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Evolving Management of Follicular Lymphoma        HUMC Oncology Fall Conference               November 3, 2011            ...
Disclosure Information                 Myron S. Czuczman, MDI have the following financial relationships to disclose:  Mem...
Outline• Background• Approach to Rx of Advanced-stage FL   – Rapidly changing terrain• Who When and Why Treat? Goals?• Wha...
Characteristics of Follicular LymphomaClinical Pattern: • Indolent clinical course (typical) • Highly responsive to therap...
Current Lymphoma Field:         Rapidly Changing Landscape• Heterogeneity/complexity of FL will not change   – We are deve...
New directions in the treatment of follicular              lymphoma (FL) in 2011• The successful use of mAbs in B-cell mal...
What are our treatment goals in FL patients?     • Increased CR and PFS rates were associated with       improved survival...
Indications for Rx* on FL clinical trials (an example)    B-symptoms    Hematopoietic failure     (Hb < 11 g/dl, granulo...
What Rx to Use @ Presentation?               @ Relapse?• Answer: “Varies”• Need additional information to gain a better  u...
Suggested Treatment Regimens            (in alphabetical order)First-line Therapy• Bendamustine + R• CHOP (cyclophosphamid...
Suggested Treatment Regimens        (in alphabetical order)Second-line and Subsequent Therapy• Chemoimmunotherapy (as in f...
NEWINFORMATION PRESENTED    IN 2010 and 2011         in FL
Biomarkers in FLRelander et al, J Clin Oncol 28(17), 2902-2913 , 2010
Bendamustine Chemical Structure     Bendamustine cross-links DNA single and double strands, inhibiting DNA                ...
Phase III Study of First-line  Bendamustine/Rituximab (B-R) Versus R-      CHOP in Indolent NHL: Efficacy                 ...
Phase III Study of First-line B-R vs. R-CHOP in               Indolent NHL: Safety                                        ...
Maintenance Therapy First-line   consolidation or extended dosing  – Chemotherapy followed by radioimmunotherapy  – Ritux...
FIT (Front-Line Indolent Trial)                                                                   Enroll       CONSOLIDATI...
Median PFS for All Patients         36.5 mos (90Y-Ib) Vs. 13.3 mos (Control; p < .0001)                     100           ...
FIT Trial: Conclusions…   •   90Y-Ibritumomab       consolidation resulted in:        – High conversion rates from PR to C...
SWOG/CALGB Trial 0016    Untreated Advanced Stage FL CHOP x 6          CHOP x 6             CHOP x 6 +                  + ...
Rituximab Maintenance for 2 Years in Patients with High Tumor      Burden FL responding to R-chemotherapy (PRIMA):        ...
Primary Rituximab and Maintenance study: PRIMA                                                                            ...
Rituximab Maintenance: Do the Results of  the PRIMA Study Define a New Standard of Care?• Current results of the PRIMA stu...
An Intergroup Randomized Trial of Rituximab vs. a Watch       & Wait Approach in Patients with Advanced Stage,            ...
Primary Endpoint: Time to        initiation of next therapy– Symptomatic enlarged LN or spleen– ‘B’ symptoms or severe pru...
Benefit of early rituximab ± maintenance over                      watch & wait in asymptomatic non-bulky FL              ...
The duration of rituximab benefit is limited!                                         100         Progression-free surviva...
Risks Associated with Prolonged             B-cell Suppression*• Hypogammaglobulinemia• Delayed neutropenia• Viral reactiv...
Next generation anti-CD20 mAbs        Name               Comparison to Rituximab                                  Status O...
B-Cells: Express Many Surface Antigens That May             Serve as Targets for mAbs                              Marker ...
NHL: emerging agents  Microenvironment                                                                    Surface markers ...
Novel Therapies in FL: Select Clinical TrialsVeungopal; 3rd Annual Considerations in Lymphoma 3(2):5-10, 2011
Effects of lenalidomide on tumor cells     and their microenvironment                Chanan-Khan and Cheson. J Clin Oncol ...
Future approach?: High CR rate with lenalidomide     plus rituximab in stage III/IV iNHL (incl. FL)    ● Interim results o...
FL-001: Phase 3 Study Design                            Primary end-point: PFS                       R2                   ...
