Sequencing Treatments in Relapsed Hodgkin Lymphoma Leonard T. - PowerPoint PPT Presentation

Sequencing Treatments in Relapsed Hodgkin Lymphoma Leonard T. Heffner, Jr., M.D. July 27, 2017 1

Hodgkin Lymphoma • Arises from B lymphocytes • Accounts for 10% or all lymphomas • <1% of all cancers in the U.S. • Incidence: 8500 in U.S. in 2016 • Mortality: 1120 in U.S. in 2016 Siegel RL, et al. CA Cancer J Clin. 2016;66(1):7-30. Winship Cancer Institute | Emory University 2

Teras LR, et al. CA Cancer J Clin. 2016;66(6):443-459. Winship Cancer Institute | Emory University 3

DeVita VT Jr. N Engl J Med. 2003;348(24):2375-2376. Winship Cancer Institute | Emory University 4

Changes in survival of all patients with all stages of Hodgkin disease (HD) treated by radiotherapy and/or combination chemotherapy at Stanford from 1960 to 2006 FFR, freedom from relapse Canellos GP, et al. J Clin Oncol. 2014;32(3):163-168. Winship Cancer Institute | Emory University 5

2, 5 and 10 yr survival rates for Hodgkin Lymphoma by Sex and Race Teras LR, et al. CA Cancer J Clin. 2016;66(6):443-459. Winship Cancer Institute | Emory University 6

Cumulative incidence of relapse in patients observed to be free from relapse >5 years after diagnosis of classical Hodgkin lymphoma in HD7 to HD12 German trials Bröckelmann PJ, et al. J Clin Oncol. 2017;35(13):1444-1450. Winship Cancer Institute | Emory University 7

Options for Treatment of Relapsed/Refractory Hodgkin Lymphoma 1.Autologous stem cell transplant 2.Radiation Therapy 3.Chemotherapy: monotherapy or combination 4.Check-point inhibitors 5.Monoclonal antibodies 6.Immunomodulatory agents 7.Second Autologous stem cell transplant 8.Allogeneic stem cell transplant Winship Cancer Institute | Emory University 8

Moskowitz CH, et al. Blood. 2001;97(3):616-623. Winship Cancer Institute | Emory University 9

Overall Survival Based on Number of Risk Factors Present at Transplant Risk Factors 1. B symptoms before ICE 2. Extranodal disease before ICE 3. CR duration <1 yr. Moskowitz CH, et al. Blood. 2001;97(3):616-623. Winship Cancer Institute | Emory University 10

75% 30% Moskowitz CH. Hematology Am Soc Hematol Educ Program. 2016;2016(1):331-338. Winship Cancer Institute | Emory University 11

Autologous Stem cell Transplant (ASCT) for Relapsed/Refractory Hodgkin Lymphoma Relapsed HL : At least 12 trials (retrospective, prospective and randomized) show high-dose ChRx (HDC) followed by ASCT can rescue 30-80% of patients. Refractory HL: At least 13 trials (all retrospective) show HDC followed by ASCT results in PFS = 40-45% and OS = 30-70% Cochrane Review: (2013) identified only 3 randomized controlled trials totaling 398 pts comparing ASCT to ChRx for relapsed/refractory HL (BNLI, HDR1 and HDR2) Perales MA, et al. Biol Blood Marrow Transplant. 2015;21(6):971-983. Fedele R, et al. J Immunol Res. 2015;968212. Winship Cancer Institute | Emory University 12

Cochrane Review of Three Randomized Controlled Trials of HDC and ASCT for Rel/Ref HL Rancea M, et al. Cochrane Database Syst Rev. 2013;(6):CD009411. Winship Cancer Institute | Emory University 13

Use of Second-line, non-Cross-resistant Chemotherapy to Achieve pre-ASCT PET Negativity Moskowitz CH, et al. Blood. 2012;119(7):1665-1670. Winship Cancer Institute | Emory University 14

Moskowitz CH, et al. Blood. 2012;119(7):1665-1670. Winship Cancer Institute | Emory University 15

Peralses MA, et al. Biol Blood Marrow Transplant. 2015;21(6):971-983. Winship Cancer Institute | Emory University 16

Overall Survival of Patients Undergoing Transplant at Emory (Unselected) N = 356 allo = 18 Relapse within 5 yrs: 100 Relapse > 5 yrs and < 10 yrs: 3 Relapse > 10 yrs and < 15 yrs: 2 Relapse > 15 yrs: 0 Unpublished data Winship Cancer Institute | Emory University 17

Alinari L, et al. Blood. 2016;127(3):287-295. Winship Cancer Institute | Emory University 18

Selected Studies of Combination Regimens for Rel/Ref cHL After ASCT GCD=Gemcitabine,carboplatin,dexamethasone GVD=gemcitabine,vinorelbine,doxorubicin GV=Gemcitabine,vinorelbine GemOx=gemcitabine,oxaliplatin ESHAP=Etoposide,methylpred,cytarabine,cisplatin Modified from: Alinari L, et al. Blood. 2016;127(3):287-295. Winship Cancer Institute | Emory University 19

Selected Studies of Novel Agents in Patients for Rel/Ref cHL After ASCT No. Prior ASCT Response PFS (mos) Lenalidomide 36 31 CR = 3 6.0 PR =16 Everolimus 19 16 CR = 5 7.2 PR = 42 Panobinostat 129 129 CR = 4 8.L PR = 23 Rituximab 22 18 CR = 4 7.8 PR = 18 2 nd ASCT 21 21 *5yr PFS=32% vs 0% OS =41% vs 13% *Relapse post first ASCT >12 mos vs <12mos Modified from: Alinari L, et al. Blood. 2016;127(3):287-295. Winship Cancer Institute | Emory University 20

