New Targets and Treatments for Follicular Lymphoma Jonathon B. Cohen, - - PDF document

1 Winship Cancer Institute of Emory University

New Targets and Treatments for Follicular Lymphoma

Jonathon B. Cohen, MD, MS Assistant Professor Div of BMT, Emory University

Disclosures

• Consulting fees from:

Pharmacyclics, and Seattle Genetics

• Contracted Research from:

Bristol‐Myers Squibb, and Janssen Pharmaceuticals, Inc.

2

Intro/Outline

• Follicular lymphoma, presentation and

indications for treatment

• Review of induction therapy options for

advanced disease

• Evidence for maintenance therapy
• Novel therapies and investigational agents for

relapsed follicular lymphoma

Clinical Presentation

• Often asymptomatic
• Slowly progressive adenopathy
• Incidental findings
• Patients are often not sick

3

Criteria for Treatment (GELF)

• Involvement of ≥3 sites, each measuring ≥ 3 cm
• Any nodal or extranodal tumor mass with a

diameter of ≥ 7 cm

• B symptoms
• Splenomegaly
• Pleural effusions or peritoneal ascites
• Cytopenias
• Leukemic presentation

FLIPI

Characteristic RR (Death) Age > 60 years 2.38 Stage III-IV 2.00 Hgb < 12.0g.dL 1.55 Elevated LDH 1.50 Nodal sites > 4 1.39

Solal‐Céligny, et al. Blood. 2004;104:1258‐1265.

4

FLIPI and OS

Risk Group

• No. of Risk

Factors 5-year OS, % 10-Year OS, % Low 0-1 91 71 Intermediate 2 78 51 High ≥ 3 53 36

Solal‐Céligny, et al. Blood. 2004;104:1258‐1265.

• Roughly half of all patients with FLIPI 3 or higher die

within 5 years

• Original FLIPI score developed in the pre-rituximab era

FLIPI: Survival Probability

Solal‐Céligny, et al. Blood. 2004;104:1258‐1265.

5

Induction Therapy: B‐R vs R‐CHOP

Bendamustine-rituximab CHOP-rituximab

Pts with previously untreated Stage III or IV NHL of the following types:

• Follicular
• Waldenström
• Marginal zone
• Small lymphocytic
• Mantle cell

Age ≥18 years WHO PS 0-2

R

Bendamustine 90 mg/m2 Day 1, 2 + R Day 1, max 6 cycles, every 4 weeks. CHOP-R, max 6 cycles, every 3 weeks.

Rummel MJ, et al. Blood. 2009;114: Abstract 405. Rummel MJ, et al. Lancet Oncol 2013.

B-R vs CHOP-R: PFS

6

B‐R vs R‐CHOP/R‐CVP

• BRIGHT study (Flinn et al, Blood 2013)

– Patients randomized to B‐R or R‐CHOP/R‐CVP (each site assigned one of the standard therapies) – Non‐inferiority study – B‐R non‐inferior to both R‐CHOP and R‐CVP with respect to CR rate. – Non‐hematologic toxicity improved with B‐R.

Novel Approaches

• B‐R + Bortezomib

– Current ECOG study in comparison to B‐R. – Overall Response Rate is 88% in relapsed FL

• R‐Lenalidomide

– CALGB Phase II Study

• Rituximab x 4, then cycles 4, 6, 8 and 10
• Lenalidomide 20mg daily days 1‐21 of a 28 day cycle x 12

– Overall Response Rate: 93% – 2‐year PFS 89%

Fowler et al, J Clin Oncol 2011; Martin et al, ASCO Abstracts 2014

7

Conclusions‐ Induction Therapy

• Bendamustine‐Rituximab appropriate in most

cases

• Studies underway to both intensify and lessen

therapy

• Expect therapy to become more tailored

based on individual risk factors

Rituximab Maintenance PRIMA: Study Design

Primary endpoint:

• Progression‐free survival (PFS) from randomization

(to rituximab maintenance or observation)

Secondary endpoints

• Event‐free survival (EFS), overall survival (OS)
• Time to next anti‐lymphoma treatment (TTNLT), time to next chemotherapy (TTNCT)
• Response rates at end of maintenance
• Safety and toxicity
• Quality of life (QoL) (FACT‐G and EORTC scales)

