evolving management of follicular lymphoma

Evolving Management of Follicular Lymphoma

HUMC Oncology Fall Conference

November 3, 2011Hackensack, NJ

Myron S. Czuczman, MDChief, Lymphoma/Myeloma Service

Head, Lymphoma Translational Research Laboratory

Professor of Medicine and Oncology

Roswell Park Cancer Institute

Buffalo, NY

Disclosure InformationMyron S. Czuczman, MD

I have the following financial relationships to disclose:

Membership on advisory committees or consultant/review panels for: Celgene, Cephalon, Genentech, Genmab, GlaxoSmithKline

Honorarium from: Celgene, Cephalon, GlaxoSmithKline, MundiPharma

I will include discussion of investigational or off-label use of products in my presentation (i.e. numerous agents are currently in clinical trials and not yet FDA-approved)

Outline• Background

• Approach to Rx of Advanced-stage FL

– Rapidly changing terrain

• Who When and Why Treat? Goals?

• What Rx to use?

– Frontline?

– Post-induction

– In Relapsed/Refractory disease?

• Where are we now?

• Future Directions / Conclusions

Characteristics of Follicular LymphomaClinical Pattern:

• Indolent clinical course (typical)

• Highly responsive to therapy but relapse is likelyTreatment decisions based on:• Stage and Bulk• FL IPI• Transformation• Sites of involvement• Prior therapy• Time from prior therapyCurrent Treatment Approach:• Frontline: Rituximab +/- chemotherapy (R-CHOP, R-Benda, R-CVP, etc)• Consolidation: Rituximab, Radioimmunotherapy (RIT)• Salvage: Clinical trial, chemoimmunotherapy; HDT/SCT; RIT

Presenter

Presentation Notes

Follicular-cell (FC) lymphomas are derived from B cells recapitulating features of the germinal-center cell. They always consist of varying proportions of different cell types and include small centrocytes with cleaved nuclei together with cleaved and large noncleaved centroblasts. Follicular-cell lymphoma was previously known as follicle center–cell (FCC) lymphoma. The new name is part of the WHO nomenclature. Immunophenotyping is useful for distinguishing these from other categories of lymphoma. Lack of CD5 distinguishes FC lymphoma from mantle-cell and small lymphocytic lymphoma. Presence of CD10 distinguishes FC from these 2 and also from marginal-zone lymphoma. However, CD10 is not invariably present on FC lymphoma cells. A cytogenetic rearrangement of t(14;18) (q32;q21) is present in 70% to 95% of cases. This change results in rearrangement of the bcl2 gene. Such a rearrangement is common to FC and DLBCL but is rare in other lymphomas. It should, however, be noted that sensitive polymerase chain reaction (PCR) techniques may reveal this arrangement even in normal peripheral blood. FC lymphomas arise in lymph nodes but spread hematogenously early in the course to involve spleen and bone marrow and occasionally peripheral blood. FC accounts for 35% of adult NHLs and typically presents as a disseminated lymphadenopathy. Painless, slowly progressive lymphadenopathy is the most frequent clinical presentation and some patients have waxing and waning lymphadenopathy. Although an indolent disease, about 50% of cases progress to diffuse large B-cell lymphoma (DLBCL) over time. Skarin AT, Dorfman DM. Non-Hodgkin's lymphomas: current classification and management. �CA Cancer J Clin. 1997;47:351-372. Jennings CD, Foon KA. Recent advances in flow cytometry: application to the diagnosis of hematologic malignancy. Blood. 1997;90:2863-2892. Mann RB, Berard CE. Criteria for the cytologic subclassification of follicular lymphomas: a proposed alternative method. Hematol Oncol. 1983;1:187-192.

Current Lymphoma Field: Rapidly Changing Landscape

• Heterogeneity/complexity of FL will not change – We are developing scientific tools to better understand it:

• Biologic, genetic, and clinical features

• Results from targeted therapies (e.g. mAbs, RIC’s, etc.) and novel Rx approaches are promising

• Historical approaches need to be critically reviewed and retested and will require data from well-designed clinical trials:– Optimal combination(s) of old and new agents?– Optimal timing and sequencing of specific therapies?– Surrogate end-points other than OS?– Are cures possible in a significant subset of patients?

