Part VII – Non-Hodgkin Lymphoma/Chronic Lymphocytic LeukemiaTuesday, July 26, 20117:30 PM – 8:30 PM ET

RTP TV: An 8-Part Live CME Webcast Series

Stephanie A Gregory, MDThe Elodia Kehm Chair of HematologyProfessor of MedicineDirector, Section of HematologyRush University Medical CenterChicago, Illinois

John P Leonard, MDRichard T Silver Distinguished Professor of Hematology and Medical OncologyProfessor of Medicine, Weill Cornell Medical CollegeNew York, New York

Neil Love, MDResearch 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: Allos Therapeutics, Amgen Inc, Astellas Pharma Global Development 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, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Millennium: The Takeda Oncology Company, Mundipharma International Limited, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi and Seattle Genetics

Disclosures for Stephanie A Gregory, MD

Advisory Committee

Amgen Inc, Cephalon Inc, Genentech BioOncology, Novartis Pharmaceuticals Corporation, Spectrum Pharmaceuticals Inc

Speakers Bureau Cephalon Inc

Disclosures for John P Leonard, MD

Consulting Agreements

Biogen Idec, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, EMD Serono Inc, Genentech BioOncology, GlaxoSmithKline, Millennium: The Takeda Oncology Company, Novartis Pharmaceuticals Corporation, Pfizer Inc, Sanofi

Agenda — Non-Hodgkin Lymphoma/Chronic Lymphocytic Leukemia

• Module 1: Follicular Lymphoma (FL)

• Module 2: Chronic Lymphocytic Leukemia (CLL)

• Module 3: Mantle-Cell Lymphoma (MCL)

• Module 4: Diffuse Large B-Cell Lymphoma (DLBCL)

• Questions and answers

Dr Gregory (Case A): Follicular Lymphoma

• 6/2004: 54 yo man with diffuse supraclavicular, bilateral axillary and inguinal and intra-abdominal adenopathy, largest 2.8 cm

• Lab results: All normal, including LDH

• Inguinal node bx: Follicular lymphoma Grade II/III

• BM bx: Positive for lymphoma (20%)

• FLIPI score: 2

Inguinal Node Biopsy Results: Follicular Lymphoma Grade 2

6-15/hpf

1. If this patient presented to you now in 2011, which first-line therapy would you generally recommend?

42%

17%

7%

17%

14%

3%

0% 5% 10% 15% 20% 25% 30% 35% 40% 45%

Other

Watch and wait

R monotherapy

R-CVP

BR

R-CHOP

Baseline CT of abdomenJune 11, 2004

Multiple intra-abdominal nodes

CT scan 12 weeks after 4 weeks of rituximab

induction

Markedly decreased adenopathy in all areas

Induction Induction rituximabrituximab

375 mg/m2 weekly x 4

Restage- week 12

End study treatment

<PR or PD

≥PR/CR

Rituximab re-treatment at Rituximab re-treatment at progressionprogression

Single 375 mg/m2 IV q4wk

Continue to rituximab failure

Rituximab maintenanceRituximab maintenance

Single 375 mg/m2 IV q12wk

Continue to rituximab failure

Primary endpoint is time to rituximab failure

RANDOMIZE

N = 600+ patients – closed

REGISTER

ECOG 4402 RESORT Trial

Dr Gregory (Case A): Follicular Lymphoma

• 6/21/2011: Remains asymptomatic in complete remission

• Labs: Normal except for mildly decreased IgG (794), IgA (144) and IgM (21)

• Patient has had no infections

• CT scans every 6 months – no evidence of disease

• Remains on clinical trial w/o Rx interruption

Ardeshna KM et al. Proc ASH 2010;Abstract 6.

