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LATEST CONCEPTS IN LARGE CELL AND HODGKIN LYMPHOMAS

LATEST CONCEPTS IN LARGE CELL AND HODGKIN LYMPHOMAS. Morton Coleman, M.D. Director, Center for Lymphoma and Myeloma New York-Presbyterian Hospital Weill Cornell Medical Center Clinical Professor of Medicine Weill Cornell Medical College Chairman, Medical Affiliates Board

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LATEST CONCEPTS IN LARGE CELL AND HODGKIN LYMPHOMAS

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  1. LATEST CONCEPTS IN LARGE CELL AND HODGKIN LYMPHOMAS Morton Coleman, M.D. Director, Center for Lymphoma and Myeloma New York-Presbyterian Hospital Weill Cornell Medical Center Clinical Professor of Medicine Weill Cornell Medical College Chairman, Medical Affiliates Board Lymphoma Research Foundation

  2. Disclosures for Morton Coleman, MD In compliance with ACCME policy, ASH requires the following disclosures to the session audience: 2012 Clinical Research Training Institute Summer Workshop, La Jolla, CA

  3. Disclosures for Morton Coleman, MD, con’t In compliance with ACCME policy, ASH requires the following disclosures to the session audience: 2012 Clinical Research Training Institute Summer Workshop, La Jolla, CA

  4. THE THRUST OF CURRENT DEVELOPMENTS • Identify subsets of patients with diffuse large B cell or Hodgkin lymphoma who are either destined to do well or fare poorly using techniques beyond the known clinical predictive factors, particuarly those techniques using molecular changes and/or PET scans. • By applying our better understanding of the (molecular) biology of these diseases, can we not only identify these subsets, but also develop and individualize treatments using less therapy for those with a good prognosis and using novel therapies for those destined to do poorly.

  5. R-CHOP-21/14 cures about 2/3 of“all comers”: Failure-free survival 1.0 0.9 0.8 0.7 0.6 Probability R-CHOP21 R-CHOP14 0.5 Events, n (%) 155 (29) 153 (28) 0.4 2-yr FFS 75% 75% 0.3 Log-rank test p=0.94 0.2 HR (95% CI) 0.99 (0.79–1.24) R-CHOP14 0.1 R-CHOP21 0.0 0 1 2 3 4 5 6 Years from randomisation Patients at Risk R-CHOP21 534 429 358 216 116 25 1 25 102 1 R-CHOP14 533 355 438 224 Cunningham et al, ASCO 2011

  6. DLBCL patients who recur post R-CHOP-21 do not do well N=228 31% Gisselbrecht C, et al. J Clin Oncol 2009; 27(15s): Abstract 8509.

  7. Overall survival of patients with DLBCL refractory to second line therapy is very poor 0.00 0.25 0.50 0.75 1.00 Proportion of Patients 0 5 10 15 20 25 Time (months) Elstrom et al , Clin Lymph Myel Leuk, 2010

  8. Germinal center vs activated B cell DLBCL Rosenwald A et al. N Engl J Med. 2002;346:1937-1947

  9. Outcome by GCB vs non-GCB gene signatures in DLBCL N=233 patients treated with R-CHOP OS PFS Lenz G, et al, NEJM November 27, 2008

  10. GCB + CD10 - ? HGAL BCL6 BCL2 - + ? non-GCB MUM1 - + FOXP1

  11. Non-GCB DLBCL is associated with high expression of target genes of NF-kB transcription factors Davis, et al, J Exp Med 2001

  12. CHOP-R + bortezomib DLBCL PFS and OS by subtype (n = 40) Ruan et al, JCO 2010

  13. PYRAMID study design DLBCL diagnosis & subtyping Hans method Non-GCB GCB Not enrolled R Vc-R-CHOP Bortezomib 1.3 mg/m2, d 1, 4 Rituximab 375 mg/m2, d 1 Cyclophosphamide 750 mg/m2, d 1 Doxorubicin 50 mg/m2, d 1 Vincristine 1.4 mg/m2, d 1 Prednisone 100 mg/d, d 1–5 Six treatment cycles q21 days R-CHOP Rituximab 375 mg/m2, d 1 Cyclophosphamide 750 mg/m2, d 1 Doxorubicin 50 mg/m2, d 1 Vincristine 1.4 mg/m2, d 1 Prednisone 100 mg/d, d 1–5 Six treatment cycles q21 days Follow up every 3 months for 2 yrs

