Copyright © 2010, Research To Practice, All rights reserved. Part IV: Follicular Lymphoma Chronic Lymphocytic Leukemia Monday, October 11, 2010 7:30 PM.

Copyright © 2010, Research To Practice, All rights reserved.

Part IV: Follicular LymphomaChronic Lymphocytic LeukemiaMonday, October 11, 20107:30 PM - 8:30 PM ET

Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

Jonathan W Friedberg, MD, MMScAssociate Professor of Medicine and HematologyChief, Hematology/Oncology DivisionJames P Wilmot Cancer CenterUniversity of RochesterRochester, New York

Brad S Kahl, MDAssociate ProfessorDirector, Lymphoma ServiceUniversity of Wisconsin School of Medicine and Public HealthAssociate Director for Clinical ResearchUW Carbone Cancer CenterMadison, Wisconsin

Neil Love, MDModeratorResearch To PracticeMiami, Florida

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Genzyme Corporation, Lilly USA LLC, Millennium Pharmaceuticals Inc, Monogram BioSciences Inc, Myriad Genetics, Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

Disclosures for Jonathan W Friedberg, MD, MMSc

Advisory Committee Genentech BioOncology

Consulting Agreements

Allos Therapeutics, Astellas Pharma US Inc, Calistoga Pharmaceuticals Inc, EMD Serono Inc, Seattle Genetics

Data Safety Monitoring Board

Lilly USA LLC

Research Support Cephalon Inc, Millennium Pharmaceuticals Inc

Stock Ownership Bristol-Myers Squibb Company

Disclosures for Brad S Kahl, MD

Advisory Committee

Celgene Corporation, Cephalon Inc, Genentech BioOncology, GlaxoSmithKline, Millennium Pharmaceuticals Inc, Roche Laboratories Inc

Paid Research N/A

Speakers Bureau N/A

N/A = Not Applicable

Bendamustine Plus Rituximab Is Superior in Respect of Progression Free Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany).Rummel MJ et al. Proc ASH 2009;Abstract 405.

Rituximab Maintenance for 2 Years in Patients With Untreated High Tumor Burden Follicular Lymphoma After Response to Immunochemotherapy. Salles GA et al. Proc ASCO 2010;Abstract 8004.

Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.Fowler N et al. Proc ASH 2009;Abstract 933. Complete Response Rates With Lenalidomide Plus Rituximab for Untreated Indolent B-cell Non-hodgkin's Lymphoma.Fowler NH et al. Proc ASCO 2010; Abstract 8036.

Phase III Randomized Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With Chronic Lymphocytic Leukemia.Knauf WU et al. J Clin Oncol 2009;27(26):4378-84.

Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: A randomised, open-label, phase 3 trial.Hallek M et al. Lancet 2010;376(9747):1164-74.

Bendamustine Combined With Rituximab (BR) in First-line Therapy of Advanced CLL: A Multicenter Phase II Trial of the German CLL Study Group (GCLLSG).Fischer K et al. Proc ASH 2009;Abstract 205.

Case History: Dr Kahl

• A 63-year-old woman with grade 1 stage IV follicular lymphoma

– Asymptomatic

– Maximum LN size 6 cm x 3 cm right iliac region

– Bone marrow involvement with 10% FL cells

– Normal LDH

1) Would you recommend treatment for this patient at this time?

51%

49%

47% 48% 49% 50% 51% 52%

Yes

No

Case History: Dr Kahl (continued)

• Patient declines treatment at this time

– Followed q-3 months

– Moderate progression over 1-year with fatigue and decreased stamina

• Patient agrees to treatment now

2) How would you treat the patient at this time?

5%

40%

10%

42%

3%

0%

0% 10% 20% 30% 40% 50%

R-CVP/R-CHOP

R-CVP/R-CHOP with maintenance rituximab

R-bendamustine

R-bendamustine with maintenance rituximab

R-chemo followed by radioimmunotherapy

Single-agent rituximab


• Patient received R-CHOP and went into CR

• Currently receiving maintenance rituximab


Follicular Lymphoma in the United States: First Report of the National LymphoCare Study

Friedberg JW et alJ Clin Oncol 2009;27(8):1202-8.

Initial Treatment in US: All Patients with Follicular Lymphoma

Friedberg JW et al. JCO 2009; 27(8):1202-8.

National Patterns of Care Study with 43 US-Based Medical Oncologists: 186 Consecutive Patients with Newly Diagnosed FL

For a patient with newly diagnosed FL, what is currently your usual preferred up-front treatment?

CI (n=25) PO (n=100)

58 yo 75 yo 58 yo 75 yo

R-CHOP 48% 4% 32% 5%

R-bendamustine 32% 72% 36% 34%

R-CVP 16% 16% 26% 32%

R-fludarabine 0% 0% 3% 4%

R monotherapy 0% 4% 1% 24%

Other 4% 4% 2% 1%

CI, Clinical Investigator; PO, Practicing Oncologist

National Patterns of Care Survey of US Medical Oncologists, 9/2010

Rituximab Maintenance for 2 Years in Patients with Untreated High Tumor Burden Follicular Lymphoma After Response to ImmunochemotherapySalles GA et al.Proc ASCO 2010;Abstract 8004.