New directions in the treatment of follicular lymphoma (FL) in 2011

• The successful use of mAbs in B-cell malignancies is inducing a paradigm shift in attitudes toward treatment:

– Therapeutic goals are moving from palliation to prolonged remission durations

– Therapeutic principles are changing from “watchful waiting” to “earlier” therapy and/or consolidation strategies designed to induce complete remissions of long duration

– Development and testing of novel targeted agents, both alone and in combination, enhance B-cell killing and improve response and survival rates… POSSIBLY EVEN CURE RATES!

Presenter

Presentation Notes

In the past, treatment for advanced B-cell malignancies was based primarily on chemotherapy and radiotherapy. For patients with low tumor burden and indolent disease, a “watchful waiting” strategy was often employed. Palliative single-agent or combination chemotherapy often produced remissions and improved symptoms and quality of life. However, overall survival rates remained unaffected, and chemotherapy-induced side effects were particularly problematic in elderly patients who are often affected by these tumors.1-4 The introduction of rituximab for the treatment of B-cell malignancies has induced a significant paradigm shift in both treatment goals and principles.1-4 The potential of therapeutic monoclonal antibodies has shifted the treatment goals from palliation to prolonged survival and even cure for several B-cell malignancies. There is a trend toward using more aggressive therapy early in the disease course in an attempt to induce complete remissions of long duration, rather than no treatment or conservative therapy for symptom management.1-4 Although rituximab is now widely integrated in the treatment of B-cell malignancies, its efficacy is variable and is often modest when employed as a single agent. A new generation of antibodies that may enhance selectivity and optimize mechanisms of B-cell killing, while minimizing treatment toxicity, is in development.5 1.Cvetković RS, Perry CM. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. Drugs. 2006;66(6):791-820. 2.Dreyling M, Buske C, Hiddemann W. Advances in molecular biology diagnostic and treatment of B-cell malignancies: indolent B-cell lymphoma. Ann Oncol. 2005;16(suppl 2):ii99-ii104. 3.Hotta T. Anti-CD20 monoclonal antibody as a new treatment modality for B-cell lymphoma. Acta Histochem Cytochem. 2002;35(4):275-279. 4.Keating MJ, Chiorazzi N, Messmer B, et al. Biology and treatment of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2003:153-175. 5.Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004;104(6):1793-1800.

What are our treatment goals in FL patients?

• Increased CR and PFS rates were associated withimproved survival:

Bachy E, et al. J Clin Oncol 2010; 8:822–829

CRPR

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15Overall survival (y)

Surv

ival

pro

babi

lity

20

references.

Indications for Rx* on FL clinical trials (an example)

B-symptoms

Hematopoietic failure(Hb < 11 g/dl, granulocytes < 1.500 /µl, thrombocytes < 100.000 /µl)

Large tumor burden(3 areas > 5 cm or 1 area > 7.5 cm)

Rapid progression(increase of tumor mass > 50% within 6 months)

Complications due to disease(pain, infarction of spleen, hyperviscosity syndrome, etc.)

* NEEDS RE-EXAMINED IN 2011!!!

* THESE PATIENTS MAY BE ALREADY INCURABLE!

What Rx to Use @ Presentation?@ Relapse?

• Answer: “Varies”

• Need additional information to gain a better understanding of how to attain optimal anti-tumor activity (i.e. optimal “sequencing”) for a given “subset” of FL pts

• Choice of Rx dependent on:

• Tumor characteristics (e.g. rate of growth, tumor size/bulk), histology, cytogenetic/molecular abnormality)

• Clinical/laboratory characteristics (e.g. FLIPI score, LDH, B-2 microglobulin)

• Patient characteristics (e.g. co-morbid conditions, Rx goals, patient’s wishes)

Suggested Treatment Regimens (in alphabetical order)

