follicular lymphoma transformed lymphoma diffuse large b-cell lymphoma

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


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)


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)




R-CHOP


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


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


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


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



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


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


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






Faculty





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






Faculty




follicular lymphoma transformed lymphoma diffuse large b-cell lymphoma

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