Brentuximab vedotin (SGN35) - Brentuximab vedotin is an anti-CD30 monoclonal antibody(SGN35) conjugated to monomethyl auaristatin E (MMAE) via a valine-citrulline peptide linker -2010: Phase I trial¹: 45 pts (42 with rel/ref HL) MTD 1.8mg/m2 IV q3wks 17/45 (38%) ORR with 11 CR (9 HL, 2 ALCL) -2012: Phase II trial²: 102 pts with rel/ref HL after auto SCT ORR: 75% with 34% CR med PFS 5.6 mos and med OS 22.4 mos Toxicity: sensory neuropathy (42%), fatigue, neutropenia, nausea, diarrhea Rare(not this trial): PML (5 pts); pancreatitis 1. Younes A, et al. N Engl J Med. 2010;363(19):1812-1821. 2. Younes A, et al. J Clin Oncol. 2012;30(18):2183-2189. Winship Cancer Institute | Emory University 21

Phase 2 Trial of BV after auto- SCT for Rel/Ref HL: OS and PFS Younes A, et al. J Clin Oncol. 2012;30(18):2183-2189. Winship Cancer Institute | Emory University 22

AETHERA Trial: Phase 3 Trial of Post-ASCT Consolidation w ith BV vs Placebo PFS by Independent Review Med PFS 42.9 vs 24.1 mos Moskowitz CH, et al. Lancet. 2015;385(9980):1853-1862. Winship Cancer Institute | Emory University 23

Aethera Trial: 3-year PFS 61% (median NYR) 43% (median 15.8 mos) Moskowitz CH. Hematology Am Soc Hematol Educ Program. 2016;2016(1):331-338. Winship Cancer Institute | Emory University 24

AETHERA Trial: Overall Survival Moskowitz CH, et al. Lancet. 2015;385(9980):1853-1862. Winship Cancer Institute | Emory University 25

Moskowitz CH. Hematology Am Soc Hematol Educ Program. 2016;2016(1):331-338. Winship Cancer Institute | Emory University 26

Phase I Study of Nivolumab in Relapsed/Refractory Hodgkin Lymphoma Ansell SM, et al. N Engl J Med. 2015;372(4):311-319. Winship Cancer Institute | Emory University 27

Pembrolizumab in Rel/Ref Classical Hodgkin Lymphoma PFS = 72.4% at 6 mos. Decrease in tumor burden from baseline K-M estimate of objective response duration Chen R, et al. J Clin Oncol. 2017;35(19):2125-2132. Winship Cancer Institute | Emory University 28

Pembrolizumab after failure of Brentuximab Vedotin in cHL Armand P, et al. J Clin Oncol. 2016 Jun 27 [Epub ahead of print]. Winship Cancer Institute | Emory University 29

Pembrolizumab in Rel/Ref Classical Hodgkin Lymphoma Chen R, et al. J Clin Oncol. 2017;35(19):2125-2132. Winship Cancer Institute | Emory University 30

Adverse Effect Profile of PD-1/PD-L1 Inhibitors • Dermatologic: rash, pruritis • Metabolic: lipid changes, hyperglycemia, hypoalbuminemia, electrolyte changes • Hematologic: anemia and lymphopenia • Gastrointestinal: nausea/vomiting; change in bowel habits, abnormal LFTs • Respiratory: cough dyspnea • Constitutional: fatigue • Immune-related: • Pneumonitis • Dermatologic: TEN • Gastrointestinal: colitis, pancreatitis • Endocrine: hypophysitis, thyroiditis, adrenal insufficiency Winship Cancer Institute | Emory University 31

The Cancer Letter June 9, 2017 Winship Cancer Institute | Emory University 32

Autologous T-cells Expressing CD30 Chimeric Antigen Receptors in Rel/Ref cHL n = 18 ORR 39 % Wang CM, et al. Clin Cancer Res. 2017;23(5):1156-1166. Winship Cancer Institute | Emory University 33

Clinical Trials at Winship Cancer Institute for Relapsed/Refractory Hodgkin Lymphoma - E4412: -Phase I study of Ipilimumab/brentuximab/nivolumab with expansion cohort - S15-00285: Phase I/II study of pembrolizumab + lenalidomide - MEDI4736-NHL-001: Phase I/II study of durvalumab (IgG monoclonal antibody against PD-L1) Winship Cancer Institute | Emory University 34

Second ASCT for Relapsed cHL • Limited data (small numbers:3-10) • CIBMTR series: 40 patients—21 cHL 19 DLBCL, FL, immunoblastic • Chemosensitive disease 73% for entire gp. 1-yr PFS 1-yr OS Relapse <6 mos 11% 22% Relapse >12 mos 64% 78% Relapse >18 mos 53% 72% Conclusion: Recommended only in selected settings Smith SM, et al. Biol Blood Marrow Transplant. 2008;14(8):904-912. Winship Cancer Institute | Emory University 35

There are NO prospective clinical trials comparing Allo-SCT to non-transplant treatment in cHL rel after ASCT Perales MA, et al. Biol Blood Marrow Transplant. 2015;21(6):971-983. Winship Cancer Institute | Emory University 36

Kharfan-Dabaja MA, et al. Bone marrow Transplant. 2014;49(5):599-606. Winship Cancer Institute | Emory University 37

Retrospective Comparison of Chemo/XRT vs Allo-RIC for HL Failure after ASCT Treatment No. Median 4-yr OS P-value Survival Allo-RIC 195 19 mos. 32% 0.08 Chemo/XR 49 45 mos. 48% T Martinez C, et al. Ann Oncol. 2013;24(9):2430-2434. Winship Cancer Institute | Emory University 38