First-line Therapy• Bendamustine + R• CHOP (cyclophosphamide, vincristine, prednisone) + R (category 1)• CVP (cyclophosphamide, vincristine, prednisone) + R (category 1)• FND (fludarabine, mitoxantrone, dexamethasone) + R• Radioimmunotherapy (category 2B)• Rituximab

First-line for Elderly or Infirm (if none of the above are tolerable)• Radioimmunotherapy• Rituximab, preferred• Single agent alkylators (e.g. chlorambucil or cyclophosphamide)

First-line Consolidation or Extended Dosing• Chemotherapy followed by radioimmunotherapy (category 1)• Rituximab maintenance (category 1)

NCCN Clinical Practice Guidelines in Oncology v.1.2010; FOLL-B

Suggested Treatment Regimens (in alphabetical order)

Second-line and Subsequent Therapy• Chemoimmunotherapy (as in first-line therapy)• FCMR (fludara, cyclophosphamide, mitoxantrone, R) (category 1)• High dose therapy with autologous stem cell rescue• High dose Rx with allogeneic stem cell rescue, (highly selected pts)• Radioimmunotherapy (category 1)• Fludarabine + R• See Second-line therapy for DLBCL (e.g. DHAP; ICE; ESHAP +/- R)

Second-line Extended dosing• Rituximab maintenance (category 1)

For patients with locally bulky or symptomatic disease, consider IFRT 4-30 Gy + additional systemic therapy

NCCN Clinical Practice Guidelines in Oncology v.1.2010; FOLL-B

NEW

INFORMATION PRESENTED

IN 2010 and 2011

in FL

Biomarkers in FL

Relander et al, J Clin Oncol 28(17), 2902-2913 , 2010

Presenter

Presentation Notes

Fig 1. Biomarkers impacting survival or transformation in follicular lymphoma (FL). Some biomarkers are controversial, resulting from treatment heterogeneity. Larger circle: features of nonmalignant cells. Inner circle: tumor cells. IR, immune response; FDC, follicular dendritic cells; IF, interfollicular; F, follicular; MVD, microvessel density; VEGF, vascular endothelial growth factor; EGF, endothelial growth factor; TNF, tumor necrosis factor; aUPD, acquired uniparental disomy; SNPs, single nucleotide polymorphisms.

Bendamustine Chemical Structure

N

NCH3

COOHN

ClH2C

ClH2C

Bendamustine

N

N

N

N

NH2

Cl

O

OH

HOCH2

Cladribine

Benzimidazole ring

NCl

Cl

N

POO

H

Cyclophosphamide

Nitrogen mustard

Carboxylic acid

MOA: Leads to mitotic catastrophe in cells

Bendamustine cross-links DNA single and double strands, inhibiting DNA replication, repair, and transcription*

* Ghandi et al. Semin Oncol. 2002;29:4

B-R (n = 260)

R-CHOP(n = 253) P Value HR

Overall Response Rate 93% 91% – –Complete response 40% 30% .0262 –

Median Progression-Free Survival 54.9 months 34.8 months .00012 0.57Median Time to Next Treatment Not reached 37.5 months .00002 0.52

Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R-

CHOP in Indolent NHL: Efficacy

Rummel et al. ASH 2009; abstract 405

CyclesB-R (n = 1450) R-CHOP (n = 1408)

Grade 3/4 Leukocytopenia 12% 38%Grade 3/4 Neutropenia 11% 46.5%G-CSF Administered 4% 20%

Number of PatientsB-R (n = 260) R-CHOP (n = 253)

Infectious Complications (All Grades) 96 127Skin (Erythema, All Grades) 42 23Allergic Skin Reactions (All Grades) 40 15

Phase III Study of First-line B-R vs. R-CHOP in Indolent NHL: Safety

Rummel et al. ASH 2009; abstract 405

Thoughts/Questions:•Will B+R replace (or has it already replaced) upfront R+CHOP/CVP?•Trial did not include FL, grade 3 histologies•PR and CR in B-R arm have identical outcomes…Why?•Await formal publication and more in depth analysis of Rummel trial… •Long-term F/U?