  14. What is a “double hit” lymphoma? • Recurrent breakpoints activating multiple oncogenes, one being MYC • BCL2+/MYC+ most common • BCL6, CCND1 and BCL3 may also occur • Can also have “triple hit”

  15. Immunophenotype of “double hit” lymphoma • CD10+, GCB phenotype • Lack MUM1, ABC phenotype • BCL2 + also present (with Myc) in a majority of cases • High proliferative index • median 90% Ki67+ Aukema et al, Blood 2011

  16. Clinical features of “double hit” lymphoma Aukema et al, Blood 2011

  17. R-CHOP and MYC rearranged DLBCL 35 (14%) with MYC rearrangements 19 also had t(14;18) 3 also had BCL6 7 “triple hit” Therefore most “MYC+” are “double” or “triple” hit EFS OS Barrans et al, JCO 2010

  18. DA-R-EPOCH and MYC+ DLBCL 9 MYC+ DLBCL 99 MYC- DLBCL Similar risk by IPI High RR/PFS in BL EFS OS Dunleavy et al, Lugano 2011

  19. Impact of Induction Regimen and Consolidative Stem Cell Transplantation in Patients with Double Hit Lymphoma (DHL): A Large Multicenter Retrospective Analysis Mitul Gandhi, Adam M. Petrich, Ryan Cassaday, Oliver Press, Khushboo A. Shah, Jeremy D. Whyman, Frederick Lansigan, Andrew Zelenetz, Namrata Shah, Timothy Fenske, Francisco J. Hernandez-Ilizaliturri, Lisa X. Lee, Stefan K. Barta, Shruthi Melinamani, Reem Karmali, Camille Adeimy, Scott Smith, Julie Vose, Neil Dalal, Chadi Nabhan, David Peace, Borko Jovanvoic, Aliyah Sohani, Andrew Evens, Jorge Castillo, Jeremy S. Abramson ASH 2013, Abstract 40

  20. DHL: Impact of R-EPOCH • Results of chi-square analysis • Improved CR compared to R-CHOP (p = .005) • Trend towards improvement w/ other regimens (p = .07) • Decreased PD compared to R-CHOP (p = .005) • Decreased PD w/ other intensive regimens (p = .003)

  21. DHL: Conclusions DHL has a poor prognosis, although a subset exists which can achieve durable CR R-EPOCH is associated with improved rates of CR and decreased rates of PD SCT does not clearly improve OS compared to observation alone in those achieving CR Novel approaches and agents are necessary to overcome unfavorable biology

  22. ASH 2013, Abstract 371 A Phase III Study of Enzastaurin in Patients with High-risk Diffuse Large B Cell Lymphoma Following Response to Primary Treatment: The PRELUDE Trial Michael Crump; Sirpa Leppä; Luis Fayad; Je Jung Lee; Alice Di Rocco; Michinori Ogura; Hans Hagberg; Frederick Schnell; Robert Rifkin; Andreas Mackensen; Fritz Offner; Lauren Pinter-Brown; Sonali Smith; Kensei Tobinai; Su-Peng Yeh; Jun Zhu; Eric D. Hsi; Marjo Hahka-Kemppinen; Scott P. Myrand; Donald Thornton; Peipei Shi; Tuan Nguyen; Boris Lin; Brad Kahl; Norbert Schmitz; Kerry J. Savage; Thomas Habermannfor PRELUDE Trial Investigators

  23. Background • Patients with DLBCL and an IPI score of 3-5 at diagnosis who relapse after R-CHOP can have a poor prognosis. • Enzastaurin is a potent and selective competitive inhibitor of PKCβ.1,2 • Enzastaurin was associated with freedom from progression in a phase II trial in a small subgroup of patients with relapsed or refractory DLBCL, thereby providing the rationale for this study.3 R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. The PRELUDE Trial 1Morgillo F, et al. Mol Cancer Ther 2008;7:1698-707; 2Dumstorf CA, et al. Mol Cancer Ther 2010;9:3158-63; 3Robertson MJ, et al. J Clin Oncol 2007;25:1741-6.

  24. Background PKCβ is the major isoform expressed in normal and malignant B cells.1,2 BTK SYK • PKCβ is required for B cell receptor signaling, activation of NFκB, and VEGF-mediated angiogenesis.3 P P PI 3K AKT • Over-expression of PKCβ mRNA and protein is associated with a poor outcome in patients with DLBCL.1 mTOR IKK PLC2 NFKB PKCβ DLBCL = diffuse large B cell lymphoma. The PRELUDE Trial 1Shipp MA, et al. Nat Med 2002;8:68-74; 2Graff JR, et al. Cancer Res 2005;65:7462-9; 3Robertson MJ, et al. J Clin Oncol2007;25:1741-6.

