Approaches for Treatment Lymphoma PowerPoint Presentation

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Case-Based Workshop With the Experts: Evolving Management Strategies in Non-Hodgkin’s Lymphoma This program is supported by educational grants from

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Owen A. O’Connor, MD, PhD Professor of Medicine and Pharmacology Deputy Director for Clinical Research and Cancer Treatment NYU Cancer Institute Chief, Division of Hematologic Malignancies and Medical Oncology NYU Langone Medical Center New York, New York Multidisciplinary Approaches for the Diagnosis and Optimal Treatment of MCL

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About These Slides Our thanks to the authors who gave permission to include their original data Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

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Program Faculty Program Director Mary Jo Lechowicz, MD Assistant Professor  Hematology/Oncology Emory University Atlanta, Georgia Core Faculty Christopher R. Flowers, MD, MS Director, Lymphoma Program Medical Director, Oncology Data Center Assistant Professor Bone Marrow and Stem Cell Transplantation Department of Hematology and Oncology Emory University Atlanta, Georgia Owen A. O’Connor, MD, PhD Professor of Medicine and Pharmacology Deputy Director for Clinical Research and Cancer Treatment NYU Cancer Institute Chief, Division of Hematologic Malignancies and Medical Oncology NYU Langone Medical Center New York, New York Julie M. Vose, MD Neumann M. and Mildred E. Harris Professor Chief, Section of Hematology/ Oncology Professor of Medicine University of Nebraska Medical Center Omaha, Nebraska

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Faculty Disclosures Christopher R. Flowers, MD, MS, has disclosed that he has received consulting fees from Celgene and Prescription Solutions and research funding from Millennium, Pfizer, and Spectrum. He has also disclosed that he has other (nonpaying advisory boards) relationships with Biogen Idec and Genentech. Mary Jo Lechowicz, MD, has no significant financial relationships to disclose. Owen A. O’Connor, MD, PhD, has disclosed that he has served as consultant for Allos, Astellas, Lilly, and Millennium and has received research support from Allos, Astellas, Lilly, Merck, Millennimum, and Spectrum. Julie M. Vose, MD, has disclosed that she has received research funding from Allos Therapeutics, AstraZeneca, Bristol-Myers Squibb, Celgene, Exelixis, Genentech, Genzyme, GlaxoSmithKline, Novartis, Pharmacyclics, and US Biotest.

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Mantle Cell Lymphoma Median age: 58 yrs M:F ratio: 3:1 Typically advanced stage B symptoms: < 50% cases 90% extranodal involvement: BM, blood, liver, GI Generalized adenopathy: 70% to 90% CNS involvement at relapse: 4% to 22% (↑ with blastoid) Fisher RI. Ann Oncol. 1996;7(suppl 6):S35-S39. Armitage JO. Oncology (Williston Park). 1998;12 (10 suppl 8):48-55. Romaguera JE, et al. Cancer. 2003;97:586-591. Gill S, et al. Leuk Lymphoma. 2008;49:2237-2239.

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Frontline MCL Therapy

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R-CHOP vs CHOP in Untreated MCL 64 patients randomized in each arm No differences observed in PFS or OS between treatment arms Lenz G, et al. J Clin Oncol. 2005;23:1984-1992.

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STiL: Frontline B-R vs R-CHOP Primary endpoint: PFS (noninferiority B-R < 10% at 3 yrs) Secondary endpoints: ORR, CR, toxicity, stem cell mobilization Bendamustine-Rituximab (n = 260) B 90 mg/m2 on Days 1, 2 + R 375 mg/m2 on Day 1 Max 6 cycles q4w R-CHOP (n = 253) Max 6 cycles q3w CD20+ FL, SLL, MZL, MCL, LPL, stage III-IV, untreated, 18 yrs of age or older (N = 549) Rummel MJ, et al. ASH 2009. Abstract 405.