Maintenance Therapy

First-line consolidation or extended dosing– Chemotherapy followed by radioimmunotherapy– Rituximab maintenance up to 2 yrs

Second-line consolidation or extended dosing– High-dose therapy with autologous stem cell

rescue– AlloSCT for highly selected patients– Rituximab maintenance

90Y-Ib consolidation (n = 208)Rituximab 250 mg/m2

IV Day 0, 7 +90Y-Ib 14.8 MBq/kg

First-line therapy with CVP, CHOP-like, fludarabine combinations, chlorambucil, or rituximab combination

INDUCTION

No further treatment (n = 206)

NRPD

CR/CRu or PR

Off Study

RANDOMIZATION

CONTROL

Enroll

6–12 wks

CONSOLIDATION

Primary end point: PFSa

aCalculation of PFS starts at enrollment, not from induction.90Y-Ib = Y-90 ibritumomab tiuxetan; IV = intravenous.Morschhauser et al, 2008.

FIT (Front-Line Indolent Trial)

Presenter

Presentation Notes

In Europe the FIT trial compared patients receiving any upfront chemotherapy with or without radiolabeled ibritumomab consolidation. This slide shows the treatment algorithm. Patients elgible for the Front-line Indolent Trial (FIT) had advanced-stage indolent NHL, and were treated with induction therapy as prescribed by their physicians. Induction therapies ranged from single agent alkylators such as chlorambucil to chemoimmunotherapy. Patients obtaining a CR/CRu or PR were then enrolled in the FIT study and randomized to recieve consolidation with 90Y-Ibritumomab Tiuxetan (90Y-Ib) or observation. The rationale for the study is that responses obtained from induction therapy can be improved by using consolidation. The goal of consolidation is to induce a higher quality resonse, thereby extending the duration of disease control while maintaining an appropraite side effect profile. Thus, the FIT study was designed to evaluate the safety and efficacy of consolidation therapy with a single dose of 90y-ib in patients who achieved a partial response or better with first-line induction treatment. PFS was the primary study endpoint. Of Note. The point of enrollment into the study is after the induction and after initial evaluation of response. The important aspect of this is how it impacts determination of PFS. PFS is calculated from the time of study enrollment to diseseas progression. So, in the context of the FIT study, PFS calcuations do not include time associated with initial therapy, which could range anywhere from 6 months to 18 months or the 6-12 week evaluation peroid between induction therapy, assement of response and enrollment into the trial. This, FIT has a conservative estimate of PFS

Median PFS for All Patients36.5 mos (90Y-Ib) Vs. 13.3 mos (Control; p < .0001)

PFS

(%)

100

60

40

20

0

80

0 6 18 30 42 54 6618 30 42 54 66

Time After Random Assignment (mos)

Control (n = 206)Median 13.3 mos

90Y-Ib (n = 208)Median 36.5 mos

2-sided log-rank p < .0001HR 0.46595% CI: 0.357–0.605

Morschhauser et al, 2008

Presenter

Presentation Notes

Fig 3. Kaplan-Meier plots for progression-free survival (PFS) in all patients. PFS plot for all randomly assigned patients. (Morschhauser et al, 2008). This is the graphical representation of median PFS in all patients enrolled on the study. The white line represents patients that recieved (90Y-Ib) showing a median PFS of 36.5 months for this population. The blue line shows the median PFS of the control arm, which is 13.3 months. These data show a statistically significant increase in PFS in patients that received 90Y-Ib It is important to note that PFS was calculated from the time of randomization to (90Y-Ib) or control, so induction therapy is not included in this calculation. The significant advantage in progression-free survival for the addition of adjuvant radiolabeled ibritumomab led to approval for that combination in the frontline therapy of patients with follicular lymphoma. For what are probably complex reasons, this treatment has not been widely adopted in the United States. However, results mentioned on the previous slide by Kaminsky with the radioantibody alone, and these results combining a variety of standard chemotherapies with radioantibodies certainly provide encouraging data for their activity in the out front setting in patients with follicular lymphoma.