  25. Disease Free Survival by Treatment Arm for ITT Population 100 80 60 40 20 0 Survival Probability Enzastaurin Placebo HR (95% Cl): 0.92 (0.689, 1.216) P = 0.541 p=0.541 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Disease-Free Survival Time (months) Patients at risk, n: Patients at Risk, (n): Disease-free Survival Time (months) Enza: Placebo: 504 383 348 259 157 45 254 197 165 138 74 18 The PRELUDE Trial

  26. Disease-free Survival – GCB vs. Non-GCB by Hans’ Algorithm GCB vs. non-GCB in the Combined Arm GCB (N=109) GCB, Enzastaurin (N=79) GCB, Placebo (N=30) Survival Distribution Function Non-GCB (N=106) Non-GCB, Enzastaurin (N=66) Non-GCB, Placebo (N=40) 1.0 0.9 0.8 1.0 0.9 0.8 1.0 0.9 0.8 Time (Months) 0.7 0.6 0.5 0.7 0.6 0.5 0.7 0.6 0.5 HR (95% Cl): 0.92 (0.56, 1.52) P=0.74 Survival Distribution Function Survival Distribution Function 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 GCB vs. non-GCB in the Placebo Arm GCB vs. non-GCB in the Enzastaurin Arm GCB, Placebo (N=30) GCB, Enzastaurin (N=79) Non-GCB, Placebo (N=40) Non-GCB, Enzastaurin (N=66) Time (Months) Time (Months) HR (95% Cl): 1.31 (0.56, 3.08) P=0.54 HR (95% Cl): 0.77 (0.42, 1.42) P=0.40 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Cox regression determined associations between DFS and GCB/non-GCB status, adjusted for IPI score (3 vs. >3), age (≤60 vs. >60), and prior radiation (yes vs. no). The PRELUDE Trial

  27. Discussion and Conclusions The PRELUDE Trial Enzastaurin did not improve DFS, EFS, or OS vs. placebo in patients with CR after initial treatment for DLBCL and an IPI score of ≥3 Safety results of PRELUDE were consistent with the established safety profile of enzastaurin when used as a single-agent therapy in lymphoma and other cancers Cell-of-origin (GCB vs. non-GCB) was not prognostic for DFS in patients with CR

  28. BENDAMUSTINE (with rituximab, vitamin R) Three studies reported: Japan, NSH, Germany Doses of B were 120mgm/m2 days 1,2 + R 375 mgm/m2 every three weeks. German study was with unrx’ed elderly (E) Responses ranged from 58% to 69% (E) CR’s ranged from 19% to 54% (E) PFS/OS ranged from 6 to 7.7(E) months Significant toxicity

  29. Approach to “variant” DLBCLs • GCB vs non-GCB • R-CHOP is standard • Various randomized trials underway • MYC+, DH, TH • Consider FISH/IHC for MYC, BCL2, BCL6 • Less favorable with R-CHOP • Unclear if other approaches better • Prospective studies underway, including R-EPOCH • Intensive BL type regimens • R-EPOCH • Less favorable outcome than other DLBCL with R-CHOP • Risk seems to be beyond age, IPI • Less favorable at progression • Rearrangements noted • BCL2 31% • BCL6 18% • C-MYC 13% • C-MYC worse PFS and OS

  30. In Hodgkin lymphoma, what role do PET Scans play in lessening (toxicity) therapy and enhancing cure? May interim PET/CAT scans be of value or should scans be used only at the end of treatment?

  31. FDG-PET: After one (two treatments) versus two cycles (four treatments) of therapy Early determination of treatment sensitivity in Hodgkin lymphoma: FDG-PET/CT after one cycle of therapy has a higher negative predictive value than after two cycles of therapy Hutchings, M., Kostakoglu,L., Coleman, M., et al. Submitted for publication

  32. Participating Nations Denmark United States Italy Poland

  33. Patient Population:126 Pts. • Stage I 8% • Stage 2 46% • Stage 3 19% • Stage4 27% • B Sxs 56% • Bulky 37%

  34. Comparison of the prognostic value of PET 1 and PET 2: Progression Free Survival at 2 Years PET 1 PET2 Negative predictive value 98% 91% Positive predictive value 63% 85% Sensitivity 95% 61% Specificity 86% 97% Concordance >90%

