Follicular LymphomaTransformed Lymphoma
Diffuse Large B-Cell Lymphoma
John P. Leonard, M.D.Richard T. Silver Distinguished Professor of Hematology
and Medical Oncology
Professor of Medicine, Weill Cornell Medical College
Associate Director, Weill Cornell Cancer Center
Copyright © 2011 Research To Practice. All rights reserved.
Interest in Topics Related to the Treatment of Patients with FL (Percent Responding 9 or 10)
30%
32%
33%
34%
35%
52%
0% 10% 20% 30% 40% 50% 60%
Treatment of relapsed FL
Rituximab maintenance
Initial therapy for patients >70 yo
“Watch and wait” vs rituximabmonotherapy
Initial therapy for patients <70 yo
New agents/regimens
Copyright © 2011 Research To Practice. All rights reserved.
31%
31%
35%
36%
38%
48%
0% 10% 20% 30% 40% 50% 60%
Radioimmunotherapy
R-CHOP alternatives
Post-transplantrelapse
Cell originbiomarkers/risk
New agents/regimens
Therapy for relapsedDLBCL
Interest in Topics Related to the Treatment of Patients with DLBCL (Percent Responding 9 or 10)
Copyright © 2011 Research To Practice. All rights reserved.
What is your usual induction regimen for an otherwise healthy 60-year-old patient who requires initial systemic treatment for FL?
3%
5%
8%
24%
9%
21%
9%
1%
20%
0% 5% 10% 15% 20% 25% 30%
Other
FCR
Rituximab monotherapy
R-CVP
BR (B at 90 mg/m2 d1, d2 q3wk)
BR (B at 90 mg/m2 d1, d2 q4wk)
BR (B at 120 mg/m2 d1, d2 q3wk)
BR (B at 120 mg/m2 d1, d2 q4wk)
R-CHOP
Copyright © 2011 Research To Practice. All rights reserved.
Do you generally recommend R maintenance after R-chemotherapy?
7%
26%
67%
0% 20% 40% 60% 80%
No
Yes,sometimes
Yes,generally
Follicular LymphomaTransformed Lymphoma
Diffuse Large B-Cell Lymphoma
John P. Leonard, M.D.Richard T. Silver Distinguished Professor of Hematology
and Medical Oncology
Professor of Medicine, Weill Cornell Medical College
Associate Director, Weill Cornell Cancer Center
2 opposite FL management approaches:
Aggressive strategies
– Objective of treatment – cure or extended survival
– CHOP-R (B-R) + R maintenance or RIT or other
– Hoping that more intensive strategy will pay off
– Downside – more toxicity in short term
Gentler strategies
– Objective of treatment – disease control, less toxicity
– Rituximab + other biologics
– Hoping that less intensity will improve QOL
– Downside – is it less effective in long term?
Bendamustine-Rituximab (B-R) vs CHOP-R
Bendamustine-RituximabBendamustine-Rituximab
CHOP-RituximabCHOP-Rituximab
FollicularFollicularWaldenström‘sWaldenström‘sMarginal zoneMarginal zoneSmall lymphocyticSmall lymphocyticMantle cellMantle cell
RRRR
StiL NHL 1-2003StiL NHL 1-2003
Bendamustine 90 mg/mBendamustine 90 mg/m22 day 1+2 + R day 1, max 6 cycles, q 4 wks. day 1+2 + R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks.CHOP-R, max 6 cycles, q 3 wks.
Rummel et al.: Rummel et al.: BloodBlood 114: 168 (abstr #405), 2009 114: 168 (abstr #405), 2009
B-R vs CHOP-R - Toxicities (all CTC-grades)B-R vs CHOP-R - Toxicities (all CTC-grades)
B-R (n = 260) CHOP-R (n = 253)
(no. of pts) (no. of pts) p-value
Alopecia – +++ < 0.0001
Paresthesias 18 73 < 0.0001
Stomatitis 16 47 < 0.0001
Skin (erythema) 42 23 = 0.0122
Allergic reaction (skin)
40 15 = 0.0003
Infectious complications
96 127 = 0.0025
- Sepsis 1 8 = 0.0190
Median Progression-Free Survival Median Progression-Free Survival
Rummel et al.: Rummel et al.: BloodBlood 114: 168 (abstr #405), 2009 114: 168 (abstr #405), 2009
BR, 54.9 months vs CHOP-R, 34.8 months
Hazard ratio, 0.57
p-value = 0.00012
Progression-Free Survival: Subentities
BR vs CHOP-R:
• Follicular, p = 0.0281
• Mantle cell, p = 0.0146
• Marginal zone, p = 0.6210
• Waldenström, p = 0.0024
Rummel et al.: Rummel et al.: BloodBlood 114: 168 (abstr #405), 2009 114: 168 (abstr #405), 2009
Randomized Trial of Rituximab VersusWatch-and-Wait in Stage II-IV Asymptomatic
Nonbulky Follicular Lymphoma: Study Design
Randomized Trial of Rituximab VersusWatch-and-Wait in Stage II-IV Asymptomatic
Nonbulky Follicular Lymphoma: Study Design
Ardeshna et al. ASH 2010; abstract 6.Ardeshna et al. ASH 2010; abstract 6.
