Managing patients with relapsed follicular lymphoma John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Professor of Medicine Associate Director, Weill Cornell Cancer Center Chief, Lymphoma/Myeloma Service Center for Lymphoma and Myeloma Case A 63-year-old male presented with follicular, grade 2 NHL with symptomatic diffuse LAN in the 5-cm range. He is treated with R-CHOP x 6 cycles and then observed. 2 ½ years later, he presents with progressive pelvic LAN in the 3- cm range on routine imaging. Bl d t h i t i d LDH i th l Blood counts, chemistries, and LDH are in the normal range. Bone marrow biopsy is negative for evidence of lymphomatous involvement. 1
Question The preferred management for this patient is: A. Close observation and monitoring B. Single agent rituximab x 4 doses C. Single agent rituximab + maintenance R D. R-Fludarabine combination regimen E. Bendamustine F. Radioimmunotherapy G. RICE or similar regimen H. RICE or similar regimen followed by AuSCT I. Other Overall survival in follicular lymphoma by FLIPI 1.0 No Nodal regions 4 Low risk 0.8 L Elevated LDH Intermediate risk 0.6 A Age 60 High risk 0.4 S Stage III/IV 0.2 H Hemoglobin <120 g/l P<10-4 0 0 1 2 3 4 5 6 7 Years Risk Group No. of Factors % of Pts 5-y OS (%) 10-y OS (%) Survival probabil ity Low 0-1 36 90.6 70.7 Intermediate 2 37 77.8 50.9 High 3-5 27 52.5 35.5 Adapted from Solal-Celigny et al. Blood. 2004;104:1258. 2
Current treatment options in indolent lymphoma Observation Single agent rituximab +/- maintenance Can adding other biologics enhance activity without major toxicity? Chemotherapy + rituximab +/- maintenance What is best chemotherapy? What is role of maintenance rituximab? Radioimmunotherapy Alone or as consolidation SCT options in first (second, later) remission Novel/investigational agents Remission Duration of Patients Receiving AuSCT for FL in Second or Later Remission St. Barts and DFCI Rohatiner et al. J Clin Oncol. 2007;25:2554-9. 3
Comparison of novel anti-cd20s Blood, Jul 2008; doi:10.1182/blood-2008-04-149161 Ofatumumab binding site Ofatumumab Rituximab binding site Human CD20 mab that binds to membrane-proximal epitope encompassing both the small loop and large loop of CD20 1,2 Approved in refractory CLL Phase I/II study in relapsed or refractory follicular lymphoma (FL) 3 ORR: 42% Median duration of response: 30 months ORR in prior rituximab-treated patients: 64% 1. Teeling et al. J Immunol 2006;177:362; 2. Teeling et al. Blood 2004;104:1793; 3. Hagenbeek et al. Blood 2008;111(12):5486 95 4
Ofatumumab in R-Refractory FL Treatment Follow up OFA 300 mg OFA 500 or 1000 mg Response evaluation 0 1 2 3 4 5 6 7 3 mo 6 9 12 18 24 Study Week Month Open label, international, multicenter study in patients with FL who were refractory to rituximab alone or in combination Pre-medications prior to ofatumumab: Paracetamol (acetaminophen) 1000 mg PO or eq. Antihistamine (cetirizine) 10 mg PO or eq. Prednisolone 100 mg IV or eq. prior to infusions 1 and 2; dose could be reduced to <100 mg for other infusions Hagenbeek et al, ASH 2009 Ofatumumab in R-Refractory FL - Response Rates 100 Number of patien nts (%) 80 60 40 20 13% 10% 11% ORR 0 95% CI Ofatumumab Ofatumumab All patients 500 mg (N=30) 1000 mg (N=86) (N=116) 87% and 91% of patients in the 500 mg group and 1000 mg group, respectively, completed all 8 infusions of ofatumumab No difference in primary endpoint (ORR) between 500 mg and 1000 mg group; hence, 2 groups were combined for secondary endpoint analyses Hagenbeek et al, ASH 2009 5