FIT Trial: Conclusions…• 90Y-Ibritumomab consolidation resulted in:

– High conversion rates from PR to CR/CRu: 78%

– High overall CR rate: 87%

• Significantly prolonged median PFS

• 90Y-Ibritumomab consolidation was well-tolerated with manageable hematologic adverse events

• Confers a durable PFS benefit for patients with advanced FL

• No unexpected toxicities emerging

• For patients who relapse:

– 90Y-Ibritumomab consolidation does not (appear to) rule out any second-line treatment approach, including ASCT

• At current follow-up: no significant difference in OS between Rx arms

Morschhauser et al. J Clin Oncol. 2008;26:5156-5164

SWOG/CALGB Trial 0016

Untreated Advanced Stage FL

CHOP x 6 CHOP x 6+ Rituximab

CHOP x 6 + 131ITositumomab

(Bexxar)

•Update: Results Pending •ASH 2011 abstract accepted as an oral presentation

Gilles Salle et al. ASCO 2010; Abstract 8004

Rituximab Maintenance for 2 Years in Patients with High Tumor Burden FL responding to R-chemotherapy (PRIMA):

A phase 3 randomized control trial

Patients were required to have at least one of the following:B-symptomsBulky disease at study entry (nodal or extranodal mass >7cm)Symtomatic splenomegaly, compressive syndrome, pleural/peritoneal effusionInvolvement of > 3 nodal sites (each > 3cm)Elevated LDH (>ULN) or β2-microglobulin (>3mg/L)

Primary Rituximab and Maintenance study: PRIMA

High tumor burden

untreated follicular

lymphoma

Rituximab maintenance375 mg/m2 q8w for 2

years

Observation

Immunochemotherapy8 x rituximab

+8 x CVP or

6 x CHOP or6 x FCM

CR/CRuPR Randomize 1:1

Salles GA, et al. J Clin Oncol 2010;28(Suppl.): Abst. 8004Time (mo)

Prog

ress

ion-

free

rate 82%

66%

Rituximab maintenancen=505

Observationn=513

Stratified HR=0.5095% CI 0.39; 0.64P<0.0001

PFS1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36

Rituximab Maintenance: Do the Results of the PRIMA Study Define a New Standard of Care?

• Current results of the PRIMA study do not allow us to evaluate a possible impact on overall survival or “responsiveness” to subsequent Rx…

• Must balance the benefits/risks (i.e. rituximab resistance or chronic B-cell depletion) and costs when using rituximab

• Novel agents (eg, different mAbs; immunoconjugates; RIT; IMiDs, etc) and/or different maintenance strategies need to be evaluated as well

Compulsory CT scan

CT scan if clinical CR

Bone marrow for histology and MRD only if CT shows CR

ARM AWatch and Wait

ARM BRituximab Induction

ARM CRituximab Induction

& maintenance

Progressive disease requiring therapy stops

protocol treatment

Clinic visits

Ardeshna et al. Blood 116: Abstract 6, 2010

Study SchemaF O LL OW

U P

Compulsory CT scan

RANDOMIZATION

An Intergroup Randomized Trial of Rituximab vs. a Watch & Wait Approach in Patients with Advanced Stage,

Asymptomatic, non-Bulky FL

Presenter

Presentation Notes

ARM B CLOSED

Primary Endpoint: Time to initiation of next therapy

– Symptomatic enlarged LN or spleen– ‘B’ symptoms or severe pruritus– Lymphomatous mass > 7cm

provided size increased by 25%– >3 nodal sites with nodes >5cm– Significant effusions– Lymphoma-related cytopenias– Near-critical organ

involvement/compression– Histological transformation

Limitation of Study:

“At the time of progression,

rituximab monotherapy

was not an option!”

Ardeshna et al. Blood 116: Abstract 6, 2010

Presenter

Presentation Notes

Emphasize that single agent rituximab was NOT an option.