An Intergroup Randomised Trial of Rituximab vs a Watch & Wait Approach

in Patients with Advanced Stage,Asymptomatic, Non-Bulky Follicular Lymphoma

Kirit M Ardeshna, Paul Smith, Wendi Qian, June Warden, Lindsey Stevens,Christopher FE Pocock, Fiona Miall, David Cunningham, John Davies, Andrew Jack,

Jan Walewski, A Burhan Ferhanoglu, Ken Bradstock and David C Linch

Rituximab (R) vs a Watch and Wait Strategy in Patients with Stage II-IV Asymptomatic, Nonbulky FL

Ardeshna K et al. Proc ASH 2010;Abstract 6.

• Improved PFS in R arms (P < 0.001)• 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 A Arm B Arm C

Intervention Observe R x 4 wk R x 4 wk

Maintenance — — R q2m x 2 yr

Number 187 84 192

CR/PR (%) 2/3 43/30 54/33

3-yr progression-free survival 33% 60% 81%

Time to next treatment 33 mo NR NR

0 1 2 3 4 5

With permission from Ardeshna KM et al. Proc ASH 2010;Abstract 6.

Proportionof patients

withno new

treatmentinitiated % requiring Rx at 3 yr

Watch and wait = 52% Rituximab = 20% Rituximab and maintenance rituximab = 9%

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Years from randomisation

Time to Initiation of New Therapy

Preliminary Results of Quality of Life (QOL) Analyses from the Intergroup Phase III Randomised Trial of Rituximab vs a Watch and Wait Approach in Patients with Advanced Stage, Asymptomatic, Non-Bulky Follicular Lymphoma (FL)Ardeshna KM et al. International Conference on Malignant Lymphoma 2011.

Salles G et al. Lancet 2011;377(9759):42-51.

PRIMA: Rituximab Maintenance After R-Chemo

• Two years of treatment: Every 8 weeks

• Three-year progression-free survival

R maintenance: 75% Control: 58%

• Gr 3-4 infection

R maintenance: 24% Control: 17%

• Treatment discontinued

R maintenance: 4% Control: 2%

PRIMA: Progression-Free Survival

Salles G et al. Lancet 2011;377(9759):42-51.

Rituximab maintenance Observation HR p-value

Progression-free survival

74.9% 57.6% 0.55 <0.0001

Median follow-up of 36 months

PRIMA: Quality of Life

Salles G et al. Lancet 2011;377(9759):42-51.

• EORTC QLQ-C30 global health status mean scores in rituximab maintenance vs observation:

– 75.5 (95% CI 72.8-78.2) vs 75.2 (95% CI 72.0-78.4), p-value = 0.89

• Mean adjusted FACT-G total scores at the end of treatment in rituximab maintenance vs observation:

– 86.6 (95% CI 85.0-88.3) vs 87.2 (95% CI 85.3-89.1), p-value = 0.68

FIT Study Schema

Not eligible

Start of study

6-12 weeks after last dose of induction

Patients with previously untreated FL

Hagenbeek A et al. Proc ASH 2010;Abstract 594.

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

No further treatment (n = 202)

CONTROL

First-line therapy with chlorambucil, CVP, CHOP, CHOP-like,

fludarabine combination or rituximab combination

INDUCTION

CR/CRu or PR

NRPD

RANDOMIZATION

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

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 to 47% in the 90Y-ibritumomab

armHR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001

With permission from Hagenbeek A et al. Proc ASH 2010;Abstract 594.

• N = 676

• Rituximab (n = 340) vs bortezomib/rituximab (n = 336)

• Progression-free survival: 11.0 vs 12.8 months, HR = 0.82, p-value = 0.039

• ≥Gr 3 AEs: 21% vs 46%

• Serious AEs: 11% vs 18%

Eligibility

High-risk FL with high tumor burden

Stage II-IV disease

Grade 1-3a disease

FLIPI-1 score of 3, 4 or 5

Arm 1BR q28d x 6

Rituximab d1, 4 wks after completion of induction,

q8wk x 2 yrs

ECOG-E2408: A Phase II Trial of BR Followed by Rituximab vs Bortezomib-BR (VBR) Followed by Rituximab vs BR Followed by Lenalidomide/Rituximab

Target Accrual = 250 (open)

www.ClinicalTrials.gov, July 2011.