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STiL: BR vs R-CHOP, All Disease Types 513 evaluable patients > 1/2 FL/18% MCL No difference in ORR between treatment arms CR B-R: 40% R-CHOP: 31% P = .03 BR toxicity profile: alopecia, neutropenia, thrombocytopenia, infections Rummel MJ, et al. ASH 2009. Abstract 405. PFS B-R: 55 mos R-CHOP: 35 mos P < .05

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Dose-Intensive Approaches

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MCL: High-Dose Therapy/ASCT—CHOP Backbone Tripled CR rate after DHAP (12% vs 61%)[2] Median EFS: 84 mos vs 51 mos prior to rituximab[1] 1. Lefrere F, et al. Leukemia. 2002;16:587-593. 2. Delarue R, et al. ASH 2008. Abstract 581. 3. Dreyling M, et al. ASH 2008. Abstract 769. Dreyling M, et al. Blood. 2005;105:2677-2684. 1.0 0.8 0.6 0.4 0.2 0 Survival Probability Yrs After End of Induction Therapy 0 1 2 3 4 5 6 ASCT IFN P = .0108 Pts at Risk, n ASCT IFN 62 38 31 17 10 3 60 33 19 9 6 2 1.0 0.8 0.6 0.4 0.2 0 P (EPS) Mos 0 10 20 30 40 50 60

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0 20 40 60 80 100 MCL: High-Dose Therapy/ASCT—More Intensive Induction Small series Long follow-up Bias? (toxic regimen) EFS, PFS, OS, and mol CR/previous CHOP—ASCT Preemptive rituximab maintenance based on QPCR MCL3/similar + ibritumomab tiuxetan prior ASCT[3] Magni M, et al. Bone Marrow Transplant. 2009;43:509-511. 2. Geisler et al. Blood. 2008;112:269-293. 3. Kolstadt, et al. ASH 2009. Abstract 932. EFS EFS A B R-HDS low risk R-HDS int-high risk MCL2 (n = 160) MCL1 (n = 41) Percent Survival Percent Survival Mos Yrs 0 2 4 6 8 10 P < .0001 0 24 48 96 0 20 40 60 80 100 P < .0001 120 108 84 72 60 36 12

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EU Trial: MCL Younger Protocol Design Primary endpoint: time to treatment failure Secondary endpoints: response rates, OS, toxicity Hermine O, et al. ASH 2010. Abstract 110. (2 + 1) x R-CHOP/DHAP alternating (stem cell mobilization after course 6) TBI 10 Gy Ara-C 4 x 1.5 g/m2 + Melphalan 140 mg/m2 + PBSCT Patients younger than 65 yrs of age with MCL, ECOG PS < 2, Ann Arbor stage II-IV, eligible for high-dose therapy 4 x R-CHOP 2 x R-CHOP DexaBEAM (stem cell mobilization) Cyclo 120 mg/kg + TBI 12 Gy PBSCT

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1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 EU Trial: Results Hermine O, et al. ASH 2010. Abstract 110. Time to Treatment Failure PP MCL Younger: Remission Duration After ASCT Probability 0 12 24 36 48 60 72 Mos Since Randomization Pts at Risk, n 208 147 99 67 29 11 0 212 134 95 66 36 11 0 R-DHAP R-CHOP HR: 0.68 P = .0382 (1-sided sequential test) Median follow-up: 32 mos R-DHAP, median not reached R-CHOP, median: 49 mos Probability 0 12 24 36 48 60 72 Mos Since Retransfusion Pts at Risk, n 133 99 69 45 19 0 133 92 66 43 15 1 0 R-DHAP R-CHOP P = .0059 Median follow-up: 30 mos R-DHAP, median not reached R-CHOP, median: 48 mos

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High-Dose Therapy/ASCT: Summary No difference in ORR (97%) or CR/CRu (79/82%) post- ASCT Hermine O, et al. ASH 2010. Abstract 110.