GA101: mechanisms of action type I versus type II antibodies Increased direct cell death Unique type II epitope & elbow-hinge modification Increased ADCC via increased affinity to the 'ADCC receptor' FcgRIIIA Effector cell B cell CD20 Lower CDC activity Due to recognition of type II epitope FcgRIIIa Complement GA101 in recurrent B-NHL : Phase I dose escalation (3+3 design) 100-2000 mg/dose Maintenance Dosing Schema Induction GA101 (Monotherapy) Maintenance 3 6 9 12 15 18 21 24 months RESPONSE ASSESSMENTS Patients achieving PR or CR with induction eligible patients with near PR with clinical benefit) (allowance made for Administered every three months at cohort dose level Response assessed every 3 months by CT Sehn et al, ASH 2009 6
Cohort GA-101 in recurrent B-NHL Overall response following induction by dose cohort (13-week assessment) No. of patients CR PR SD PD 100/200 mg 3 1 2 200/400 mg 3 2 1 400/800 mg 3 2 1 800/1200 mg 3 3 1200/2000 mg 3 3 Non evaluable 1000/1000 mg 7 4 2 1 Total 22 5 13 3 1 24% 62% 14% Sehn et al, ASH 2009 Subcutaneous humanized anti-cd20 Veltuzumab in B-cell NHL 80-320 mg/m2 every 2 weeks x 4 doses Prior lines of therapy: 5T Treatment tnaïve, 6 with ith1 prior rx, 4 with ith2+ prior rx Patients (n=15) Overall response rate All evaluable pts 8/15 (53%) Follicular l lymphoma 7/12 (53%) Non-Follicular lymphoma 1/3 (33%) Chronic lymphocytic leukemia 0/8 (0%) Infections (3 pts): pneumonia, transient upper respiratory infections Allen et al, J Clin Oncol 2009; 27(suppl): (abstract 8530). 7
Anti-lymphoma antibodies in the clinic Cheson and Leonard, NEJM 2008 Multicenter Epratuzumab + Rituximab Strauss, et al, JCO 2006 Duration of Response 8
Radiolabeled anti-cd20 antibodies Yttrium 90 ibritumomab tiuxetan (Zevalin) Iodine 131 tositumomab (Bexxar) Pretargeted (investigational) Secondary agent to amplify radiation i dose and enhance specificity Common themes regarding radiolabeled anti-cd20 antibodies Treatment done in a week (2 injections) Gamma camera imaging g or counts a component Manageable radiation safety issues Toxicity is principally infusion-related and hematologic Baseline hematologic status relevant Blood count monitoring required for 3 months Important long-term toxicity usually absent RR 60-80%, CR 30% Some patients have durable remissions Myeloablative therapy promising 9
Where should we consider the use of radioimmunotherapy in NHL? Current data clearly support use in: Relapsed low-grade/transformed NHL Advantages over rituximab +/chemorx debatable Chemotherapy-refractory low-grade NHL Rituximab-refractory low-grade NHL Transformed NHL Responsive disease but with short remissions Potential utility in: Upfront therapy (alone or in sequence with chemotherapy) Relapsed/refractory patients with other histologies IMIDs in lymphoid malignancies IMID effects Inhibits TNF Inhibits angiogenesis (bfgp, VEGF) Stimulates T cells (CD8+) Inhibits IL-12 Induces apoptosis Alters cytokines Affects stromal cells Inhibits pro-survival factors (Akt) Cool RM et al. Pharmacotherapy. 2002;22:1019; D Amato RJ et al. Proc Natl Acad Sci USA. 1994;91:4082; Meierhofer C et al. BioDrugs. 2001;15:681; Thalidomide s various effects in myeloma [figure]. Available at: http://www.multiplemyeloma.org/treatments/3.04.asp; Weber D et al. J Clin Oncol. 2003;21:16; Bartlett JB et al. Nature Reviews/Cancer. 2004;4:314 10
