow up
ARM B
Rituximab Induction
ARM C
Rituximab Induction
& maintenance
ARM B CLOSED due to perceived benefit from maintenance.
Visits every 2 months
Progressive disease
Progressive disease
requiring therapy
stops protocol
treatment

7. Progression-free survival
3yr PFS
W+W=33%
R4=60%
R4+RM=81%
1.0
0.9
0.8
Proportion of
patients
progression-
free
0.7
0.6
0.5
0.4
0.3
0.2
Events
Totals
W+W
108
181
0.1 R4 33 83
R4 + M 33
189
0.0 1 2 3 4 5
Years from randomisation
HR (Rituximab vs W+W) = 0.46, 95%CI = 0.33, 0.65, p<0.001
HR (Rituximab + M vs W+W) = 0.21, 95%CI = 0.15, 0.29, p<0.001
HR (Rituximab + M vs Rituximab) = 0.43, 95%CI = 0.24, 0.72, p=0.001

8. 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

9. 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

10. Intergroup study of rituximab vs watch and wait (Ardeshna, K et al)
Comparing “apples to oranges”
Not fair to look at time to “new” treatment between no treatment and rituximab
More interesting questions to possibly come from the study
Overall survival
Time to second treatment
Transformation rate
Response to initial treatment
Still open question if asymptomatic FL patients benefit from treatment -> expectant observation is still appropriate management.
My impressions.
Question of whether it delays time to second treatment. Will not be answered due to differences in initial treatment in the watch and wait group.

11. 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

12. 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
Reasonably homogenous population

13. 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
ECOG 4402 (RESORT) is a phase III randomized trial of rituximab in patients with low-tumor-burden indolent NHL.
Induction rituximab: Patients receive rituximab IV once a week for 4 weeks. Patients are re-evaluated 8 weeks after the completion of induction rituximab. Patients with a PR or CR to induction rituximab are randomized to 1 of 2 treatment arms.
Arm I (scheduled rituximab): Patients receive a single dose of rituximab IV once every 12 weeks until disease progression and in the absence of unacceptable toxicity. Patients are followed at least annually for 15 years from study entry.
Arm II (re-treatment rituximab): Patients receive rituximab IV once a week for 4 weeks upon disease progression, provided TTP is more than 6 months.
*Continue until treatment failure
No response to retreatment or PD within 6 months of R
Initiation of cytotoxic therapy or Inability to complete rx

14. 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

15. 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

16. 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)

17. Baseline Characteristics at Randomization
RR (N=134)
MR (N=140)
Age
59.5 (26-86)
58.9 (25-86)
Gender (M/F)
46/54%
PS (0/1)
84/15%
87/10%
Stage
III
56%
48% IV
43%
51%
FLIPI
0-1
15%
16% 2
46%
3-5
39%
41%
B2M elevated

18. 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

19. Primary Endpoint: Time to Treatment Failure

20. Time to First Cytotoxic Therapy

21. 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

22. Toxicity Second malignancies
9 RR arm
7 MR arm
One progressive multifocal leukoencephalopathy
MR arm
Deaths
10 RR arm
12 MR arm

23. 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

24. 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

25. Conclusions
Both strategies appear to delay time to chemotherapy compared to historical controls
How to interpret?
Given the excellent outcomes with RR
86% chemotherapy free at 3 years
Given the lack of QOL difference
Given fewer AE failures
Given fewer R doses required with RR
Rituximab retreatment is our recommended strategy if opting for rituximab monotherapy in LTB FL

26. Initial Treatment of Indolent Lymphoma
Expectant observation
Treatment
Rituximab
Immunochemotherapy
R-CHOP
R-CVP
R-Bendamustine
R-Fludarabine

27. Initial Treatment of Indolent Lymphoma
“R-CVP vs R-CHOP vs R-FM for the initial treatment of patients with advanced stage follicular lymphoma” - FOLL05 IIL trial
Federico M. et al
Fondazione Italiana Linfomi
Presented at the International Conference on Malignant Lymphoma
Lugano, Switzerland
June 15-18, 2011
Thank Dr. Federico for sharing slides

35. Indolent Lymphoma Watch and wait still reasonable
Initial treatment with single agent rituximab for low tumor burden FL
Prefer repeated treatment rather than maintenance rituximab
Initial immunochemotherapy with R-CHOP superior efficacy but more toxic
Thank you
Dr. Brad Kahl and Dr. M. Federico for slides
Dr. Andy Chen for Lugano meeting information