Benefit of early rituximab ± maintenance over watch & wait in asymptomatic non-bulky FL

Ardeshna KM, et al. Blood 2010;116: Abstract 6

PFS:

Group 3y-PFS (%)

Watch & Wait (WW) 33

Rituximab (R) 60

Rituximab maintenance (M)

81

No difference in OS between treatment arms

R=80%

Pts not requiring Rx (%):W+W=48

TTNT:

R+M=91%R+M:

Prop

ortio

n of

pts

with

no n

ew T

x in

itiat

ed

19 192

19 84

83 187Events Totals

WW:

R:

0.0

0.2

0.4

0.6

0.8

1.0

Time from randomization (y)0 1 2 3 4 5

• Is this clinically meaningful?• Cost versus benefit?

The duration of rituximab benefit is limited!

•Within 3 yrs, the majority of patients become refractory to rituximab

•New treatments are still needed for follicular NHL

•Unlikely that R maintenance will be utilized with each course of Rx

0

20

40

60

80

100

0 12 24 36 48 60Time (mo)

Prog

ress

ion-

free

sur

viva

l (%

)

Maintenance

Retreatment

P=0.937

Hainsworth JD, et al. J Clin Oncol 2005;23:1088–1095

Risks Associated with Prolonged B-cell Suppression*

• Hypogammaglobulinemia• Delayed neutropenia• Viral reactivation (Hepatitis B; JC virus)• Increased infections associated with

rituximab maintenance• Restricted response to vaccinations• Development of acquired rituximab

resistance (under investigation)* Presentation by M. S. Czuczman, ASCO 2010

Next generation anti-CD20 mAbs

Name Comparison to Rituximab StatusOfatumumab1,2 •Human mAb

•Novel membrane proximal CD20 epitope

•Stronger CDC•Slower dissociation rate•Stronger binding to B-cells

•FDA-approved in r/r CLL•S/P Ph III in rituximab-refractory FL•Ph III: in CLL, FL, DLBCL•Several Ph II trials (also RA and MS)

GA1011 •Type II anti-CD20 (glycol-engineered Fc Region)

•Increased ADCC/Apoptosis•Stronger binding to effectors•Limited CDC

•S/P Ph I trials•Ph III Benda vs. Benda + GA101 in rituximab-refractory indolent NHL

•Several Ph II trials

Veltuzumab1 •Humanized IgG1 mAb •Single a.a. change in CDR3-VH (Asn to Asp)

•Epratuzumab framework•Slower dissociation rate•Stronger CDC•Enhances epratuzumabactivity

•Low-dose subq formulation

•S/P Ph I/II studies (IV)•Phase I/II sub q in NHL/CLL•Phase I subq in ITP

1. Robak T & Robak E. Biodrugs 2011;25:13–25. 2. Lin TS. Pharmacogenomics and Personalized Medicine 2010;3:51–59.

31

B-Cells: Express Many Surface Antigens That May Serve as Targets for mAbs

Antigen expression variable1,2

Most involved in B-cell growth, differentiation, proliferation, and activation; other functions include1,2: – Immune regulation – Complement inhibition

Many are targets of therapeutic mAbs for current or potential use in B-cell malignancies1,2

B-Cell

CD19

CD20

CD21

CD22

CD23

CD38

B-cell receptor(BCR)

CD40

CD52

CD46, CD55, CD59

CD74

CD80

Marker

1Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program. 2007;2007:233-2422Hotta T. Acta Histochem Cytochem. 2002;35(4):275-279