Lenalidomide for Relapsed/Refractory Indolent Lymphoma Study No. of Pts Regimen Witzig et al 43 Lenalidomide monotherapy Dutia et al 16 Lenalidomide +R (R 2 ) Ahmadi et al 15 Lenalidomide, dexamethasone, and R PFS for Patients Receiving Lenalidomide + 100 R 80 Efficacy ORR: 23%, CR: 7% PFS: 4.4 mos; DOR >16.5 mos ORR: 75%, CR: 31% PFS: 12 mos ORR: 53%, CR: 33% PFS: 86% at 10.9 mos Survival (% %) 60 40 20 0 0 5 10 15 20 Time (Months) Witzig. J Clin Oncol. 2009;27:5404; Dutia. ASH. 2009 (abstr 1679); Ahmadi. ASH. 2009 (abstr 1700). Relapsed follicular NHL CALGB 50401 Relapsed Follicular NHL after 1 rituximab based regimens R A N D O M I Z E Lenalidomide Rituximab + Lenalidomide 11
Study O Connor, 2005 Goy, 2005 Strauss, 2006 Single-Agent Bortezomib in Relapsed Indolent Lymphoma Subtype Evaluable Patients (N) CR/CRu PR OR FL 9 1/1 5 7 (77%) MZL 2 0 2 2 (100%) SLL 3 0 0 0 FL 5 0/1 0 1 (20%) SLL 4 1/0 0 1 (25%) WM 2 0 1 1 (50%) FL 11 0 2 2 (18%) WM 5 0 2 2 (40%) CRu=unconfirmed CR; WM=Waldenström s macroglobulinemia. O Connor. J Clin Oncol. 2005;23:676; Goy. J Clin Oncol. 2005;23:667; Strauss. J Clin Oncol. 2006;24:2105. Grade 1/2 FL Documented relapse or progression following prior therapy PR response to rituximab with TTP 6 months Accrual goal: N=670 Phase III LYM-3001 Trial: Bortezomib Plus Rituximab in Relapsed/Refractory FL Primary endpoint: PFS R A N D O M I Z E Bortezomib 1.6 mg/m 2 weekly on days 1,8,15, and 22 + Rituximab 375 mg/m 2 once a week on days 1,8,15, and 22 of cycle 1, then 375 mg/m 2 on day 1 of cycles 2 to 5 Rituximab 375 mg/m 2 once a week on days 1,8,15, and 22 of cycle 1, then 375 mg/m 2 on day 1 of cycles 2 to 5 5 35-day cycles US National Institutes of Health Web site. http://clinicaltrials.gov/ct2/show/nct003128 45?term=LYM-3001&rank=1. Accessed July 2, 2008. 12
Bendamustine in rituximab-refractory indolent NHL 100 pts (first 38 analyzed), rituximab-refractory indolent NHL (no response to R or response < 6 months) Median 3 prior regimens (range 1-10), 47% also chemoresistant Bendamustine administered 120 mg/m2 over 1 hr days 1, 2 every 21 days Toxicities primarily grade 3 and 4 hematologic, grade 1 and 2 nausea ORR 84% (29% CR), median PFS 9.7 months Kahl, B, et al, ASH 2007, Abstract 1351 Bendamustine + rituximab in relapsed/refractory indolent and MCL: Efficacy Efficacy: # of Patients (%) FL SLL MCL Marginal Zone Total (n=24) (n=17) (n=16) (n=6) (n=63) ORR 23 (96%) 17 (100%) 12 (75%) 5 (83%) 57 (90%) CR 17 (71%) 9 (53%) 8 (50%) 4 (67%) 38 (60%) PR 6 (25%) 8 (47%) 4 (25%) 1 (17%) 19 (30%) Median duration of progression-free survival: 30 months Median overall survival: 65 months Safety: Grade 3 Grade 4 % of Grade 3/4 Leukocytopenia 32 3 16% Thrombocytopenia 6 1 3% Anemia 2-1% Rummel ASCO 2007, Abstract 8034 13