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Comparison of Dose-Intensive/High-Dose Therapy in MCL Ara-C–containing induction regimens for MCL 1. Geisler CH, et al. ASH 2007. Abstract LBA1. 2. Cortelazzo S, et al. ASH 2007. Abstract 1282. 3. Romaguera JE, et al. J Clin Oncol. 2005;23:7013-7023. 4. Fayad L, et al. Clin Lymphoma Myeloma. 2007;8(suppl 2):S57-S62. *4 MDS and 3 solid tumors. Compare to R-CHOP PFS 25% at 52 yrs

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SWOG 0213: R-HyperCVAD in MCL Epner EM, et al. ASH 2007. Abstract 387. *No details on dose reductions Yrs From Registration 0 20 40 60 80 100 0 1 3 5 2 4 OS PFS Patients (%) 6

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Kahl BS, et al. Ann Oncol. 2006;17:1418-1423. CR, CRu, PR ASSESS Rituximab 375 mg/m2 on Day 1 + Cyclophosphamide 300 mg/m2 q12 hrs on Days 1-3 + Doxorubicin 50 mg/m2 48-hr CI on Days 1-2 + Vincristine 2 mg IV on Day 3 + Dexamethasone 40 mg PO on Day 1-4 Rituximab 375 mg/m2 once wkly × 4 q6m × 4 22 untreated MCL Toxicity mainly hematologic Median PFS: 37 mos PFS Median OS: not reached 0 10 20 30 40 50 60 0 20 40 60 80 100 OS Mos Patients Alive (%) Median follow-up: 37 mos No vincristine or steroids on Day 11/no methotrexate, no Ara-C/monthly cycles x 6 Modified R-HyperCVAD: Design

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NCCN Study in MCL: PFS LaCasce A, et al. ASH 2009. Abstract 403.

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NCCN Study in MCL: OS LaCasce A, et al. ASH 2009. Abstract 403.

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Forstpointner R, et al. Blood. 2004;104:3064-3071. FCM vs R-FCM in Relapsed Indolent Lymphoma 4 cycles FCM vs R-FCM Relapsed indolent lymphoma Fludarabine Cyclophosphamide Mitoxantrone Fludarabine Cyclophosphamide Mitoxantrone + Rituximab R 128 patients evaluable with relapsed indolent NHL; 48 evaluable patients with MCL

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1. Zelenetz A, et al. ASCO 2006. Abstract 7560. 2. Smith M, et al. ASH 2007. Abstract 389. Frontline Radioimmunotherapy in MCL

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Radioimmunotherapy in MCL 1. Gopal AK, et al. Blood. 2002;99:3158-3162. 2. Krishnan A, et al. J Clin Oncol. 2008;26:90-95.

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Relapsed/Refractory MCL

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1. Inwards DJ, et al. Cancer. 2008;113:108-116. 2. Ogura M, et al. ASH 2009. Abstract 3694. 3. Rummel MJ, et al. J Clin Oncol. 2005;23:3383-3389. 4. Robinson KS, et al. J Clin Oncol. 2008;26:4473-4479. Relapsed/Refractory MCL

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Single-Agent Y-90 Ibritumomab Tiuxetan for Relapsed/Refractory MCL N = 34 Median age: 68 yrs; median previous regimens: 3 Dosed by platelet count ≥ 150,000 cells/mm3: 0.4 mCi/kg < 150,000 to ≥ 150,000 cells/mm3: 0.3 mCi/kg ORR: 31% Median EFS: 6 mos (28 mos for patients with response) Median OS: 21 mos Grade 3/4 thrombocytopenia: 24%; grade 3/4 neutropenia: 32% Wang M, et al. J Clin Oncol. 2009;27:5213-5238.

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1. O’Connor OA, et al. Br J Haematol. 2009;145:34-39. 2. Goy A, et al. J Clin Oncol. 2005;23:667-675. 3. Strauss SJ, et al. J Clin Oncol. 2006;13:2105-2112. 4. Belch A, et al. Ann Oncol. 2007;18:116-121. 5. Fisher RI, et al. J Clin Oncol. 2006;24:4867-4874. Similar ORR across studies and for untreated/relapsed 1.5 mg/m2 1.3 mg/m2 Bortezomib: Summary of Efficacy in Mantle Cell Lymphoma

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PINNACLE Trial Update Response/Subsets Analysis *Refractory subgroup: no response or response with TTP < 6 mos to last previous line of therapy. †High-intensity subgroup: ASCT or therapies containing high-dose cytarabine or ifosfamide/carboplatin etoposide. Goy A, et al. Ann Oncol. 2009;20:520-525. Among patients who achieved CR/CRu: median DOR not reached at 26.4 mos

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Early Data of Combination Bortezomib With Common MCL Regimens 1. Mounier N, et al. ASCO 2007. Abstract 8010. 2. Ruan J, et al. ASH 2009. Abstract 2682. 3. Kahl B, et al. ASH 2008. Abstract 265. 4. Kahl BS, et al. ASH 2009. Abstract 1661. 5. Romaguera J. ICML 2008. Abstract 444. 6. Friedberg JW, et al. ASH 2009. Abstract 924.