Rituximab Maintenance

(n = 505)Observation

(n = 513)Hazard Ratio p-value

2-Year PFS 82% 66% 0.50 <0.0001

Effect on PFS with Rituximab Maintenance versus Observation in Phase III PRIMA Trial (N = 1,018)

Salles GA et al. Proc ASCO 2010;Abstract 8004.

Do you currently use rituximab maintenance for patients receiving R-chemotherapy as front-line therapy for FL?

CI (n = 25) PO (n = 100)

Yes, always or almost always 36% 53%

Yes, sometimes 36% 32%

Yes, rarely 20% 7%

No 8% 8%



Which of the following best describes how long you generally recommend that R maintenance be administered?

CI (n = 23) PO (n = 92)

2 years 83% 74%

1 to < 2 years 9% 13%

< 1 year 4% 3%

Indefinitely (until progression) 4% 9%

Other 0% 1%



Which of the following R maintenance regimens do you generally use?

CI (n = 23) PO (n = 92)

1 dose q 3 mos for 2 yrs 39% 32%

1 dose q 8 wks for 2 yrs 35% 16%

1 dose q 2 mos for 4 cycles 13% 1%

4 wkly doses q 6 mos for 2 yrs 9% 41%

1 dose q 3 mos until disease progression 4% 10%



RESORT: Phase III Trial of Rituximab for Patients with Low Tumor Burden Indolent Non-Hodgkin’s Lymphoma (NHL)

Estimated enrollment: 389 (closed)

Rituximab IV once a week for 4 weeks upon

disease progression

Rituximab IV once every 13 weeks until disease

progression

Stage III/IV NHL with low tumor burden treated with induction

rituximab

R

www.clinicaltrials.gov, October 2010.


Bendamustine Plus Rituximab versus R-CHOP as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III German Study

Rummel MJ et al.ASCO/ASH Joint Session 2010; Abstract 405.

BR (n = 260)

R-CHOP (n = 253)

Hazard Ratio p-value

Overall Response

92.7% 91.3%Not

ReportedNot

Reported

Complete Response

39.6% 30.0%Not

Reported0.0262

PFS (All Patients)

54.9 months 34.8 months 0.57 0.00012

PFS (Patients with FL)

Not Reached 46.7 months 0.63 0.0281

Rummel MJ et al. ASCO/ASH Joint Session 2010.

Efficacy Data: BR versus R-CHOP in Indolent Lymphomas

Rummel MJ et al. ASCO/ASH Joint Session 2010.

All Grades BR (n = 260) R-CHOP (n = 253) p-value

Alopecia — +++ <0.0001

Paresthesias 6.9% 28.9% <0.0001

Stomatitis 6.2% 18.6% <0.0001

Erythema 16.2% 9.1% 0.0122

Allergic Reaction (skin) 15.4% 5.9% 0.0003

Infectious Complications

36.9% 50.2% 0.0025

Sepsis 0.38% 3.2% 0.0190

Non-Hematologic Safety Data: BR versus R-CHOP

When administering bendamustine ± rituximab for younger patients (≤65 years) with FL, what dose and schedule do you generally use?

CI (n = 25) PO (n = 100)

90 mg/m2 IV on d 1 and 2 q28 d 76% 24%

120 mg/m2 IV on d 1 and 2 q21 d 8% 26%

90 mg/m2 IV on d 1 and 2 q21 d 8% 20%

120 mg/m2 IV on d 1 and 2 q28 d 0% 18%

Other 0% 2%

I have not administered B ± R for younger patients with FL

8% 10%



Erik Rupard, MDFort Gordon, GA

In a patient with CD20-dim or negative FL, what is the role of rituximab as part of initial induction or as maintenance?

Assuming this patient needs treatment, is rituximab-bendamustine the right choice?

Neal Fishbach, MDFairfield, CT

Is ofatumumab-maintenance an option for a patient with FL who is in remission with front-line rituximab-bendamustine and has been having very severe hypersensitivity reactions with rituximab.

Case History: Dr Friedberg

• A 45-year-old woman presents with CVA and advanced stage FL

– R-CHOP x 6

– R-maintenance x 2 years

• 1 year later, lung mass biopsy-confirmed recurrent Grade 1 FL

• Treated on study with VBR (bortezomib, bendamustine, rituximab) x 6

3) Patient in remission after 6 cycles of VBR. How would you manage the patient at this time?

5%

22%

16%

19%

38%

0% 5% 10% 15% 20% 25% 30% 35% 40%

Proceed with ASCT

Refer for allo-SCT

Observation

Rituximab maintenance

Bortezomib maintenance

Case History: Dr Friedberg (continued)

• Patient observed and remains in remission two years after VBR therapy


Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL StudyFowler N et alProc ASH 2009;Abstract 933.