PI3K Delta Inhibition Offers a Novel Targeted       Therapy in B-Cell MalignanciesCourtesy of Calistoga Pharmaceuticals
PI3K Promotes Survival and Growth of CancerOkkenhaug Nat Rev Immunol, 2003
BTK* Regulates Multiple Cellular Processes in B-cell neoplasms                                                      •B-cel...
Targeted Therapy, Novel Agents                     Being Tested in FL• Btk inhibition in B-cell malignancies   – PCI-32765...
Where are we going? / Conclusions Use of “risk analysis” to “individualize” Rx in future Ongoing translational research ...
Evolving Management of Follicular Lymphoma
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Evolving Management of Follicular Lymphoma

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Myron Czuczman, M.D., Professor Chief, Lymphoma/Myeloma Service, Dept. of Medicine Head, Lymphoma Translational Research Laboratory Dept. of Immunology Roswell Park Cancer Center
Evolving Management of Follicular Lymphoma

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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Evolving Management of Follicular Lymphoma

  1. 1. Evolving Management of Follicular Lymphoma HUMC Oncology Fall Conference November 3, 2011 Hackensack, NJ Myron S. Czuczman, MD Chief, Lymphoma/Myeloma Service Head, Lymphoma Translational Research Laboratory Professor of Medicine and Oncology Roswell Park Cancer Institute Buffalo, NY
  2. 2. Disclosure Information Myron S. Czuczman, MDI 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, MundiPharmaI 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)
  3. 3. 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
  4. 4. 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
  5. 5. 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?
  6. 6. 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!
  7. 7. What are our treatment goals in FL patients? • Increased CR and PFS rates were associated with improved survival: 1.0 CR PR 0.8 Survival probability 0.6 0.4 0.2 0 0 5 10 15 20 Overall survival (y)Bachy E, et al. J Clin Oncol 2010; 8:822–829
  8. 8. 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! references.
  9. 9. 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)
  10. 10. 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)• RituximabFirst-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
  11. 11. 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
  12. 12. NEWINFORMATION PRESENTED IN 2010 and 2011 in FL
  13. 13. Biomarkers in FLRelander et al, J Clin Oncol 28(17), 2902-2913 , 2010
  14. 14. Bendamustine Chemical Structure Bendamustine cross-links DNA single and double strands, inhibiting DNA replication, repair, and transcription* ClH2C Bendamustine Carboxylic acid N N ClH2C COOH Nitrogen mustard N Benzimidazole ring CH3 NH2 Cl N N Cyclophosphamide Cl N N O O N P HOCH2 Cl O N Cladribine HMOA: Leads to mitotic catastrophe in cells OH* Ghandi et al. Semin Oncol. 2002;29:4
  15. 15. Phase III Study of First-line Bendamustine/Rituximab (B-R) Versus R- CHOP in Indolent NHL: Efficacy B-R R-CHOP P Value HR (n = 260) (n = 253)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 0.52Rummel et al. ASH 2009; abstract 405
  16. 16. Phase III Study of First-line B-R vs. R-CHOP in Indolent NHL: Safety Cycles B-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 Patients B-R (n = 260) R-CHOP (n = 253) Infectious Complications (All Grades) 96 127 Skin (Erythema, All Grades) 42 23 Allergic Skin Reactions (All Grades) 40 15Thoughts/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? Rummel et al. ASH 2009; abstract 405
  17. 17. 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
  18. 18. FIT (Front-Line Indolent Trial) Enroll CONSOLIDATION 90Y-Ib consolidation R INDUCTION (n = 208) A First-line therapy with CVP, N Rituximab 250 mg/m2 6–12 wks IV Day 0, 7 + CHOP-like, fludarabine D 90Y-Ib 14.8 MBq/kg combinations, chlorambucil, O or rituximab combination M CR/CRu I or PR Z A T Primary end point: PFSa I O CONTROL NR N PD No further treatment (n = 206) Off StudyaCalculation of PFS starts at enrollment, not from induction.90Y-Ib = Y-90 ibritumomab tiuxetan; IV = intravenous.Morschhauser et al, 2008.