Arm A Watch-and-Wait
Arm BRituximab 375 mg/m2/week × 4
Arm CRituximab 375 mg/m2/week ×
4→375 mg/m2 q 2 months × 12
Eligibility criteria:•Stage II-IV FL•Grade 1-3a•Asymptomatic•ECOG PS 0/1•Low tumor burden
RANDOMIZE
(n = 187)
(n = 84)
(n = 192)
Primary endpoint: time to initiation of new therapy
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL:
Efficacy and safety
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL:
Efficacy and safety
Ardeshna et al. ASH 2010, Abstract 6.
Response at 25 monthsArm A
(N = 187)Arm B
(N = 84)Arm C
(N = 192)
ORR 8% 53% 79%
CR/CRu 4% 40% 70%
PR 4% 13% 9%
Initiated new treatment 44% 23% 10%
HR for median TTNT0.37
(34 months)0.20 0.57
No treatment at 3 years 48% 80% 91%
3-year PFS 33% 60%81%
(P < 0.001 vs. A)
3-year OS 95% (no significant difference)
Safety
Serious adverse events 14 6 25
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL
With permission from Ardeshna et al. ASH 2010, Abstract 6.
HR (Rituximab vs W+W) = 0.37, 95% CI = 0.25, 0.56, p < 0.001HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p < 0.001HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p = 0.10
Proportion of patients with
no new treatment initiated
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL
With permission from Ardeshna et al. ASH 2010, Abstract 6.
HR (Rituximab vs W+W) = 0.46, 95% CI = 0.33, 0.65, p < 0.001HR (Rituximab + M vs W+W) = 0.21, 95% CI = 0.15, 0.29, p < 0.001HR (Rituximab + M vs Rituximab) = 0.43, 95% CI = 0.24, 0.72, p = 0.001
PRIMA: Study designPRIMA: Study design
PD/SDoff study
Rituximab maintenance375 mg/m2
every 8 weeks for 2 years‡
Observation‡
CR/CRuPR
Random 1:1*
Immunochemotherapy8 x Rituximab
+8 x CVP or
6 x CHOP or6 x FCM
High tumor burden
untreated follicular
lymphoma
INDUCTION MAINTENANCE
Registration
* Stratified by response after induction, regimen of chemo and geographic region‡ Frequency of clinical, biological and CT-scan assessments identical in both armsFive additional years of follow-up
Salles et al, ASH 2010.
Primary endpoint (PFS): 36 monthsfollow-up
Primary endpoint (PFS): 36 monthsfollow-up
Salles GA et al. Proc ASH 2010;Abstract 1788.
Observationn = 513
R Maintenancen = 505
3-yr progression-free survival (PFS)
58% 75%
Hazard ratio (95% CI) 0.55 (0.44-0.68)
p-value <0.0001
Safety during rituximab maintenanceSafety during rituximab maintenance
Observationn = 508
Rituximabn = 501
Any adverse event 35% 52%
Grade ≥2 infections 22% 37%
Grade 3/4 adverse events 16% 23%
Grade 3/4 neutropenia <1% 4%
Grade 3/4 infections <1% 4%
Salles GA et al. Proc ASH 2010;Abstract 1788.
FIT Study Schema
First-line therapy with chlorambucil, CVP, CHOP,
CHOP-like, fludarabine combination, or rituximab
combination
INDUCTION
90Y-ibritumomab (n = 207)
Rituximab 250 mg/m2 IV on day −7 and day 0 +
90Y-ibritumomab 14.8 MBq/kg (0.4 mCi/kg)[max 1184 MBq (32 mCi)]
on day 0
CONSOLIDATION
NRPD
CR/CRu or PR
Not eligible
RANDOMIZATION
RANDOMIZATION
No further treatment (n = 202)
CONTROL
Start of study
CVP = cyclophosphamide, vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CR = complete response; CR/u = unconfirmed CR; PR = partial response; NR = no response; PD = progressive disease. Morschhauser et al. J Clin Oncol 2008;26:5156-5164.
6-12 weeks after last dose of induction
Patients with previously untreated FL
Hagenbeek et al, ASH 2010.