Bendamustine, Bortezomib and Rituximab Phase II, multicenter study Patient population: relapsed, indolent B-cell or mantle cell NHL. Exclusion: prior ASCT or RIT within 4 months; prior allosct at any time. Schema: 28 day cycle Day 1 Day 4 Day 8 Day 11 Bendamustine 90mg/m2 x x Rituximab 375 mg/m2 x Bortezomib 1.3 mg/m2 x x x x Friedberg et al, ASH 2009 BVR patient population Median 4 prior regimens Category n (%) Indolent Follicular 16 (52)* Small lymphocytic 3 (10) Lymphoplasmacytic 2 (6) Marginal zone 3 (10) Mantle cell lymphoma 7 (23) * FL grade 1 (N=7); FL grade 2 (N=3); FL grade 3 (N=5); FL NOS (n=1) Friedberg et al, ASH 2009 14
BVR - Response Rate* % of ITT Population Category (N = 29) Overall response rate 79 Complete response 51 Partial response 28 Stable disease 10 Progressive disease 10 *One patient not evaluable for response; one patient not eligible and never received therapy Friedberg et al, ASH 2009 BVR - Progression-free survival PFS at 1 year=74%; PFS for responding pts at 1 year = 86% Friedberg et al, ASH 2009 15
Bortezomib, Bendamustine, Rituximab VERTICAL Study Design Cycle 1 Days 1 2 8 15 22 35 R B Cycles 2 5 V Days 1 2 8 15 22 35 Patients received five 35-day treatment cycles When given on the same day, the order of administration was V B R Fowler et al, ASH 2009 Comparison with Other VR and BR Follicular Lymphoma Therapies Study VERTICAL Rummel et al. JCO 2005 Robinson et al. JCO 2008 de Vos et al. JCO 2009 Regimen VBR BR BR VR Pi Prior therapies, median (range) 2 (1 11) 1 (1 3) 1 (1 4) 2 (0 3) Prior rituximab, % 100 0 56 90 Median prior rituximab therapies (range) 2 (1 6) N/A 1 (1 3) NR Refractory to last prior rituximab therapy, % 39 N/A NR NR FLIPI risk, Low / Intermediate / High, % 30 / 33 / 37 17 / 25 / 58* 33 / 33 / 33* 33 / 33 / 33 Bulky disease >7 cm: 21% 5 cm: 56% NR >7 cm or 3 nodes from sites >3 cm: 18% ORR, % 86 96* 93 # 41* CR, % 53 71* 41 # 10 Gr 3/4 anemia, % 3 1 2 NR Gr 3/4 neutropenia, % 27 NR 36 3 Gr 3/4 thrombocytopenia, % 6 3 9 0 *FL patients only; # indolent lymphoma patients only; weekly regimen reported; CR/Cru; of assessable cycles 16
Phosphatidylinositol 3-Kinase (PI3K) Signaling Pathway Population CAL-101 Clinical Response Rate No. Evaluable No. of PR Response Rate No. of SD on study Indolent NHL 15 9 60% 3 Aggressive NHL MCL DLBCL 12 7 5 6 6 0 50% 86% 0% CLL 17 4 24% 7 AML 9 0 0% 1 1 PR=partial response; SD=stable disease Flinn et al, ASH 2009 17
Phase I study of the Btk inhibitor PCI-32765 in relapsed aggressive NHL Bruton s tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling Dosing: 1.25 mg/kg/day with escalation to 2.5, 5.0, 8.3, 12.5, 17.5 mg/kg 29 patients have been enrolled on cohorts 1-4 (12 FL, 7 CLL/SLL, 4 DLBCL, 4 MCL, 2 MZL) One DLT (neutropenia), most AEs have been < grade 2 Response Patients (n=19) ORR 42% CR 1 (SLL) PR 7 (4 CLL/SLL, 2 MCL, 1 FL) Advani et al. ASCO 2010, Abstract 8012 Summary Novel anti-cd20 antibodies are under evaluation but potential advantages relative to rituximab remain unclear New antibodies with different targets are under exploration, largely in combination with rituximab older-newer drugs are under evaluation in NHL in combination regimens Various new agents are safe and active Drug development in NHL is becoming more complex due to disease and treatment heterogeneity 18