RArm 2

VBR q28d x 6Rituximab as in Arm 1

Arm 3BR q28d x 6

Lenalidomide q28d x 13 immediately after induction

Rituximab as in Arm 1

B = bendamustine, V = bortezomib, R = rituximab

Dr Leonard (Case B): Follicular Lymphoma

• 8/2006: Currently 61 yo otherwise healthy female artist w/2-cm groin node; asymptomatic

• Bx: Follicular Grade II/III

• Imaging: Diffuse lymphadenopathy (LAN) 2-3 cm range

• Observed 3 years, slowly progressive disease

• Imaging: Mass over 12 cm

• Labs remain normal including LDH

58-year-old 75-year-old

R-CHOP 32% 5%

R-bendamustine 36% 34%

R-CVP 26% 32%

Rituximab monotherapy 1% 24%

What is currently your usual preferred regimen for a patient with FL who requires initial treatment?

Patterns of Care in Medical Oncology: Management of NHL and CLL 2010.

Dr Leonard (Case B): Follicular Lymphoma

• Bendamustine/rituximab therapy is initiated• Excellent response, 75% LAN reduction, no

symptoms• Tolerated well but dose reduction in last 2 cycles

– Mild cytopenias, fatigue, nausea, IV hydration needed

• 9/2010: R maintenance initiated every 2 months• Patient doing well

Before BR After BR

RAPID-FIRE QUESTIONS

• 59 yo man with bulky follicular lymphoma but minimally symptomatic. What is the optimal regimen?

• After bendamustine fails, what is the next step?

• Does rituximab change the natural history of follicular lymphoma?

• Patient with poor performance status whose FL progressed on rituximab monotherapy

Follicular Lymphoma

Dr Leonard (Case C): CLL

• Currently 75 yo married businessman presents with mild lymphoadenopathy and lymphocytosis

• PMH: Diabetes, hyperlipidemia

• Followed off therapy

• Develops progressive lymphocytosis (70k) anemia, splenomegaly, fatigue

• Trisomy 12 (intermediate risk)

2. Which first-line therapy would you generally recommend for this patient?

6%

6%

37%

25%

20%

6%

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

Other

Chlorambucil

R-CHOP

BR

FR

FCR

National Patterns of Care Among Clinical Investigators (N = 25): Preferred Initial Treatment for Younger and Older Patients with CLL (Normal Cytogenetics)

Patterns of Care in Medical Oncology: Management of NHL and CLL 2010.

60 yo 75 yo

FCR 68% 12%

FR 17% 33%

BR 8% 29%

Dr Leonard (Case C): CLL

• F-R x 6 cycles (delayed cycle 6)

• Tolerated well, mild cytopenias

• Patient is active with minimal symptoms

Informative for Prognosis or Therapy Decision-Making?

• Cytogenetics and/or FISH

– t(11;14)

– t(11q;v)

– +12

– del(13q)

– del(17p)

• Molecular Genetic Analysis

– Immunoglobulin heavy chain variable gene (IgHV) mutation status

• Flow Cytometry or Immunohistochemistry

– CD38

– Zap 70

CLL-8: Progression-Free Survival with FC versus FCR

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

Chemoimmunotherapy Chemotherapy p-value

Progression-free survival

51.8 mos 32.8 mos <0.0001

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

FCR(n = 408)

FC(n = 409)

Hazard ratio p-value

3-year PFS 65% 45% 0.56 <0.0001

3-year OS 87% 83% 0.67 0.01

Impact of FC versus FCR on Progression-Free and Overall Survival in CLL

Eligibility

Untreated Binet C CLL or

Binet B or A with ≥ one of

B-symptoms, progressive lymphocytosis, marrow failure; massive, progressive or painful splenomegaly; or massive lymph nodes or nodal clustersNo 17p deletion by FISH

FCR

BR

Phase III Trial of Combined Immunochemotherapy with FCR versus BR in Previously Untreated CLL

Target Accrual = 550 (open)

www.ClinicalTrials.gov, April 2011.