  19. 19. Median PFS for All Patients 36.5 mos (90Y-Ib) Vs. 13.3 mos (Control; p < .0001) 100 2-sided log-rank p < .0001 HR 0.465 95% CI: 0.357–0.605 80 90Y-Ib (n = 208) Median 36.5 mos PFS (%) 60 40 Control (n = 206) Median 13.3 mos 20 0 0 6 18 18 30 30 42 42 54 54 66 66 Time After Random Assignment (mos)Morschhauser et al, 2008
  20. 20. 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-Ibritumomabconsolidation 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 armsMorschhauser et al. J Clin Oncol . 2008;26:5156-5164
  21. 21. SWOG/CALGB Trial 0016 Untreated Advanced Stage FL CHOP x 6 CHOP x 6 CHOP x 6 + + Rituximab 131ITositumomab (Bexxar)•Update: Results Pending•ASH 2011 abstract accepted as an oral presentation
  22. 22. Rituximab Maintenance for 2 Years in Patients with High Tumor Burden FL responding to R-chemotherapy (PRIMA): A phase 3 randomized control trialPatientswere required to have at least one of the following:B-symptomsBulky disease at study entry (nodal or extranodal mass >7cm)Symtomatic splenomegaly, compressive syndrome, pleural/peritoneal effusionInvolvement of > 3 nodal sites (each > 3cm)Elevated LDH (>ULN) or β2-microglobulin (>3mg/L) Gilles Salle et al. ASCO 2010; Abstract 8004
  23. 23. Primary Rituximab and Maintenance study: PRIMA Rituximab maintenance Immunochemotherapy 375 mg/m2 q8w for 2 High tumor 8 x rituximab years burden + CR/CRu untreated 8 x CVP or Randomize 1:1 PR follicular 6 x CHOP or lymphoma 6 x FCM Observation 1.0 PFSProgression-free rate 82% 0.8 Rituximab maintenance n=505 0.6 Observation 66% n=513 0.4 Stratified HR=0.50 95% CI 0.39; 0.64 0.2 P<0.0001 0.0 0 6 12 18 24 30 36 Time (mo) Salles GA, et al. J Clin Oncol 2010;28(Suppl.): Abst. 8004
  24. 24. 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
  25. 25. An Intergroup Randomized Trial of Rituximab vs. a Watch & Wait Approach in Patients with Advanced Stage, Asymptomatic, non-Bulky FL Study Schema F ARM A O R Watch and Wait Clinic visits L A L N ARM B O D Rituximab Induction W O M ARM C U I Rituximab Induction P Z & maintenance A T Progressive disease Compulsory CT scan Compulsory I requiring therapy stops CT scan if clinical CR CT scan O protocol treatment N Bone marrow for histology and MRD only if CT shows CRArdeshna et al. Blood 116: Abstract 6, 2010
  26. 26. Primary Endpoint: Time to initiation of next therapy– Symptomatic enlarged LN or spleen– ‘B’ symptoms or severe pruritus Limitation of– Lymphomatous mass > 7cm Study: provided size increased by 25% “At the time of– >3 nodal sites with nodes >5cm progression,– Significant effusions rituximab– Lymphoma-related cytopenias monotherapy– Near-critical organ was not an involvement/compression option!”– Histological transformationArdeshna et al. Blood 116: Abstract 6, 2010
  27. 27. Benefit of early rituximab ± maintenance over watch & wait in asymptomatic non-bulky FL 1.0 TTNT: PFS: Group 3y-PFS (%) 0.8 Proportion of pts with Watch & Wait (WW) 33 no new Tx initiated Rituximab (R) 60 0.6 Rituximab 81 maintenance (M) 0.4 Events Totals WW: 83 187 Pts not requiring Rx (%): 0.2 R: 19 84 W+W=48 R=80% R+M: 19 192 R+M=91% 0.0 0 1 2 3 4 5 Time from randomization (y) No difference in OS between treatment arms • Is this clinically meaningful? • Cost versus benefit?Ardeshna KM, et al. Blood 2010;116: Abstract 6
  28. 28. The duration of rituximab benefit is limited! 100 Progression-free survival (%) 80 P=0.937 60 Maintenance 40 20 Retreatment 0 0 12 24 36 48 60 Time (mo) •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 RxHainsworth JD, et al. J Clin Oncol 2005;23:1088–1095
  29. 29. 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
  30. 30. Next generation anti-CD20 mAbs Name Comparison to Rituximab Status Ofatumumab1,2 •Human mAb •FDA-approved in r/r CLL •Novel membrane proximal •S/P Ph III in rituximab-refractory FL CD20 epitope •Ph III: in CLL, FL, DLBCL •Stronger CDC •Several Ph II trials (also RA and •Slower dissociation rate MS) •Stronger binding to B-cells GA1011 •Type II anti-CD20 (glycol- •S/P Ph I trials engineered Fc Region) •Ph III Benda vs. Benda + GA101 in •Increased ADCC/Apoptosis rituximab-refractory indolent NHL •Stronger binding to effectors •Several Ph II trials •Limited CDC Veltuzumab1 •Humanized IgG1 mAb •S/P Ph I/II studies (IV) •Single a.a. change in CDR3- •Phase I/II sub q in NHL/CLL VH (Asn to Asp) •Phase I subq in ITP •Epratuzumab framework •Slower dissociation rate •Stronger CDC •Enhances epratuzumab activity •Low-dose subq formulation1. Robak T & Robak E. Biodrugs 2011;25:13–25. 2. Lin TS. Pharmacogenomics and Personalized Medicine 2010;3:51–59.