0
25
50
75
100
0 12 24 36 48 60
Cu
mu
lati
ve P
erce
nta
ge
90Y-ibritumomabControl
207202
108144
N F
90Y-ibritumomab
Control
207 174
117
133
83
113
67
98
65
80
46
At risk:PFS from Time of Randomization (Months)
Overall PFS for Treatment Groups
90Y-ibritumomab: n = 207Median PFS: 49 mo
Control: n = 202 Median PFS: 15 mo
The 5-year overall PFS was 29% in the control arm compared with 47% in the 90Y-ibritumomab
armHR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001
202
With permission from Hagenbeek et al, ASH 2010.
R-ACVBP (vs R-CHOP in DLBCL < 60 aaIPI = 1)
Increased dose-intensity (mg/
m2.wk) compared to R-CHOP
Sequential consolidation using second-line agents
– Ifosfamide, VP16, Ara-C
CNS prophylaxis
– High-dose IV Methotrexate
– Intrathecal Methotrexate
R-ACVBP (every two weeks)
– PDN: 60 mg/m2; d1-d5
– Ritux: 375 mg/m2 ; d1
– Doxo: 75 mg/m2; d1
– CPM: 1200 mg/m2; d1
– Vindesine: 2 mg/m2; d1 & d5
– Bleomycin 10 mg; d1 & d5
– Methotrexate (IT) 15 mg; d1
– G-CSF 5 µg/kg/d; d6-d13
Methotrexate
– 3 g/m2; d1-d15
R-Ifosfamide-VP16
– Ritux: 375 mg/m2; d1
– Ifosfamide: 1.5g/m2; d1
– VP16: 300 mg/m2; d1
Ara-C
– 100 mg/m2 sc, d1-d4
x 2.25 x 2.4 x 1.5
Doxo: 37,5 CPM: 600 Rituximab: 187
Doxo: 16.7 CPM: 250 Rituximab: 125
R-ACVBP
R-CHOP
LNH 03-2B study
*No radiotherapy in both arms
ClinicalTrials.gov: NCT00140595
R60 3 12 15 189 21
R-ACVBP 14
R-CHOP 21
Wks
MTX R-IFM-VP16 Ara-C
0 2 4 6 10 14 24 Wks
4 IT-MTX
New DLBCLAge 18-59aaIPI 1
380 patients have been included:
– 196 (R-ACVBP) and 184 (R-CHOP)
Pathological review: 344 patients (91%)
Median follow-up: 44 months
Analyses are on an intent-to-treat basis.
R-ACVBP (vs R-CHOP in DLBCL < 60 aaIPI = 1)
ORR 92% vs 88%
Recher et al, ASH 2010.
• 3-Year Progression-Free Survival:
– R-ACVBP (n = 196), 87%
– R-CHOP (n = 183), 73%
– p = 0.0015
– HR = 0.482
• 3-Year Overall Survival:
– R-ACVBP (n = 196), 92%
– R-CHOP (n = 183), 84%
– p = 0.0071
– HR = 0.439
Toxicity (grade ≥ 3)R-ACVBPR-CHOP
Toxic deaths: 5/196 (2.6%) in the R-ACVBP arm vs 3/184 (1.6%) in the R-CHOP arm
Recher et al, ASH 2010.
Beyond R-CHOP-21 in younger patients with DLBCL
R-ACVBP R-EPOCH R-CHOP-14 Auto SCT in first remission R-CHOP + novel agents
– Epratuzumab
– Bortezomib
– Lenalidomide
– Enzastaurin
– Azacitidine
Copyright © 2011 Research To Practice. All rights reserved.
What Clinicians Want to Know
A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical
Management of Select Hematologic Cancers
Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois
Faculty
Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD
ModeratorNeil Love, MD
Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek
Copyright © 2011 Research To Practice. All rights reserved.
What schedule of R maintenance do you use?
5%
29%
33%
33%
0% 10% 20% 30% 40%
I don't use
MaintenanceR q6m
MaintenanceR q3m
MaintenanceR q2m
Copyright © 2011 Research To Practice. All rights reserved.
What Clinicians Want to Know
A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical
Management of Select Hematologic Cancers
Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois
Faculty
Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD
ModeratorNeil Love, MD
Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek
Copyright © 2011 Research To Practice. All rights reserved.
Do you use interim PET scans in diffuse large B-cell lymphoma?
18%
33%
49%
0% 10% 20% 30% 40% 50% 60%
No
Yes, in selectpatients
Yes, in mostpatients
Copyright © 2011 Research To Practice. All rights reserved.
What Clinicians Want to Know
A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical
Management of Select Hematologic Cancers
Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois
Faculty
Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD
ModeratorNeil Love, MD
Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek
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