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”

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

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

Adequacy of Stem Cell Collections Regimen Median CD34+ stem cells Mobilization Failure Rate ICE Moskowitz Blood x10 6 /kg ( ) 14% Outpatient ICE Hertzberg Ann Oncol x10 6 /kg ( ) 7% ESHAP Akhtar BMT x10 6 /kg3% DHAP (NHL) Jostings Ann Oncol x10 6 /kg (3.1 – 59) 4%

Low Rates of Febrile Neutropenia RegimenAuthorIncidence ICE (NHL) Moskowitz J Clin Oncol % “neutropenia with hospitalization” ICE (NHL + 13 HL) Abali Ca Invest % Outpatient ICE (NHL + 5 HL) George BMT % ESHAP (22 HL) Aparicio Ann Oncol % DHAP (NHL) Jostings Ann Oncol %

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

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 ( ) BV + Aug ICE 9.41 ( ) –Med follow-up 10 mo post-ASCT (n = 39) 3 early relapses 1 death due to PML Moskowitz ASH 2013 ; Abst 2099

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 ( ) 7 underwent ASCT LaCasce: Biol Blood Marrow Transp: 2014, Abst 230

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: /j.bbmt Median F/U – 12 mo 1-yr PFS – 92%

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: Carson: Cancer 2014; 120:

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: $ etoposide = $68.22 ifosfamide = $440 mesna = $ carboplatin = $156 pegfilgrastim = $ Hosp adj expenses per day MO ($1998) NY ($1954) Total: $ ESHAP: $ methylpred: $44.70 etoposide = $68.22 cisplatin = $ cytarabine = $ dexameth eye gtts = $21.10 pegfilgrastim = $ Brentuximab vedotin 1.8 mg/kg x 80 kg = 144 mg $19, /

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, Cycles of ESHAP $ * Costs do not consider increased risk of febrile neutropenia

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

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?

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

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

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