What Second Line Regimen Should We Use for Recurrent Hodgkin Lymphoma

Prior to Transplant?

Brentuximab Based Therapy Chemotherapy-based Approaches

Catherine DiefenbachNew 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

Regimen No pts

ORR (CR) Gr 3/4Neutropenia

TRM

ICE Moskowitz Blood 2001

65 88% (30%) NS 0

Outpt ICE (13 HL)Hertzberg Ann Oncol 2006

7589% (29%)HL 100%

(31%)82% 0

ESHAPAparicioAnn Oncol 1999

22 73% (41%) 32% 4%

DHAPJosting Ann Oncol 2005

102 88% (21%) 88 0

Adequacy of Stem Cell Collections

Regimen Median CD34+ stem cells

Mobilization Failure Rate

ICEMoskowitz Blood 2001

7x106/kg (0.1 - 80) 14%

Outpatient ICEHertzberg Ann Oncol 2006

4.8x106/kg (2.8 - 37.8) 7%

ESHAPAkhtarBMT 2006

7.6x106/kg 3%

DHAP (NHL)JostingsAnn Oncol 2002

6x106/kg(3.1 – 59) 4%

Low Rates of Febrile Neutropenia

Regimen Author Incidence

ICE (NHL) MoskowitzJ Clin Oncol 1999

12.9% “neutropenia with hospitalization”

ICE (NHL + 13 HL) AbaliCa Invest 2008 8.2%

Outpatient ICE (NHL + 5 HL)

GeorgeBMT 2012 14.8%

ESHAP (22 HL) AparicioAnn Oncol 1999 27%

DHAP (NHL) JostingsAnn Oncol 2002 8.9%

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

AugICE if PET pos

– 71% (30/42) required AugICE

– 26% (8/30) PET+ following AugICE

– Febrile Neutropenia 43%

– Median CD34 x 106/kg• BV 6.28 (2.96-13.29)

• BV + AugICE 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

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 CD34x106/kg 3.4 (1.7-11.8)

• 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 mo2-yr PFS – 59%3-yr PFS – 40%

Chen R et al. Blood, 119: 6379: 2012Chen R et al. DOI: 10.1016/j.bbmt.2014.06.037

Median F/U – 12 mo1-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; 75:1326-322 Carson: Cancer 2014; 120:2464-71

Cost ComparisonsDrug prices 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 regimensICE: $1337.42• etoposide = $68.22•ifosfamide = $440•mesna = $673.20•carboplatin = $156•pegfilgrastim = $5359.62Hosp 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/

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

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 vedotin Chemotherapy based Approaches