R

German CLL Study Group

RAPID-FIRE QUESTIONS

• FCR versus BR for up-front therapy: Which agents, when and for whom?

• What is the recommended dose of bendamustine for elderly patients?

• Is there still a role for single-agent chlorambucil?

Chronic Lymphocytic Leukemia

• What is the optimal use of alemtuzumab in CLL?

• Role of bone marrow biopsy in CLL

• Guidelines regarding re-treatment with rituximab: Role of ofatumumab

Chronic Lymphocytic Leukemia

Dr Gregory (Case D): Mantle-Cell Lymphoma

• 2/2008: 61 yo male w/progressive asymptomatic lymphadenopathy in left neck and right groin

• 8/2008: Lymph node bx = MCL– Staging workup– CT CAP: Diffuse cervical, axillary, inguinal and

mesenteric adenopathy, largest 4.7 cm in the inguinal area

– Labs: Normal including LDH and beta2 microglobulin

– BM bx: 10% involvement by lymphoma

Low Power Cross Sectional Lymph Node Biopsy Showing Replacement by MCL

High Power Showing MCL

Immunohistochemistry

CD5

CD20

CYCLIN D1

KI-67

Bone Marrow Biopsy Showing Involvement by Lymphoma

Initial Staging CT Scan: 8/2008

Mesenteric LN: 4.5 x 3.1 cmInguinal LN 4.7 x 3.2 cm

3. Which treatment would you generally recommend for this patient as first-line therapy?

15%

27%

24%

31%

3%

0% 10% 20% 30% 40%

R-CHOP

R-CHOP ASCT

R-hyper-CVAD or other Ara-C-containing regimen

BR

Other

• 8/2008 - 1/2009: Patient treated on ECOG-E1405

– 8/2008 - 1/2009: Randomized to VcR-CVAD– Randomized to SCT w/o rituximab maintenance

• 4/2011: Patient remains in CR as of last office visit

Dr Gregory (Case D): Mantle-Cell Lymphoma

E1405: A Phase II Study of VcR-CVAD Induction Followed by Maintenance Rituximab for Untreated MCL

REGISTER

SD, PR, CR

Rituximab Maintenance

Rituximab: 375 mg/m2 IV weekly over 4 consecutive weeks.

To begin 4-6 weeks after chemo q6m for a total of 4 courses.

Autologous Stem Cell Transplantation

This treatment arm is optional.

Transplant-eligible pts may be consolidated with ASCT using the institution’s local guidelines.

Patients will be monitored for PFS and OS.

Patients receiving maintenance rituximab may have stem cells harvested (for possible future use).

Patients who come off protocol therapy to receive ASCT may have stem cells harvested according to local institutional guidelines.

Accrual Goal = 72

VcR-CVAD induction

Inguinal LN Smaller: 2.8 x 1.4 cm

Restaging Scan After 4 Cycles: 12/2008

No abnormal inguinal adenopathyNo abnormal intra-abdominal adenopathy

Restaging Scan After 6 Cycles: 1/2009

No abnormal intra-abdominal adenopathy

Rituximab Maintenance Significantly Prolongs Duration of Remission in Elderly Patients with Mantle Cell Lymphoma. First Results of a Randomized Trial of the European MCL Network

Kluin-Nelemans J et al.European Hematology Association 2011;Presidential Symposium.