*Stratified by response after induction, regimen of chemo, and geographic region

†Frequency of clinical, biological and CT-scan assessments identical in both arms

Five additional years of follow-up

Registration High tumor burden untreated follicular lymphoma Immunochemotherapy 8 x Rituximab + 8 x CVP or 6 x CHOP or 6 x FCM INDUCTION MAINTENANCE CR/Cru PR Rituximab maintenance 375 mg/m2 every 8 weeks for 2 years† Observation† Random 1:1*

PD/SD

• ff study

Salles GA, et al. J Clin Oncol. 2010;28(7s): Abstract 8004.

8

R-CHOP N = 885 Randomized N = 769

* 15 pts in 3 sites closed prematurely

Patients evaluable (N = 1202)* R-CVP N = 272 Patients registered: N = 1217 R-FCM N = 45 Randomized N = 222 Randomized N = 28 Observation N = 513 Rituximab N = 505

‡ 1 pt died during the

randomization process

Induction Maintenance

• 9 pts did not receive chemo
• 147 pts withdrew during or at

the end of induction (failure to respond; toxicity)

• 28 pts failed to be randomized

Patient disposition

Patients randomized: N = 1018‡

PRIMA‐ PFS OUTCOME

3‐year PFS: 79% (R Maint) 57.6% (Obs) Salles G, Lancet 2011.

9

PRIMA ‐ OS

No significant OS benefit

E4402 (RESORT)

• Pts with low tumor burden treated with R x 4

followed by maintenance vs retreatment at progression.

Kahl et al, ASH 2011 Time to Treatment Failure Time to Chemotherapy

10

Maintenance Rituximab‐ Summary

• Likely a PFS benefit and opportunity to delay

next therapy

• Unclear role after B‐R (E2408 may help answer

this)

• No evidence of OS benefit
• Should be discussed individually with each

patient

Relapsed/Refractory FL

B‐cell receptor signaling pathway

Woyach et al, Blood 2012

11

Ibrutinib – BTK inhibitor

• Phase I Study of Ibrutinib

– MTD not reached; standard dose is 560mg – ORR 54.5%, median duration of response 12.3 months

• Ongoing multisite study just completed

enrollment

Fowler et al, ASH 2012

Idelalisib – PI3Kδ inhibitor

• Phase 2 Study of Idelalisib

– Dose 150mg twice daily – Response rate 57%, median duration 12.5 months

• Toxicities:

– Neutropenia – LFT abnormalities – Diarrhea – Pneumonia

Gopal et al, NEJM 2014

12

CD20 Antibodies

• Ofatumumab:

– ORR 10‐13% – Median PFS: 5.8 months

Czuczman et al, Blood 2012

CD20 Antibodies

• GA101 – Obinutuzumab

– Phase II study in rel/ref follicular lymphoma – ORR 55% at recommended dose – Median PFS 11.9 months

Salles G, et al. J Clin Oncol 2013

13

BCL2 Inhibitor – ABT199

• Oral agent active in several subtypes of NHL
• Responses seen in 2/7 patients with follicular

lymphoma in Phase I Study.

• Toxicities:

– Tumor lysis syndrome – Cytopenias – Febrile Neutropenia

Davids et al, ASCO Abstracts 2013

Agents Under Investigation at Emory

• ABT‐199
• Nivolumab (PD1 inhibitor)
• Buparlisib (Pan‐selective PI3K inhibitor)
• Alisertib (Aurora Kinase inhibitor)

14

Other Treatments for Rel/Ref FL

• Chemo‐immunotherapy

– B‐R – R‐CVP/R‐CHOP – Fludarabine – Salvage NHL regimens

• Radioimmunotherapy
• Lenalidomide
• Autologous/Allogeneic Transplants

Conclusions

• Several options that are better than R‐CHOP

for induction therapy

• Consider maintenance rituximab in all cases,

but with no clear OS benefit

• Numerous options for relapsed/refractory FL
• Strongly consider enrollment on clinical trial
• For fit/motivated patients, transplant can be

considered