1. What Second Line Regimen Should We Use for Recurrent Hodgkin Lymphoma Prior to Transplant? Brentuximab Based TherapyChemotherapy-based Approaches Catherine Diefenbach New York University Nina Wagner “Somewhere in the Midwest”

2. Arguments Supporting Chemotherapy- Based Salvage Regimens 1.DATA!! (and relative lack thereof for BV) –Chemosensitivity –Stem cell collection 2.Unknown PML risk with BV pre-ASCT 3.Cost 4.Alternative roles for BV to enhance cure –upfront –post-ASCT maintenance

3. Comparison of HL Pre-ASCT Salvage Regimens RegimenNo pts ORR (CR)Gr 3/4 Neutropenia TRM ICE Moskowitz Blood 2001 6588% (30%)NS0 Outpt ICE (13 HL) Hertzberg Ann Oncol 2006 75 89% (29%) HL 100% (31%) 82%0 ESHAP Aparicio Ann Oncol 1999 2273% (41%)32%4% DHAP Josting Ann Oncol 2005 10288% (21%)880

4. Adequacy of Stem Cell Collections Regimen Median CD34+ stem cells Mobilization Failure Rate ICE Moskowitz Blood 2001 7x10 6 /kg (0.1 - 80) 14% Outpatient ICE Hertzberg Ann Oncol 2006 4.8x10 6 /kg (2.8 - 37.8) 7% ESHAP Akhtar BMT 2006 7.6x10 6 /kg3% DHAP (NHL) Jostings Ann Oncol 2002 6x10 6 /kg (3.1 – 59) 4%

5. Low Rates of Febrile Neutropenia RegimenAuthorIncidence ICE (NHL) Moskowitz J Clin Oncol 1999 12.9% “neutropenia with hospitalization” ICE (NHL + 13 HL) Abali Ca Invest 2008 8.2% Outpatient ICE (NHL + 5 HL) George BMT 2012 14.8% ESHAP (22 HL) Aparicio Ann Oncol 1999 27% DHAP (NHL) Jostings Ann Oncol 2002 8.9%

6. Chemo-Based Salvage Regimens Summary High response rates Adequate stem cell collections Vast majority proceed to ASCT (86% with ICE) Many cured with approach (5 yr PFS 50-60%) Low incidence of febrile neutropenia

7. PET Adapted Sequential Therapy with BV and Augmented ICE –42 pts treated with 2 cycles of BV (6 doses) followed by 2 cycles Aug ICE if PET pos –71% (30/42) required Aug ICE –26% (8/30) PET+ following Aug ICE –Febrile Neutropenia 43% –Median CD34 x 10 6 /kg BV 6.28 (2.96-13.29) BV + Aug ICE 9.41 (4.56-31.43) –Med follow-up 10 mo post-ASCT (n = 39) 3 early relapses 1 death due to PML Moskowitz ASH 2013 ; Abst 2099

8. BV + Bendamustine Salvage BV 1.8 mg/kg Q21 (max 16) + Benda D1,2 (max 6) –Stem cell collection permitted after 2 cycles with pause in tx and resumption of BV post-ASCT 23/13 evaluable for toxicity/response –77% CR (10/13) PR 15% (2/13) SD 8% (1/13) 9 underwent mobilization –median 2 aphereses –Median CD34x10 6 /kg 3.4 (1.7-11.8) 7 underwent ASCT LaCasce: Biol Blood Marrow Transp: 2014, Abst 230

9. RIC AlloSCT following BV Associated with Continuous Pattern of Progression Median F/U – 30 mo 2-yr PFS – 59% 3-yr PFS – 40% Chen R et al. Blood, 119: 6379: 2012 Chen R et al. DOI: 10.1016/j.bbmt.2014.06.037 Median F/U – 12 mo 1-yr PFS – 92%

10. Risk of PML PML risk is increased with lymphoma (Incidence Ratio 8.3, HL not included) and ASCT (Incidence ratio 35.4 per 100,000 person years) 1 In 5 cases of PML treated with BV, onset was rapid (median 7 weeks after initiation) 2 Will BV pre-ASCT increase risk of PML? 1 Amend: Neurology 2010; 75:1326-32 2 Carson: Cancer 2014; 120:2464-71

11. Cost Comparisons Drug p rices based on Average Wholesale Price as listed in Lexi-Comp Hospital Cost estimated from WUSM and the Henry J. Kaiser Foundation* Assume 80kg male, 5”10, BSA 2 Chemotherapy regimens ICE: $1337.42 etoposide = $68.22 ifosfamide = $440 mesna = $673.20 carboplatin = $156 pegfilgrastim = $5359.62 Hosp adj expenses per day MO ($1998) NY ($1954) Total: $12592.04 ESHAP: $5727.64 methylpred: $44.70 etoposide = $68.22 cisplatin = $122.40 cytarabine = $111.60 dexameth eye gtts = $21.10 pegfilgrastim = $5359.62 Brentuximab vedotin 1.8 mg/kg x 80 kg = 144 mg $19,548.00 http://kff.org/other/state-indicator/expenses-per-inpatient-day /

12. Cost Comparisons Cont. 3 Cycles of BV at 1.8 mg/kg $58,644 2 Cycles of BV (3 wks on, 1 week off) at 1.2 mg/kg $78,192 3 Cycles of ICE $37,776.12 3 Cycles of ESHAP $17173.92 * Costs do not consider increased risk of febrile neutropenia

13. Concerns BV probably not effective to pursue as single agent Addition of BV to chemotherapy increases toxicity and cost Continuous progressions years after ASCT (Keller, Biol Blood Marr Transp 2012), calls into question a 2 year benchmark and further highlights the importance of a maintenance approach

14. Unanswered Pivotal Questions Is BV-Sensitivity equivalent to Chemosensitivity? Does improved CR rate with BV-based treatment equate to better outcomes? Is the likelihood of cure higher with BV- based approaches?

15. Why BV may be best in upfront setting More upfront cures in highest risk group May avoid toxicity of ASCT in greater number Demonstrated safety in Phase I/II studies –Younes, ASH 2011 –Ansell, ISHL 2013 –Abramson, ISHL 2013 Await data from the ongoing Phase III trial to determine a PFS benefit –60% accrued to 1040 pt study

16. Why post-ASCT Maintenance BV may be a better alternative than Salvage BV Pre-ASCT In relapsed setting, the median DOR for BV is short (DOR 6.7 mo in pivotal phase II study) –Median cycles: 9 AETHERA Trial: Phase 3 placebo-controlled study of Maint BV following ASCT –N = 327 –Median cycles = 15 –Interim analysis based on safety and futility recommends continuation Moskowitz: Biol Blood Marr Transp 20 (2014), Abst 148

17. Before letting BV “take over”… Need to confirm safety, efficacy, and determine the best positioning of BV to enhance outcomes. In the meantime, stick with what we know works Brentuximab vedotinChemotherapy based Approaches