European MCL Maintenance Study

• >60 yo with Stage II-IV MCL

• Not eligible for HDT

EligibilityCR/CRu or PR

RANDOMIZATION

RANDOMIZATION

R-CHOP

R-FC

RANDOMIZATION

RANDOMIZATION

R maintenance375 mg/m2 q2m

IFN maintenance

Kluin-Nelemans J et al. European Hematology Association 2011;Presidential Symposium.

Efficacy (N = 223 evaluable) Rituximab IFNHazard

ratio p-value

Remission duration – All pts 51 mos 24 mos 0.56 0.0117

Overall survival – All pts

3-yr OS – CHOP-R inductionNR

85%NR

70%NR—

NS0.0375

Gr 3/4 Adverse Events

Leukocytopenia 17% 36% — —

Thrombocytopenia 7% 16% — —

Infection 7% 7% — —

Outcomes of Maintenance Therapy in Elderly Patients (Median: 70 yo) with MCL (Median F/U: 30 Months)

Kluin-Nelemans J et al. European Hematology Association 2011;Presidential Symposium.

“Rituximab maintenance after R-CHOP induction should be considered the new standard for elderly patients with MCL.”

Treatment

Chemo-Immunotherapy and ASCT

Bortezomib D1,8,15,22 every 56 days x 10

Bortezomib D1,4,8,11 every 21 days x 4

A Randomized Phase II Trial of Maintenance vs Consolidation Bortezomib Therapy Following Aggressive Chemo-Immunotherapy and ASCT for Previously Untreated MCL

Target Accrual = 150 (active, not recruiting)

www.ClinicalTrials.gov, April 2011.

Protocol ID: CALGB-50403

R

Dr Leonard (Case E): Mantle-Cell Lymphoma

• Currently 66 yo married female teacher

– 1998: Presents with lymphocytosis, splenomegaly, originally CLL suspected

• 2007: Dx of MCL on positive FISH for t(11;14)

• Watched for 9 years

• 2/2010: Increased lymphocytosis, splenomegaly, anemia

Dr Leonard (Case E): Mantle-Cell Lymphoma

• 2/2010: CHOP-R x 3 cycles, minimal response progression

• Oral PEP-C x 2 months progression

• BR x 6 cycles, excellent response for 4 months

– Progresses 7/2010

• Part B R-hyper-CVAD (methotrexate/ARA-C) x 1 cycle, not tolerated well

• 3/2011: Btk inhibitor (PCI-32765) on study

– Excellent response for past 3 months

Before Btk Inhibitor After Btk Inhibitor

The Btk Inhibitor, PCI-32765, Induces Durable Responses with Minimal Toxicity in Patients with Relapsed/Refractory B-Cell Malignancies: Results from a Phase I Study

Fowler N et al. Proc ASH 2010;Abstract 964.

Response with PCI-32765 in Relapsed/Refractory B-Cell Malignancies in a Phase IA Study

Fowler N et al. Proc ASH 2010;Abstract 964.

100%

80%

60%

40%

20%

0%

Be

st

Res

po

ns

e, %

MCL CLL/SLL DLBCL FL

7/978% 9/13

69%

2/729%

4/1331%

CR

PR

Dr Gregory (Case F): DLBCL

• 1999: 20 yo male college student with DLBCL – No B symptoms, no PMH– Positive for CD20, CD10 and CD45– IPI Score: 1

• 5/2000: Completes CHOP x 8

• Restaging CT after 4 cycles: 50% in mass size, negative Gallium scan

• 6/2000: Restaging PET scan high SUV in mediastinum

• Biopsy: DLBCL

• 8/2000: ESHAP salvage therapy, BEAM, autoSCT

• Post-transplant consolidative RT to mediastinum

• Repeat CT scans: Negative for 5 years

• Patient lost to follow-up

Dr Gregory (Case F): DLBCL

• 8/2009 (9 years later): Negative CTs

• 1/2010: Bilateral inguinal adenopathy found on PE, largest 3.7 cm left inguinal area

• CT CAP: 2.9 x 3.7 cm, left inguinal lymph node, enlarged left para-aortic nodes and mass around rectal area

