October 2011 A SPECIAL MEETING REVIEW EDITION Volume 9, Issue 10, Supplement 24 Highlights From the Pan Pacific Lymphoma Conference August 15–19, 2011 Kauai, Hawaii Special Reporting on: • Aggressive T-Cell Lymphomas • Novel Agents With Activity in CLL/SLL • PTCL—Update on Novel Therapies • Agents Targeting the Stromal Elements of the Lymph Node • Inducing Apoptosis in Lymphoma Cells Through Novel Agents With Expert Commentary by: Bruce D. Cheson, MD Deputy Chief Division of Hematology-Oncology Head of Hematology Lombardi Comprehensive Cancer Center Georgetown University Hospital Washington, DC Eb: E W Th O N www.clinicaladvances.com ENGINEERING T H E N E X T GENERATION OF ANTIBODY-DRUG CONJUGATES 003203_sgncor_adcadvcaho_fa4.indd 2 8/25/11 11:13 AM An innovative approach to improving outcomes in patients with cancer Antibody-drug conjugates (ADCs) use a conditionally stable linker to combine the targeting specificity of monoclonal antibodies with the tumor-killing power of potent cytotoxic agents.1,2 This could allow potent drugs to be delivered directly to tumor cells with minimal systemic toxicity. Optimizing the parameters for clinical success Scientists at Seattle Genetics are focused on parameters critical to the effective performance of ADCs, including target antigen selection,3,4 linker stability5-7 and potent cytotoxic agents.4,7,8 Elements of an antibody-drug conjugate Linker ADCs link precision and Antibody attaches the cytotoxic agent to specific for a tumor-associated the antibody. Newer linker potency for greater activity antigen that has restricted systems are designed to be expression on normal cells4,8 systemically stable and release A preclinical (in vivo) study demonstrated the cytotoxic agent in that the ADC is more active than the targeted cancer cells4,8,9 Cytotoxic agent antibody alone (mAb) or the admixture kills target cells when 10 internalized and released4,8 (mAb + cytotoxic agent unlinked) The future of drug treatment in cancer Seattle Genetics is dedicated to improving the lives of people with cancer by developing innovative therapies for hematologic malignancies and solid tumors. Visit the ADC Technology page at www.seattlegenetics.com for more information and to download the ADC scientific slide deck to learn more about this novel technology. Download ADC scientific slide deck > REFERENCES: 1. Ducry L, Stump B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjug Chem. 2010;21(1):5-13. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23(9):1137-1146. 3. Carter P, Smith L, Ryan M. Identification and validation of cell surface antigens for antibody targeting in oncology. Endocr Relat Cancer. 2004;11(4):659-687. 4. Carter PJ, Leadership in antibody-drug Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14(3):154-169. 5. Alley SC, Benjamin DR, Jeffrey SC, et al. Contribution of linker stability to the activities of anticancer immunoconjugates. Bioconjug Chem. conjugate development 2008;19(3):759-765. 6. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41(1):98-107. 7. Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: targeted drug delivery www.seattlegenetics.com for cancer. Curr Opin Chem Biol. 2010;14(4):529-537. 8. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol. 2009;13(3):235-244. 9. Polson AG, Calemine-Fenaux J, Chan P, et al. Antibody-drug conjugates for the treatment of non–Hodgkin’s lymphoma: target and linker-drug selection. Cancer Res. 2009;69(6): 2358-2364. 10. Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778-784. Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2011 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA US/ADC/2011/0027 003203_sgncor_adcadvcaho_fa4.indd 3 8/25/11 11:13 AM S pecial m eeting r eview edition Aggressive T-Cell Lymphomas r. Andrej R. Shustov dis- tion to disease subtype, international T-cell lymphoma, who usually have cussed aggressive T-cell prognostic index (IPI) scores factor extremely poor outcomes, showed lymphomas at the 2011 Pan into a prognosis.5 a 5-year OS rate of 44% and 5-year DPacific Lymphoma Conference.1 The Attempts were made to improve PFS rate of 40%. Patients with PTCL World Health Organization (WHO) outcomes in patients with PTCL unspecified (n=62) showed a 5-year recognizes 3 subfamilies of peripheral by applying consolidated high-dose OS of 45%, although 5-year PFS was T-cell lymphoma (PTCL): extranodal, therapy and autologous hematopoietic only 34%. nodal, and leukemic T-cell lympho- stem cell transplantation. However, Despite these encouraging results, mas. Nodal disease is the most com- several