Presenter

Presentation Notes

B-cells express a wide variety of cell surface antigens throughout their development1,2 These antigens may be expressed in few, many, or most B-cell developmental stages While many of these antigens are expressed by multiple cell types, some are B-cell–specific B-cell–specific antigens regulate many important cellular processes that include cellular differentiation, proliferation, apoptosis, immune regulation, and complement inhibition1,2 Since a number of these antigens are expressed on the surface of malignant B-cells, they represent potential targets for therapeutic MAbs A number of therapeutic MAbs targeting different B-cell–specific surface antigens are commercially available or in development for the treatment of B-cell malignancies3-8: CD20: rituximab (Rituxan); ibritumomab (Zevalin); tositumomab (Bexxar); ocrelizumab; ofatumumab (HuMax-CD20) CD22: epratuzumab; inotozumab; CD23: lumiliximab CD40: SGN-40; HCD122 CD52: alemtuzumab (Campath) CD74: milatuzumab CD80: galiximab 1.Bonilla FA. B cell development. UpToDate. 2007. http://www.uptodate.com. Accessed Nov 2, 2007. 2.Hotta T. Anti-CD20 monoclonal antibody as a new treatment modality for B-cell lymphoma. Acta Histochem Cytochem. 2002;35(4):275-279. 3.Bello C, Sotomayor EM. Monoclonal antibodies for B-cell lymphomas: rituximab and beyond. Hematology Am Soc Hematol Educ Program. 2007;2007:233-242. 4.Buske C, Weigert O, Dreyling M, Unterhalt M, Hiddemann W. Current status and perspective of antibody therapy in follicular lymphoma. Haematologica. 2006;91(1):104-112. 5.Czuczman MS. Anti-CD80 monoclonal antibody: galiximab. Haematologica Reports. 2005;1(8):35-36. 6.Fanale MA, Younes A. Monoclonal antibodies in the treatment of non-Hodgkin's lymphoma. Drugs. 2007;67(3):333-350. 7.Kwekkeboom J, De Boer M, Tager JM, De Groot C. CD40 plays an essential role in the activation of human B cells by murine EL4B5 cells. Immunology. 1993;79(3):439-444. 8.Stein R, Mattes MJ, Cardillo TM, et al. CD74: a new candidate target for the immunotherapy of B-cell neoplasms. Clin Cancer Res. 2007;13(suppl 18):5556s-5563s.

Surface markers

NHL: emerging agents

Chemotherapy

CD40

CD22

CD20

CD80

1. Kahl B. SeminHematol 2008;45:90–94. 2. Gregory SA, et al. Oncology 2010;24:5. 3. Cheson BD, et al. Clin Lymphoma Myeloma Leuk 2010;10:452–457. 4. Gerber H-P, et al. Blood 2009;113:4352–4361. 5. Tageja N, et al. J Hematol Oncol 2009;2:50. 6. Delmonte A, et al. Oncologist 2009;14:511–525. 7. Witzig TE & Gupta M. Hematology Am Soc Hematol Educ Program 2010;2010:265–270. Adapted slide courtesy of DeVos, UCLA

Microenvironment

Bendamustine3*

Proteasome inhibitors:

Bortezomib;2,5,6

2nd generation6

Bcl-2 family inhibitors:ABT-263,5

GX 15-0706

mTORinhibitors:

Everolimus6,7

Temsirolimus6,7

HDAC inhibitors:Vorinostat (SAHA)6

Panobinostat (LBH589)6

BCR-signaling7

“Pathways”PKC inhibitors:Enzastaurin6,7

Anti-CD20 mAb/ radioimmunotherapy

(RIT)2*

Anti-CD19 mAb4

Anti-CD22 mAb/ immunoconjugates/

RIT1,2*

Bevacizumab1

Lenalidomide2*

*Denotes agent is licensed for a B-cell NHL indication

BTK inhibitor

Presenter

Presentation Notes

Only very few novel drugs have been FDA-approved for aggressive lymphomas in the last 10 years. This is certainly not due to a lack of trying, As there are manly new drugs currently in clinical development. This slide depicts some of them, tested in DLBCL. The targets are the microenvironment, surface markers, an ever growing list of pathways, and there are also novel chemotherapeutics.