  31. 31. B-Cells: Express Many Surface Antigens That May Serve as Targets for mAbs Marker  Antigen expression variable1,2 B-cell receptor (BCR)  Most involved in B-cell growth, differentiation, proliferation, CD19 and activation; other functions CD20 include1,2: CD21 CD22 B-Cell CD23 – Immune regulation CD38 – Complement inhibition CD40 CD52  Many are targets of therapeutic CD46, CD55, CD59 mAbs for current or potential CD74 use in B-cell malignancies1,2 CD801Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program. 2007;2007:233-2422Hotta T. Acta Histochem Cytochem. 2002;35(4):275-279 31
  32. 32. NHL: emerging agents Microenvironment Surface markers CD22 Bevacizumab1 CD40 Anti-CD20 mAb/ radioimmunotherapy CD20 Lenalidomide2* CD80 (RIT)2* Anti-CD19 mAb4 Chemotherapy Anti-CD22 mAb/ immunoconjugates/ Bendamustine3* RIT1,2* “Pathways” Bcl-2 family Proteasome PKC inhibitors: HDAC inhibitors: inhibitors: inhibitors: mTOR Enzastaurin6,7 Vorinostat (SAHA)6 ABT-263,5 Bortezomib;2,5,6 inhibitors: 6,7 Panobinostat (LBH589)6 2nd generation6 Everolimus 6,7 BCR-signaling 7 GX 15-0706 Temsirolimus BTK inhibitor *Denotes agent is licensed for a B-cell NHL indication1. Kahl B. SeminHematol 2008;45:90–94. 2. Gregory SA, et al. Oncology 2010;24:5. 3. Cheson BD, et al. ClinLymphoma Myeloma Leuk 2010;10:452–457. 4. Gerber H-P, et al. Blood 2009;113:4352–4361. 5. Tageja N, etal. 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
  33. 33. Novel Therapies in FL: Select Clinical TrialsVeungopal; 3rd Annual Considerations in Lymphoma 3(2):5-10, 2011
  34. 34. Effects of lenalidomide on tumor cells and their microenvironment Chanan-Khan and Cheson. J Clin Oncol 26:1544; 2008
  35. 35. 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 100 84% 79% High CR/CRu rate Response (%) 80 60 40 16% 16% 20 5% 5% 0 ORR CR/CRu PR SD Adverse events: Well-tolerated • Rash in 10 patients (erythematous and transient; Grade3/4 n=6)Fowler N, et al. Blood 2009;114: Abst 1714; Updated at ASCO 2010, Abst 8036
  36. 36. FL-001: Phase 3 Study Design Primary end-point: PFS R2 R2 maintenance1st lineFL S R CR, CRu, PRn = 1000 R-Chemo Rituximab maintenance• 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
  37. 37. PI3K Delta Inhibition Offers a Novel Targeted Therapy in B-Cell MalignanciesCourtesy of Calistoga Pharmaceuticals
  38. 38. PI3K Promotes Survival and Growth of CancerOkkenhaug Nat Rev Immunol, 2003
  39. 39. BTK* Regulates Multiple Cellular Processes in B-cell neoplasms •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 •*Btk = Bruton’s tyrosine kinase •**PCI-32765 = Btk inhibitor •Burger JA and Gandhi V. Blood 2009 114(12):2560-1
  40. 40. 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
  41. 41. 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!

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