phase II studies examining this several studies suggest that alloge- mon, and among these the most com- treatment show very modest overall neic transplant may be preferable to mon is PTCL not otherwise specified survival (OS), suggesting that this treat- autologous transplant for patients (NOS), followed by angioimmuno- ment is not very effective for PTCL. with high-risk disease. In a study by blastic T-cell lymphoma, extranodal A study of 83 patients by Reimer and Le Gouil and colleagues, although NK-/T-cell lymphoma (nasal type), colleagues suggests that patients with treatment-related mortality was 34%, adult T-cell leukemia/lymphoma, and high IPI/prognostic index for PTCL the 5-year OS was close to 60% for anaplastic large cell lymphoma (ALK- (PIT) in particular may not benefit patients with PTCL who underwent positive and ALK-negative).2 These from high-dose therapy/autologous allogeneic stem cell transplantation.8 subtypes account for approximately hematopoietic stem cell transplanta- Very encouraging early results 90% of all PTCL patients. tion, with 3-year progression-free were also obtained by Corradini and Diagnosis can be challenging survival (PFS) of 36%.6 colleagues using non-myeloablative because most types of T-cell lymphoma In the NLG-T-01 trial, 121 allogeneic transplant, with 5-year OS do not have a specific immunopheno- patients (median age, 55 years) received and 5-year PFS of 80% and 64%, type. Therefore, a correct diagnosis cyclophosphamide, doxorubicin, vin- respectively, with survival curves show- requires a combination of molecular cristine, etoposide, and prednisone ing a clear plateau.9 Finally, a study of 17 analysis, clinical presentation, mor- (CHOEP) therapy every 14 days for patients with multiple PTCL histologies, phology, and genetics. The incidence 3 cycles. Patients with a complete and 5 patients with refractory disease at of PTCL varies geographically and response (CR) or partial response the time of transplant, showed a 3-year appears to be increasing.3,4 The clini- (PR) then received another 3 cycles of OS of 59% and 3-year PFS of 53%.10 cal outcomes critically depend on the CHOEP every 14 days. Patients who Thus, for selected patients, allogeneic T-cell lymphoma subtype, but in most still showed a CR or PR then under- transplants might provide long-term subtypes, the outcomes are generally went stem cell collection and beam- control of the disease and possibly cure poor. Fewer than 30% of patients with supported autologous large stem the drug-resistant lymphoma effect. the most common subtypes remain cell transplant.7 The subgroup of 21 The last few years have seen the alive 5 years after diagnosis.2 In addi- patients with enteropathy-associated development of some promising new Disclaimer Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation. ©2011 Millennium Medical Publishing, Inc. 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. 4 Clinical Advances in Hematology & Oncology Volume 9, Issue 10, Supplement 24 October 2011 HIGHLIGHTS F r O m THE 2011 P an P acific Ly m pho m A confe r ence therapies based on selective targeting of specific cellular pathways. Pralatrex- What Are the Newer Agents That Have Clinical Activity in MCL? ate is a novel antifolate that inhibits the activity of dihydrofolate reductase Dr. Jonathan W. Friedberg reviewed new agents under investigation in mantle (DHFR), with a mechanism of action cell lymphoma (MCL).1 Although bortezomib is already approved for treating similar to that of methotrexate. Once MCL, newer agents and novel combinations are showing promising activity internalized, the molecule is gluta- that could surpass that of bortezomib. A phase II study enrolled patients with mated, which prevents its escape from relapsed, indolent B-cell lymphoma or MCL. Patients received bendamustine the cell. PROPEL (Pralatrexate in (90 mg/m2, days 1 and 4), rituximab (375 mg/m2, day 1), and bortezomib (1.3 Patients With Relapsed or Refractory mg/m2, days 1, 4, 8, and 11). The 7 MCL patients had an overall response rate Peripheral T-cell Lymphoma) was the (ORR) of 71% (range, 36–92%). In comparison, the pivotal trial of bortezomib first large, prospective, multicenter, monotherapy yielded an ORR of 32%.2 Median progression-free survival with single-arm, open-label, international 3 trial conducted for relapsed/refrac- the combination therapy was approximately 23 months, and the combination tory PTCL.11 This pivotal phase II was reasonably well tolerated, with 63% of patients completing all 6 treatment study had 109 evaluable patients with cycles.