Jonathan W. Friedberg M.D., M.M.Sc.
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Transcript of Jonathan W. Friedberg M.D., M.M.Sc.
Jonathan W. Friedberg M.D., M.M.Sc.
University of Rochester Medical Center
Optimal frontline therapy for Follicular lymphoma:
Do we need to start with chemotherapy?
NO!
Follicular Lymphoma is Heterogeneous
Solal-Céligny et al. Blood. 104:1258
• Age (>60)Age (>60)• Ann Arbor stage (III-IV)Ann Arbor stage (III-IV)• Hemoglobin level (<120 g/L)Hemoglobin level (<120 g/L)• Serum lactate dehydrogenase (>ULN)Serum lactate dehydrogenase (>ULN)• Number of involved nodal sites (>4)Number of involved nodal sites (>4)
Follicular Lymphoma International Prognostic Index
FL-IPI clinical prognostic scoring system
Follicular LymphomaOverall Survival According to FL-IPI
Risk Group Factors (#) Patients (%) 5-Year OS (%) 10-Year OS (%)
Low 0–1 36 91 71
Intermediate 2 37 78 51
High ≥3 27 53 36
Time (Months)
Su
rviv
al P
rob
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0.8
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0 12 24 36 48 60 72 84 96 108 120
Low
Intermediate
High
P<10-4
0.0
Solal-Céligny et al. Blood. 104:1258
NEJM 351:2159
T cells
Macrophages
Macrophages
Dendritic cells
“Immune-response 1”
“Immune-response 2”
FavorableOS: > 10 years
UnfavorableOS: < 4 years
Biological heterogeneity of follicular lymphoma:Impact of nodal microenvironment
What is the aim of therapy in an incurable disease like follicular lymphoma?
• “Clinical benefit”
– Symptom relief (note most patients are not symptomatic)
– Quality of life
• Physical: decreased transfusions, decreased infections, etc.
• Psychological: “…better to be in remission…..”
– Change the natural history of disease
• Transformation, Overall survival
• Delay need for toxic therapy
Follicular LymphomaCommon Management Approach
After Staging Evaluation
Early stageAdvanced stage
Low Tumor Burden
Advanced stage
High Tumor Burden
Involved
Field RadiationObservation Therapy
TRANSFORMATION
Follicular LymphomaCommon Management Approach
After Staging Evaluation
Early stageAdvanced stage
Low Tumor Burden
Advanced stage
High Tumor Burden
Involved
Field RadiationObservation Therapy
TRANSFORMATION
“Watch and Wait” Strategy for Select Indolent NHL Patients
• Study of asymptomatic, advanced stage, low-grade NHL found no difference in OS between immediate chlorambucil vs delay of therapy until progression1
• Chlorambucil: 5.9 yr• Observation: 6.7 yr
• Current NCCN Guidelines recommend observation for select indolent NHL patients particularly if2:
• Advanced Age • Asymptomatic• Low Tumor Burden
1Ardeshna KM, et al. Lancet. 2003;362:516-522. 2NCCN guidelines. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.
Randomized Trial of Rituximab vs W&W in Patients With Stage II-IV Asymptomatic Non-Bulky FL
Ardeshna K, et al. Blood. 2010;116:5a. Abstract 6.
• Summary• Improved PFS in R arms (P < 0.001)• Improved time to initiation of new treatment in the R arms: 33
mo vs. not reached at 4 yr (P < 0.001)• No difference in OS (P > 0.5)• Quality of life no worse
Arm AArm A Arm BArm B Arm CArm C
Intervention Observe R x 4 wk R x 4 wk
Maintenance -- -- R q 2 mo x 2 yr
Number 186 84 192
CR/PR (%) 3/6 45/33 49/36
PFS 30% 60% 80%
TNT 33 mo NR NR
Ardeshna et al, ASH 2010 Plenary
Watchful waiting (WW) vs active treatment (AT): Lymphocare
2,727 patients with newly diagnosed FL enrolled
1,822 Stage III/IV
AT group n = 1,462
WW groupn = 270
R-monotherapy n = 232
R-chemotherapy n = 1,019
Other† n = 211
31 patients excluded*59 patients excluded*
Sinha et al, ASH 2011
Baseline characteristics (WW vs AT)
Characteristic, % WW
(n = 270)AT
(n = 1,462) p-value
Age, median years (range)61
(34–91)60
(22–97)0.9003
Male 45 49 0.2601FL grade: 1–2 79 68
0.0002
310 20
Mixed or unknown 11 12FLIPI risk: Good 18 14
< 0.0001 Intermediate 48 35 Poor 34 51
ECOG PS: 0 85 61< 0.0001
≥ 115 39
Patients receiving AT had higher percentages of stage IV, LDH > ULN, Hgb < 12 g/dL, and more than one extranodal site
Race, number of nodal sites and bone marrow involvement were not significantly different between groups (Pearson chi-square test, p > 0.05)
No differences in overall survivalat 5 years of follow-up
WW(n = 270)
R-mono(n = 232)
R-chemo(n = 1,019)
Other(n = 211)
Median follow-up time, months
60 57 59 62
Median OS Not reached
Deaths, % 18 25 20 18
SAKK 35/98 trial design: Standard vs. SAKK 35/98 trial design: Standard vs. Prolonged Rituximab in indolent NHLProlonged Rituximab in indolent NHL