• PET/CT: Consistent with abdominal lesion involving retroperitoneal lymph nodes, abdominal lymph nodes; celiac and pelvic lesion consistent with neoplasm, presumably lymphoma

– Enlarged metabolically active lesion rectal region

• MUGA: LVEF — 52%

PET Scan at Relapse: 2010

Dr Gregory (Case F): DLBCL

• Colonoscopy: Rectal erythema, edematous folds, friability and an aphthous ulcer; biopsy negative for DLBCL

• BM bx: Negative• LN bx: DLBCL• Flow cytometry: Bright CD45, CD20, CD19, CD10

and monoclonal kappa • Labs: Normal, LDH 280• Patient received 2 cycles of R-ICE and repeat auto

transplant• Presently in complete remission one year

post-transplant

• IPI = 1– A = Age of 30– P = Performance Status - 1– L = LDH: 280– E = Extra Nodal -1– S = Stage - IIE? (Was mass arising from rectum?

Or was this a nodal mass pushing in on rectum?)

Dr Gregory (Case F): DLBCL

Maintenance with Rituximab After Autologous Stem Cell Transplantation in Relapsed Patients with CD20 Diffuse Large B-cell Lymphoma (DLBCL): CORAL Final Analysis

Gisselbrecht C et al. Proc ASCO 2011;Abstract 8004.

CORAL: EFS by Post-ASCT Maintenance Rituximab versus Observation

Gisselbrecht C et al. Proc ASCO 2011;Abstract 8004.

PFS and OS also did not differ between post-ASCT maintenance rituximab and observation.

Rituximab (n = 122)

Observation(n = 120) p-value

Event-free survival 45% 47% 0.7435

4. Do you order specific screening tests for hepatitis for patients who are about to initiate treatment with rituximab and who have no history of or risk factors for hepatitis?

68%

9%

0%

23%

0% 10% 20% 30% 40% 50% 60% 70% 80%

No

Yes, both hepatitisB and C

Yes, hepatitis Conly

Yes, hepatitis Bonly

NCCN Clinical Practice Guidelines in Oncology, Non-Hodgkin Lymphomas, v3.2011.

Hepatitis B Screening in Patients Receiving Anti-CD20 Antibody (Rituximab)

• No risk factors:– Hepatitis B surface antigen and core antibody

• Risk factors or prior history of hepatitis B:– Add e-antigen

• If positive, check viral load and consult with gastroenterologist

R-CHOP2 cycles

R-ICE 4 cycles

www.clinicaltrials.gov, July 2011.

Eligibility Criteria

Bulky Stage II or Stage III/IV DLBCL

Target Accrual: 99

ECOG-E3404: Response-Adapted Therapy for Aggressive NHL Based on Early PET Scanning

R-CHOP4 Cycles

PETSCAN

+

-

Interim Positron Emission Tomography Scans in Diffuse Large B-cell Lymphoma: An Independent Expert Nuclear Medicine Evaluation of the Eastern Cooperative Oncology Group E3404 Study

Horning SJ et al.Blood 2010;115(4):775-7.

Interim PET Scans

Horning SJ et al. Blood 2010;115(4):775-7.

• PET scans read by three independent reviewers

• Moderate agreement among readers (68% by ECOG criterion)

• Proportion of positive PET scans relatively low (range 16% to 34%)

• PET interpretation should be standardized

RAPID-FIRE QUESTIONS

• What is the role of maintenance therapy in follicular lymphoma after transformation?

• Use of bendamustine/rituximab in DLBCL

• Would you ever consider a transplant at first remission?

• Is there any clinical benefit to using dose-dense R-CHOP?

Diffuse Large B-Cell Lymphoma

Schedule of Events

Tuesday, August 2Chronic Myeloid LeukemiaSusan M O’Brien, MDNeil P Shah, MD, PhD