  35. The RAPID Trial in Patients With Clinical Stages IA/IIA Hodgkin Lymphoma and a “Negative” PET Scan After 3 Cycles ABVD Radford J, Barrington S, Counsell N, Pettengell R, Johnson P, Wimperis J, Coltart S, Culligan D, Lister A, Bessell E, Kruger A, Popova B, Hancock B, Hoskin P, Illidge T, O’Doherty M

  36. RAPID Trial Design Initial treatment: ABVD x 3 Reassessment: if NR/PD, patient goes off study if CR/PR, FDG-PET scan performed PET-positive PET-negative 4th cycle ABVD then IFRT Randomization IFRT No further treatment Radford J, et al. Blood. 2012;120: Abstract 547.

  37. Outcomes After Median Follow-Up of 45.7 Months Radford J, et al. Blood. 2012;120: Abstract 547.

  38. Summary 602 pts registered between 2003 and 2010 75% PET-negative at central review after ABVD x 3 In the randomized PET-negative population, 3 yr PFS is 93.8% IFRT and 90.7% NFT Risk difference -3% is within the maximum allowable difference of -7% Radford J, et al. Blood. 2012;120: Abstract 547.

  39. Conclusion Patients with a negative PET scan after 3 cycles ABVD have an excellent prognosis without further treatment, and for these patients RT can be avoided Radford J, et al. Blood. 2012;120: Abstract 547.

  40. Commentary These data are similar to those reported from Argentina several years ago. Would the slightly higher rate of false negative PET scans at cycle 3 seen in those patients not receiving adjuvant radiotherapy been avoided had the PET been performed at cycle 2, or better yet, cycle 1 Response-adapted therapy based on quality- controlled/assured PET imaging may become the future standard of care in early-stage HL Radford J, et al. Blood. 2012;120: Abstract 547.

  41. An Individual Patient-Data Comparison of German Hodgkin Study Group HD10 and HD11 Combined Modality Therapy and NCIC Clinical Trials Group HD.6 ABVD Alone Hay AE, Klimm B, Chen BE, Goergen H, Shepherd LE, Fuchs M, Gospodarowicz M, Borchmann P, Connors JM, Markova J, Crump M, Lohri A, Winter JN, Dorken B, Pearcey RG, Volker D, Horning SJ, Eich HT, Engert A, Meyer RM

  42. Comparison of NCIC CTG HD.6 and GHSG HD10 and HD11 Staging, Eligibility and Preferred Arms 2 ABVD + 20 Gy IFRT 4 ABVD + 30 Gy IFRT Early, favorable HD10 Early, unfavorable HD11 Advanced GHSG 4 – 6 ABVD alone NCIC CTG HD.6 Favorable Unfavorable Advanced Not necessarily to scale Hay AE, et al. Blood. 2012;120: Abstract 549.

  43. Comparison of NCIC CTG HD.6 and GHSG HD10 and HD11 Staging, Eligibility and Preferred Arms Very good prognosis B or Bulk Early, favorable HD10 Early, unfavorable HD11 Advanced GHSG NCIC CTG HD.6 Favorable Unfavorable Advanced Not necessarily to scale Hay AE, et al. Blood. 2012;120: Abstract 549.

  44. Outcomes: All Patients Hay AE, et al. Blood. 2012;120: Abstract 549.

  45. Overall Summary Combined modality therapy (CMT) improves disease control by 4%-7% Superior long-term overall survival with CMT is highly unlikely The relatively long term outcomes associated with IFRT remain to be clarified Hay AE, et al. Blood. 2012;120: Abstract 549.

  46. What’s new for refractory/relalpsing disease? Evolving Data on Brentuximab Vedotin

  47. Brentuximab Vedotin Mechanism of Action Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-CD30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released G2/M cellcycle arrest MMAE disruptsmicrotubule network Apoptosis

  48. Long-Term Survival Analyses of an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma RChen, AK Gopal, SE Smith, SM Ansell, JD Rosenblatt, KJ Savage, JM Connors, A Engert, EK Larsen, EL Sievers, A Younes

  49. Overall survival after treatment with Brentuximab vedotin • Median observation time from 1st dose: • All patients = 29.5 months (range, 1.8 to 36.9) • CR patients = 29.1 months (range, 2.6 to 34.3) • 60/102 patients (59%) remain alive; median OS has not been reached (95% CI: 28.7, NE) • Estimated 24-month survival rate* = 65% (95% CI: 55, 74)

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