375 mg/m375 mg/m² every 2 months x ² every 2 months x 44
n = 151n = 151
PDPDoffofftrialtrial
n = 202n = 202
ProlongedProlonged375 mg/m²375 mg/m²weekly x 4weekly x 4
StandardStandard
RSD,PR,CRSD,PR,CR
Characteristics of the patientsCharacteristics of the patients
IncludedIncluded RandomisedRandomised
(n = 202)(n = 202) (n = 151 )(n = 151 )
Median ageMedian age 5757 5757
PS 0-IPS 0-I 94 %94 % 97 %97 %
Stage III-IVStage III-IV 85 %85 % 85 %85 %
Involved BMInvolved BM 52 %52 % 50 %50 %
Bulky (Bulky (>> 5 cm) 5 cm) 53 %53 % 48 %48 %
Elevated LDHElevated LDH 37 %37 % 30 %30 %
Previous chemotherapyPrevious chemotherapy 68 %68 % 66%66%
Prolonged vs. standard rituximab EFS:Blood 103:4416 2004
Effect of schedule on event free survival:Effect of schedule on event free survival:Update 2009Update 2009
P = 0.0007 Median FU: 9.4 years
25% still in remissionat 8 years
EFS in chemo-naïve responders:EFS in chemo-naïve responders:Update 2009Update 2009
P<0.0001P<0.0001
45% of chemo-naiveresponders in remission
at 8 years
Overall Survival:Overall Survival:Update 2009Update 2009
P = 0.09
Conclusions: Ghielmini et alConclusions: Ghielmini et al
•Prolonged rituximab therapy is safe
•With 8 total doses of rituximab, the chance of being still in remission is ~25% at 5 and 8 years.
•Trend toward improved overall survival
•Excellent outcome for selected patients treated with rituximab alone.
•Would patients do better with chemotherapy?•Is it worth the risks?
E4402 (RESORT) Schema
Rituximabre-treatment atprogression*
375 mg/m2 qw 4
RANDOMIZE
Rituximab375 mg/m2 qw
4CR or PR
RituximabMaintenance*
375 mg/m2 q 3 months
*Continue until treatment failureNo response to retreatment or PD within 6 months of R
Initiation of cytotoxic therapy or Inability to complete rx
Kahl et al, ASH 2011
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
Primary Endpoint: Time to Treatment Failure
Time to First Cytotoxic Therapy
90% of patients did not require cytotoxic therapy for first 5 years of
diagnosis
Conclusions: RESORT
• In this study of previously untreated low tumor burden FL:– Rituximab retreatment was as effective as
maintenance rituximab for time to treatment failure
– No benefit in QOL or anxiety at 12 months with MR
– Virtually all of these selected patients did extremely well without chemotherapy
Indolent CD20+ lymphoma
Central pathology
review
RANDOMIZATION
Rituximab x 4
Rituximab x 4
+ IFN x 5 weeks
EVALUATION
Rituximab x 4
+ IFN x 5 weeks)
SD, PD off protocol therapy
CR, CRu PR MR
Rituximab 375mg/m2 i.v. day 1
IFN-2a
3.0 MIU/day s.c. daily (Week 1)
4.5 MIU/day s.c. daily (Weeks 2–5)
Rituximab x 4
Randomized phase III trial ML16865
CHEMOTHERAPY
Kimby et al, ASH 2012
Overall survival: ITT follicular lymphoma patients
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6 18 30 36 42 480 12 24 54 60 66 72 78 84
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Patients at risk:
Rituximab only
Rituximab + IFN
Time (months)
% pts with event Median 95% CI p value
Rituximab 13% NE NE
Rituximab + IFN 10% NE NE 0.4289
p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)
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6 18 30 36 42 480 12 24 54 60 66 72 78 84
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Patients at risk:
Rituximab only
Rituximab + IFN
Time to treatment failure: ITT follicular lymphoma patients (n=257)
Time (months)
% pts with event Median 95% CI p value
Rituximab 67% 23.2 18.1–31.3
Rituximab + IFN 66% 31.7 21.9–43.3 0.3627
p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)
Many patients with follicular lymphoma do not require chemotherapy
• Watch and wait– No overall survival benefit with early treatment– No change in transformation with early treatment
• Rituximab:– Highly active therapy in a variety of schedules– Long responses and outstanding survival
Phase 2 study of lenalidomide and rituximab for follicular lymphoma
Pre-Treatment Post-Treatment
Positive Negative Positive Negative
N 44 1 3 42*
% 98% 2% 7% 93%
1. Juweid, M. et al. JCO. 2007. 25(5): 571-578.
Lenalidomide 20 mgRituximab 375 mg
3 year PFS: 81%
PET Imaging Results
Progression-free survival
Fowler et al, ASH 2012
RELEVANCE Study Design(Rituximab and LEnalidomide versus Any ChEmotherapy)
1st line FL
N=1000R
R2
R + Chemo
R2 Maintenance
Rituximab Maint.
• R+Chemo:•Investigator’s choice of R-CHOP, R-CVP, BR
• Lenalidomide 20mg for 6 cycles, then 10mg if CR
Thank you!Questions?