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Lenalidomide: IMiDs Lenalidomide mechanism of action remains poorly understood Antiangiogenic, microenvironment, direct antiproliferative, NK, and T-regs List AF. N Engl J Med. 2007;357:2183-2186. Copyright © 2007 Massachusetts Medical Society. All rights reserved.

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Lenalidomide in MCL: Phase II NHL-003 Trial N = 203; MCL pts, n = 53 Median number of previous Rx: 3 (1-8) DOR: NR (13.7 mos in previous NHL-002 trial) Zinzani PL, et al. ASH 2008. Abstract 262. Reeder CB, et al. ASH 2008. Abstract 1560. Czuczman MS, et al. ASH 2008. Abstract 268. Habermann TM, et al. Br J Haematol. 2009;145:344-349.

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CALGB 50501: Bortezomib + Lenalidomide in Rel/Ref MCL—Planned Interim Analysis Eligibility Histologically documented MCL (CD5+, CD23-, cyclin D1+) Measurable disease PD 0-2 Previous treatment with ≥ 1 regimen (including autologous SCT) No previous radioimmunotherapy No ≥ 3 grade 3 PN Morrison VA, et al. ASCO 2010. Abstract 8106.

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CALGB 50501: Bortezomib + Lenalidomide in Rel/Ref MCL—Planned Interim Analysis Induction therapy given every 21 days for 8 cycles Lenalidomide 20 mg PO QD on Days 1-14 Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11 Responding patients at 6 mos continued to maintenance therapy Primary endpoint: ORR Secondary endpoints: TTP, DFS/OS, correlating changes in activate NK/T cells and plasma cytokines with response Morrison VA, et al. ASCO 2010. Abstract 8106.

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CALGB 50501: Bortezomib + Lenalidomide in Rel/Ref MCL—Planned Interim Analysis Target accrual: 54 patients Planned interim analysis performed at 19 patients Grade 3/4 toxicity data for 31 patients Anemia: 3/0 Leukopenia: 3/0 Thrombocytopenia: 19/13 Fatigue/asthenia: 19/0 Dyspnea: 16/0 Morrison VA, et al. ASCO 2010. Abstract 8106. Infection: 6/0 Motor neuropathy: 13/0 Sensory neuropathy: 3/0 Hypotension: 13/0

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Targeting the PI3K/mTOR Pathway Key pathway for multiple receptor tyrosine kinases/cell proliferation and protein translation Activated Ras PI3K PIP2 PIP3 PTEN ILK PDK1 Akt pAkt ppAkt pTSC2 + TSCI TSC1-TSC2 Rheb.GTP Rheb.GTP Rapamycin + FKBP12 p70S6k eIF4E.4EBP-1 complex Cyclin D1 mRNA Cyclin D1 protein p70S6k S6 P P P 4E-BP1 + eIF4E Rapamycin + FKBP12 Protein S6

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Hess G, et al. J Clin Oncol. 2009;27:3822-3829. Temsirolimus 175 mg QW x 3 then 25 mg QW Relapsed/refractory MCL Required rituximab anthracycline alkylating agent (N = 162) Investigators’ choice single agent Temsirolimus 175 mg QW x 3 then 75 mg QW Multicenter, open-label, phase III trial Temsirolimus (CCI-779) in MCL

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Temsirolimus (CCI-779) in MCL *P vs investigator choice = .0019; †P vs investigators’ choice = .0009 Hess G, et al. J Clin Oncol. 2009;27:3822-3829.

