13th Annual Hematology & Breast
Cancer Update
Update in Lymphoma
Craig Okada, MD, PhD
Assistant Professor, Hematology
January 20, 2010
Governors Hotel, Portland Oregon
Initial Treatment of Indolent Lymphoma


Expectant observation
Treatment
» Rituximab
» Immunochemotherapy
–R-CHOP
–R-CVP
–R-Bendamustine
–R-Fludarabine
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
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
19
R-fludarabine based
11
R-other
11
Chemotherapy alone
4
Radiation alone
5
Freiberg et al, J Clin Oncol 2006;24:7527
ASH 2010 - 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?
Thank Dr. Ardeshna for sharing his slides
R
A
N
D
O
M
I
S
A
T
I
O
N
ARM A
Watch and Wait
Clinic visits
Continued
follow up
ARM B
Rituximab Induction
ARM C
Rituximab Induction
& maintenance
Progressive disease
requiring therapy
stops protocol
treatment
Compulsory
CT scan
CT scan
only if
clinical CR
Compulsory
CT scan
Bone marrow for histology and MRD only if CT shows CR
Progression-free survival
3yr PFS
W+W=33%
R4=60%
R4+RM=81%
1.0
0.9
0.8
Proportion 0.7
of
0.6
patients
progression- 0.5
free
0.4
0.3
Events Totals
181
W+W 108
33
83
R4
189
R4 + M 33
0.2
0.1
0.0
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
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
0.2
% not requiring Rx at 3yr
W+W=48%
R4=80%
R4+RM=91%
Totals
W+W Events
83
187
R4
19
84
R4 + M 19
192
0.1
0.0
0
1
2
3
Years from randomisation
4
5
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
Overall survival
1.0
0.9
% of
patients
alive
0.8
0.7
3yr OS=95%
0.6
0.5
0.4
0.3
0.2
W+W
R4
R4 + M
0.1
0.0
0
1
Events Totals
9
187
4
84
8
192
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
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.
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
eastern cooperative
oncology group
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
eastern cooperative oncology group
E4402 (RESORT) Schema
Rituximab
375 mg/m2
qw  4
CR or PR
R
A
N
D
O
M
I
Z
E
Rituximab
Maintenance*
375 mg/m2
q 3 months
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
13
eastern cooperative oncology group
E4402 Major Eligibility
 Indolent NHL





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
eastern cooperative oncology group
E4402 (RESORT) Objectives
 Primary
 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
eastern cooperative oncology group
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)
eastern cooperative oncology group
Baseline Characteristics at Randomization
RR (N=134)
MR (N=140)
59.5 (26-86)
58.9 (25-86)
Gender (M/F)
46/54%
46/54%
PS (0/1)
84/15%
87/10%
• III
56%
48%
• IV
43%
51%
• 0-1
15%
16%
• 2
46%
43%
• 3-5
39%
41%
B2M elevated
46%
39%
Age
Stage
FLIPI
eastern cooperative oncology group
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
eastern cooperative oncology group
Primary Endpoint: Time to Treatment Failure
eastern cooperative oncology group
Time to First Cytotoxic Therapy
eastern cooperative oncology group
Toxicity
RR
Grade 3
RR
Grade 4
MR
Grade 3
MR
Grade 4
Neutrophils
--
2
--
--
Platelets
1
--
--
--
Fever w/o neutropenia
--
--
1
--
Infection
--
--
1
--
Fatigue
1
--
3
--
LV dysfunction
--
--
1
--
Hypertension
1
--
1
--
Syncope
1
--
--
--
Insomnia
--
--
1
--
Hearing loss
--
--
1
--
Larynx pain
--
--
1
--
TOTALS
4
2
10
0
eastern cooperative oncology group
Toxicity
 Second malignancies
 9 RR arm
 7 MR arm
 One progressive multifocal leukoencephalopathy
 MR arm
 Deaths
 10 RR arm
 12 MR arm
eastern cooperative oncology group
Treatment Information
 Analysis of # doses rituximab received, including 4
induction doses
Min
RR (n = 120)
4
MR (n = 130)
5
Max
16
Median
4
Mean
4.5
31
15.5
15.8
eastern cooperative oncology group
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
eastern cooperative oncology group
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
eastern cooperative oncology group
Initial Treatment of Indolent Lymphoma


Expectant observation
Treatment
» Rituximab
» Immunochemotherapy
–R-CHOP
–R-CVP
–R-Bendamustine
–R-Fludarabine
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
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