Lymphoma & Myeloma 2015 Chemotherapy-based approaches are the optimal second-line therapy prior to stem cell transplant in relapsed HL Jeremy S. Abramson, MD
Relevant Disclosure Consulting for Seattle Genetics
HDT/ASCT for relapsed/refractory Hodgkin lymphoma Schmitz, et al. Lancet. 2002.
Reasons to replace standard re-induction chemotherapy 1. Allow more patients to reach transplant due to decreased toxicity 2. Improve response rate and quality to get more patients to transplant 3. Improve long term outcomes
How many patients do not reach transplant due to toxicity? n % transplanted Not transplanted due to toxicity ICE Moskowitz 2001 65 86% 0% ICE/aICE +/- GVD Moskowitz 2012 97 88% 5% Mini-BEAM Martin 2001 55 82% 2% GVD Bartlett 2007 49 76% 2% The most common reason not to proceed to transplant is chemorefractory disease, NOT chemotherapy toxicity. By definition, these patients are fit for high-dose chemotherapy
Response to traditional chemotherapy re-induction n ORR CRR Transplant ICE Moskowitz 2001 65 88% 26% 86% ICE/aICE +/- GVD Moskowitz 2012 97 88% 60% (PET -) 88% Mini-BEAM Martin 2001 55 84% 51% 82% GVD Bartlett 2007 49 65% 20% 76% DHAP Josting 2002 102 88% 21% NR IGEV Santoro 2007 91 81% 54% NR
Second-line therapy for HL is NOT an unmet medical need IGEV mini-beam ASHAP MINE Dexa-BEAM ICE DHAP GVD GDP ESHAP PR CR 0 20 40 60 80 100 % response rate
Brentuximab vedotin monotherapy in relapsed HL CR PR SD Younes, et al. JCO 2012 Gopal, et al. Blood 2015
Brentuximab monotherapy as induction therapy MDACC study n=46 33 (72%) required aice 12 (26%) achieved CR by BV 32 (70%) transplanted only after aice +/- additional chemo All 12 BV CRs transplanted Moskowitz, et al. Lancet Onc 2015
Cornell/City of Hope experience with BV alone n=37 18 (49%) received combination chemo 11 (30%) proceeded to ASCT in CR 13 (32%) achieved CR by BV and proceeded to ASCT 5 (14%) proceeded to ASCT in less than CR 3 (8%) proceeded to ASCT in less than CR Chen, et al. BBMT 2015 (prepub online)
Brentuximab monotherapy versus standard chemo Complete PET response Transplanted BV alone Moskowitz 2015 BV alone Chen 2015 ICE/aICE +/- GVD Moskowitz 2012 26% 26% 32% 48% 60% 88% Brentuximab vedotin monotherapy does NOT improve complete response rate, or rate of transplantation
Event Free Survival for MDACC BV +/- aice Durability remains unproven Moskowitz, et al. Lancet Onc 2015
Would BV combinations work better: BV + Bendamustine Phase 1: Safety (N=10) Bendamustine 90 mg/m 2 and brentuximab vedotin 1.8mg/kg De-escalate dose of bendamustine if 4/10 patients experience dose-limiting toxicity (DLT*) Stop trial if <2 patients achieve CR Determine dosing level of bendamustine Assess safety and tolerability Phase 2: Expansion (N=40+) Bendamustine at selected dose and brentuximab vedotin 1.8 mg/kg * DLT= any cycle 1 toxicity requiring a dose delay of 14 days Assess best response (Cheson 2007) Assess duration of response and progressionfree survival (PFS) LaCasce et al. Proc ASH 2014
Study Design Main eligibility: 18 years old, Classical HL, R/R disease after frontline chemotherapy, ECOG performance status 0 2 LaCasce et al. Proc ASH 2014 CT.gov #NCT01874054
Patients N=54 Median age, (range) 37 years (27 51) Gender (% male/female) 57/43 ECOG status, n (%) 0 35 (65) 1 18 (33) 2 1 (2) Median time since HL diagnosis, (range) 13.8 months (8.8 20.4) Stage III/IV at diagnosis, n (%) 29 (54) Baseline disease status, n (%) Primary refractory 27 (50) Relapsed 27 (50) No. of patients with remission duration >1 yr 17 No. of patients with remission duration 1 yr 10 Majority of patients received ABVD as their frontline therapy LaCasce et al. Proc ASH 2014
Best Response on Combination Therapy N=48 n (%) 95% CI Best clinical response* Complete remission (CR) 40 (83) 69.8. 92.5 Partial remission (PR) 6 (13) Stable disease (SD) 1 (2) Progressive disease (PD) 1 (2) Objective response rate (ORR [CR + PR]) 46 (96) 85.8, 99.5 *Prior to ASCT Majority of CRs (34/40) achieved at Cycle 2 restage LaCasce et al. Proc ASH 2014
Progression-Free Survival Median PFS not reached o 4 progressions and 1 death subsequent to ASCT (8 events overall) Medians also not yet estimable for response duration LaCasce et al. Proc ASH 2014
Brentuximab vedotin has proven utility POST transplant in high-risk patients with relapsed Hodgkin lymphoma Moskowitz, et al. Lancet Onc 2015 Moskowitz CH et al. Lancet. 2015;385:1853-1862.
Brentuximab may have a future role in upfront therapy Phase I study of BV plus ABVD/AVD in advanced stage patients Phase II study of BV plus AVD in limited stage nonbulky patients without XRT Younes et al. Lancet Onc 2013 Abramson et al. Proc ICML 2015
Conclusions Combination chemotherapy produces higher CR rates and allows more patients to proceed to transplant than BV alone Current data suggest a small proportion of patients will benefit from BV alone, which warrants further study in larger trials with longer follow up to confirm durability BV already has a role as consolidation therapy following ASCT in high risk patients BV is under study as a component of upfront therapy, and in novel combinations for relapsed disease
A voice of agreement regarding BV monotherapy The high response rate to brentuximab vedotin in the second-line setting warrants further studies with novel regimens containing brentuximab vedotin to use as part of the first salvage treatment, which could ultimately reduce the need for intensive salvage chemotherapy. - Alison J. Moskowitz