• 35% had high risk FLIPI at diagnosis• Patients had received a median of two prior therapies• 39% were refractory to their last rituximab-containing

therapy

Response Rates with Bortezomib, Bendamustine and Rituximab (VBR) in Relapsed-Refractory FL: Phase II VERTICAL Study (N = 63)

Overall Response

Complete Response

Partial Response

84% 47% 37%

Fowler N et al. Proc ASH 2009;Abstract 933.

Adverse Events in Relapsed-Refractory FL with Bortezomib, Bendamustine and Rituximab (VBR): Phase II VERTICAL Study

All Grades Grade 3 Grade 4

Nausea 79% 3% 0%

Vomiting 44% 5% 0%

Fatigue 65% 10% 0%

Diarrhea 57% 3% 0%

Peripheral Neuropathy 27% 6% 0%

Grade 3-4 Anemia Grade 3-4 NeutropeniaGrade 3-4

Thrombocytopenia

3% 25% 6%

Fowler N et al. Proc ASH 2009;Abstract 933.

Margaret Deutsch, MDRaleigh, NC

What should be the preferred regimen for an octogenarian who has been previously treated with R-CVP for follicular lymphoma, and now needs re-treatment?

Case History: Dr Kahl

An 82-year old man, with 10-year history of untreated CLL, develops B symptoms

– WBC 300,000/mm3, Hb 9.0 g/dL, Platelets 95,000/mm3

– Bulky cervical adenopathy and palpable splenomegaly

4) What other information is necessary at this time?

15%

6%

6%

40%

33%

0% 10% 20% 30% 40% 50%

Bone marrow evaluation

CLL FISH panel

CD38 status

ZAP-70 status

IgVH mutational status


• A bone-marrow evaluation is done and shows diffuse involvement of bone-marrow with CLL (80% of marrow)

• FISH panel reveals del11q and trisomy 12

5) How would you treat this patient?

1%

15%

13%

47%

8%

4%

12%

0% 10% 20% 30% 40% 50%

Chlorambucil

Fludarabine

Bendamustine

Rituximab-bendamustine

FCR

FR

Other

What is your usual preferred initial regimen for a patient with CLL requiring treatment?

CI (n = 24) PO (n = 100)

60 yo 75 yo 60 yo 75 yo

FCR 68% 4% 68% 12%

FR 28% 52% 17% 33%

R-bendamustine 4% 40% 8% 29%

Alemtuzumab 0% 0% 0% 0%

Other 0% 4% 7% 26%




Addition of Rituximab to Fludarabine and Cyclophosphamide in Patients with Chronic Lymphocytic Leukaemia: A Randomised, Open-Label, Phase III Trial

Hallek M et al.Lancet 2010;376(9747):1164-74.

Hallek M et al. Lancet 2010;376(9747):1164-74.

FCR(n = 408)

FC(n = 409)

Hazard Ratio p-value

3-Year OS 87% 83% 0.67 0.01

Impact of FCR on Overall Survival in CLL


Efficacy and Safety of Oral Fludarabine Phosphate in Previously Untreated Patients With Chronic Lymphocytic Leukemia

Rossi JF et al.J Clin Oncol 2004;22(7):1260-7.

Efficacy IWCLL Criteria NCI Criteria

Overall response 71.6% 80.2%

Complete remission 37.0% 12.3%

Partial remission 34.6% 67.9%

Rossi JF et al. J Clin Oncol 2004;22(7):1260-7.

Efficacy and Safety of Oral Fludarabine (N = 81)

WHO Toxicity Any Grade Grade III/IV

Granulocytopenia 77.8% 32.1%

Anemia 24.7% 9.9%

Thrombocytopenia 24.7% 4.9%


Low-Intensity Fludarabine, Cyclophosphamyde, Rituximab (FCR) as Front-Line Treatment for Follicular Lymphoma. Efficacy and Toxicity Profile of the Oral Versus Intravenous Administration

Marin-Niebla A et al.Proc ASH 2009;Abstract 2690.

Efficacy FCRiv FCRoral p-value

Overall response 89.2% 100% 0.03

Complete remission 54.0% 70.9% 0.01

Marin-Niebla A et al. Proc ASH 2009;Abstract 2690.

Efficacy and Safety of FCR IV versus FCR Orally Administered (N = 86)

Toxicity FCRiv FCRoral

Neutropenia (Gr 3/4) 56.7% 65.3%

Infection rate 35.1% 30%

Richard Polkinghorn, MDBrunswick, ME

For a patient with newly diagnosed CLL with an adverse FISH panel, would the choice of initial induction be different than if the patient did not have the adverse marker?

Neal Fishbach, MDFairfield, CT

Where do we place ofatumumab in the treatment algorithm of CLL?

Dr. Steven Paul, MD, PhD

When would you treat a patient with CLL, no symptoms, slightly enlarged spleen, not palp node; WBC 19,000 with 70% lymphs, nl platelets, and Hgb of 11? Patient has an 85% ZAP 70 score.

Copyright © 2010, Research To Practice, All rights reserved. Part IV: Follicular Lymphoma Chronic Lymphocytic Leukemia Monday, October 11, 2010 7:30 PM.

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