Download - 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
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!
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
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)
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
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
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
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
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
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
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!