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Kouroukis CT, et al. J Clin Oncol. 2003;21:1740-1745. Lin TS, et al. Leuk Lymphoma. 2002;43:793-797. Byrd JC, et al. Blood. 2007;109:399-404. Targeting Cyclin/CDK complexes Flavopiridol Semisynthetic flavone analogue of rohitukine (Indian tree) that blocks several CDKs, including complex CDK4-cyclin D1 Initial schedules: ORR 11% (only PR)/strong binding to human proteins LC50 required 5 x higher with human serum Pharmacologically modified schedules very promising 30-min bolus followed by 4-hr infusion CLL ORR 45%, med DOR > 12 mos, even in p53-deleted pts 55% grade 3/4 lysis syndromes +++, thrombocytopenia Other CDK inhibitors coming: PD0332991 ++

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Gemcitabine in MCL Single-agent gemcitabine (N = 18; 9 newly diagnosed, 9 relapsed)[1] Response rate: 5/18 (28%) CR: n = 1; PR: n = 4 Median treatment response duration: 10.6 mos Gemcitabine/mitoxantrone/rituximab for relapsed/refractory (N = 16)[2] Best responses CR: 20%; PR: 27% Grade 3/4 toxicities: neutropenia (100%), thrombocytopenia (67%), leukopenia (53%), anemia (33%) Median PFS and OS not reached at 10.7 mos 1. Hitz F, et al. Hematol Oncol. 2009;27:154-159. 2. Garbo LE, et al. Invest New Drugs. 2009;27:476-481.

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MIPI and Survival in Patients Receiving RHCVAD and R-MTX-Ara-C Single-agent, retrospective cohort study Study designed to identify predictors of survival on patients on first-line RHCVAD therapy Primary endpoints: OS and PFS assessed by chart review Analysis included 53 patients with advanced MCL receiving RHCVAD alternating with R-MTX-Ara-C every 21 days (median: 6 cycles) Mato AR, et al. ASCO 2010. Abstract 8092.

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MIPI and Survival in Patients Receiving RHCVAD and R-MTX-AraC: Results Median OS and PFS not yet reached (median follow-up: 18 mos [range: 35-74]) MIPI classified 47%, 29%, and 24% of patients as low, intermediate, and high risk MIPI did not identify 3 distinct categories by K-M analysis for OS or PFS Univariate analysis showed blastoid variant only significant predictor for OS (HR: 9.4; 95% CI: 1.2-53.1) Age, ECOG PS, WBC, LDH, β2-microglobulin not predictive of OS Blastoid variant (HR: 8.8; P .05) and β2-microglobulin (HR: 1.9; P .01) were independent predictors for PFS Mato AR, et al. ASCO 2010. Abstract 8092.

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Tam CS, et al. Blood. 2009;113:4144-4152. Risk-Adapted Transplantation in MCL Retrospective study of mature results of 17 yrs of transplantation experience in 121 MCL patients at M. D. Anderson Cancer Center AUTO1 (n = 50): patients who received autologous SCT during first CR or PR AUTO2 (n = 36): patients who received autologous SCT for relapsed/refractory disease NST (n = 35): patients who received nonmyeloablative SCT for relapsed/refractory disease

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Tam CS, et al. Blood. 2009;113:4144-4152. This research was originally published in Blood. © American Society of Hematology. MCL: ASCT/Allogeneic Transplantation Single institution/not very large numbers ASCT in first CR > ASCT in relapse (but no plateau either way) Mini-allo ~ 50% at 5 yrs: prediction is PBSCT and chimerism ≥ 95% PFS (Mos) Proportion Alive Without Progression 0 0.2 0.4 0.8 1.0 0 144 AUTO1 (n = 50) AUTO2 (n = 36) 0.6 12 24 36 48 60 72 84 96 108 120 132 NST (n = 35) P = .01 P = .01 OS (Mos) Proportion Alive 0 0.2 0.4 0.8 1.0 0 144 AUTO1 (n = 50) AUTO2 (n = 36) 0.6 12 24 36 48 60 72 84 96 108 120 132 NST (n = 35) P = .02 P = .10* *P = .006 at 4 yrs landmark

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Other Novel Agents in MCL

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Go Online for More CCO Hematology/Oncology Activities! Conference coverage of key data hematology/oncology meetings Treatment updates in various tumor types and hematologic malignancies Downloadable slide sets for use as a self-study resource or in your own non-commercial presentations clinicaloptions.com/oncology