Novel Therapies in FL: Select Clinical Trials

Veungopal; 3rd Annual Considerations in Lymphoma 3(2):5-10, 2011

Chanan-Khan and Cheson. J Clin Oncol 26:1544; 2008

Effects of lenalidomide on tumor cells and their microenvironment

Future approach?: High CR rate with lenalidomide plus rituximab in stage III/IV iNHL (incl. FL)

● Interim results of phase II trial (n=19) assessed after 3 cycles; 10 patients with FL had achieved a CR at 6 cycles (below)

● Updated data at ASCO 2010 (n=30): 16 of 17 FL pts (94%) CR rate

Res

pons

e (%

)

Adverse events: Well-tolerated• Rash in 10 patients (erythematous and transient; Grade3/4 n=6)

84% 79%

5%16%

Fowler N, et al. Blood 2009;114: Abst 1714; Updated at ASCO 2010, Abst 8036

High CR/CRu rate

0

20

40

60

80

100

ORR CR/CRu PR SD

84% 79%

5%16%

FL-001: Phase 3 Study Design

1st lineFLn = 1000

RS

R2 maintenance

Rituximab maintenance

R2

R-Chemo

CR, CRu, PR

Primary end-point: PFS

• R2 = Rituximab + Lenalidomide• R-Chemo

─ investigator choice of R-CHOP, R-CVP, R-B• Lenalidomide 20 mg x 6 cycles, if CR then 10 mg

─ subjects with PR after 6 cycles receive additional 3–6 m of lenalidomide 20 mg• Co-primary endpoints

─ surrogate endpoint (for initial approval): CR/CRu rate at 1.5 years─ PFS

Presenter

Presentation Notes

Taken together all the data just presented made directional for two studies which are now ready to start. One is FL001 Celgene study which will randomize R-Chemo (Investigator choice of R-CHOP, R-CVP, R-B) vs R2 Lenalidomide 20-mg x 6 cycles, if CR 10-mg, subjects with PR after 12 cycles receive add’l 3~6 months of lenalidomide 20-mg Rituximab weekly x 4, then on day 1 of each cycle 2 to cycle 6, then every other cycle

PI3K Delta Inhibition Offers a Novel Targeted Therapy in B-Cell Malignancies

Courtesy of Calistoga Pharmaceuticals

PI3K Promotes Survival and Growth of Cancer

Okkenhaug Nat Rev Immunol, 2003

BTK* Regulates Multiple Cellular Processes in B-cell neoplasms

•*Btk = Bruton’s tyrosine kinase•**PCI-32765 = Btk inhibitor

•Burger JA and Gandhi V. Blood 2009 114(12):2560-1

•B-cell receptor (BCR) signaling

•PCI-32765** blocks BCR signals and induces apoptosis

•Chemokine-mediated lymphocyte migration and adhesion

•PCI-32765 reduces lymphadenopathy

•Cytokine secretion•PCI-32765 blocks CCL3/4, TNFα

Targeted Therapy, Novel Agents Being Tested in FL

• Btk inhibition in B-cell malignancies– PCI-32765 shows clinical benefit with single-agent PO dosing1

– 52% ORR in 48 evaluable pts• 78% in MCL; 29-33% in FL, DLBCL, MZL, MALT

– Well tolerated, minimal toxicities at <12.5 mg/kg/day

• CAL -101: Oral PI3K inhibitor– Clinical benefit in pts with r/r indolent NHL, MCL, and CLL2

– Well tolerated with minimal hematologic toxicity– Most frequent AE: reversible increase in ALT/AST– 55% ORR in indolent NHL (n=24); 62% in MCL (N=16)

1Fowler KH et al. ASH 2010 Abst 964 2Kahl B et al. ASH 2010 Abst 1777

Where are we going? / Conclusions Use of “risk analysis” to “individualize” Rx in future Ongoing translational research will identify additional novel

therapeutic targets; Biomarkers associated with response to a given agent are needed

“Targeted” combo therapies increase direct anti-tumor activity while decreasing non-specific toxicities

Problem: How to best combine active agents?... Improve induction? Concurrent vs sequential? Role of “maintenance” (especially with new agents!) • Need well-designed clinical trials and participation by a

large number of pts…

Achieveable Goal: Prolongation of life and quality-of-life in patients with novel non-cross-resistant targeted agents!

evolving management of follicular lymphoma

Business

acta histochem

induce complete

suggested

extended dosing

phase iii

cd20 monoclonal

line indolent

monoclonal