Recurrent HL after Autotransplant in CR with Brentuximab: Koen van Besien, MD, PhD Weill Cornell Medical College

Recurrent HL after Autotransplant in CR with Brentuximab: ALLO Koen van Besien, MD, PhD Weill Cornell Medical College

Koen van Besien, MD, PhD Weill Cornell Medical College Recurrent HL after Autotransplant in CR with Brentuximab: But is that the issue? Koen van Besien, MD, PhD Weill Cornell Medical College

Frequency of Response to Brentuximab in Refractory Relapsed HL Zinzani, Hematologica, 98, 1231, 2013

Scenario of HL Failure MS Age, PMH 49, CAD, Stents, MI, HTN, HCHOL Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM R1 ABVD x6 + IT MTX: PR PD R 2 DICE x3: PR PD R3 Brentuximab x3: PR PD R4 R5+R6 Donor Cond+GVH Current Status

Scenario of HL Failure MS SK Age, PMH 49, CAD, Stents, MI, HTN, HCHOL 34 Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM NS, IIA R1 ABVD x6 + IT MTX: PR PD ABVDx4 +XRT CT  Rel 9 m R 2 DICE x3: PR PD DICE x 2 + BUVP Auto: CR  Rel 6 m R3 Brentuximab x3: PR PD Brentuximab x9: CR R4 R5+R6 Donor Cond+GVH Current Status

Scenario of HL Failure MS SK SG Age, PMH 49, CAD, Stents, MI, HTN, HCHOL 34 39 Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM NS, IIA NS, II B R1 ABVD x6 + IT MTX: PR PD ABVDx4 +XRT CT  Rel 9 m ABVD x6 PRPD R 2 DICE x3: PR PD DICE x 2 + BUVP Auto: CR  Rel 6 m DICE x2: SD R3 Brentuximab x3: PR PD Brentuximab x9: CR GND  CBV Auto (pul tox): CR Rel 6 m R4 PEPC: PD R5+R6 Brentuximab x 5: PR  PD Donor Cond+GVH Current Status

Scenario of HL Failure MS SK SG SC Age, PMH 49, CAD, Stents, MI, HTN, HCHOL 34 39 24, ADD, Obesity Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM NS, IIA NS, II B NS, IV B (liver) R1 ABVD x6 + IT MTX: PR PD ABVDx4 +XRT CT  Rel 9 m ABVD x6 PRPD ABVD x6 PRPD R 2 DICE x3: PR PD DICE x 2 + BUVP Auto: CR  Rel 6 m DICE x2: SD ICE x2:PD R3 Brentuximab x3: PR PD Brentuximab x9: CR GND  CBV Auto (pul tox): CR Rel 6 m Brentuximab x2:PD R4 PEPC: PD R5+R6 Brentuximab x 5: PR  PD Donor Cond+GVH Current Status

Scenario of HL Failure MS SK SG SC Age, PMH 34 Hist/Ext NS, IIA R1 ABVDx4 +XRT CT  Rel 9 m R 2 DICE x 2 + BUVP Auto: CR  Rel 6 m R3 Brentuximab x9: CR R4 R5+R6 Donor Cond+GVH Current Status

Treatment Options for Continue Brentuximab Second Auto Transplant Allo Transplant

Treatment Options for Continue Brentuximab: Second Auto Transplant Limited Durability Toxicity Second Auto Transplant Allo Transplant

Duration of Response to Brentuximab in HL Duration of CR in alive patients Black Circles: Allogeneic Transplant Gray Circles: Autologous Transplant Zinzani, Hematologica, 98, 1231, 2013

Progression-free Survival Comparison All Patients versus Patients with CR 12 of 15 patients who remain in long-term follow-up with no evidence of disease had CR; the remaining 3 patients had PR Presented by S Smith et al, EHA 2012

Brentuximab Vedotin Significant Adverse Events Grade 3-4 (from Phase II studies) Peripheral neuropathy 8-10% Neutropenia 20% Fever/neutropenia 0% Thrombocytopenia 8-14% Progressive Multifocal Leukencephalopathy? 3 reported cases after 2, 2, and 8 doses of BV BOXED WARNING in BV label Pulmonary Toxicity when given in combination with Bleomycin Contraindication in BV label *Leukemia & Lymphoma 53(11): 2283,2012

Treatment Options for Continue Brentuximab: Second Auto Transplant Limited Durability Toxicity Second Auto Transplant Limited Applicability Allo Transplant

Second Autologous TX in HL and NHL relapsing after previous Auto SCT Alive 4 7 Dead 15 14 Primary disease 10 8  Interstitial pneumonia 1  Infection  Organ failure  New malignancy 2  Other, not specified Smith S, BBMT 2008, 14, 904-912

Treatment Options for Continue Brentuximab: Second Auto Transplant Limited Durability Toxicity Second Auto Transplant Allo Transplant

Proof of Principle: DLI for Relapsed Disease (n=24) 79% ORR (14 CR, 5 PR) 13 responders (11CR) had no prior salvage 46% had no significant GvHD Relapse incidence 1.00 0.75 0.50 33% 3yr 0.25 0.00 1 2 3 4 5 6 7 8 9 Time post last DLI (years) Nov 06 - Feb 08 Peggs, KS, et al. J Clin Oncol 2011;29:971-978

Reduced-intensity Allo-SCT vs. Chemotherapy for Relapse Following ASCT Overall survival 1.0 0.8 0.6 Surviving RIT group (n=38) 0.4 0.2 Control group (n=34) P=0.0001 0 1000 2000 3000 4000 5000 Time (days) Thomson KJ, et al. BMT 2008;41:765–770

Donor vs. No Donor Analysis in Patients Relapsed Post ASCT Progression free survival Overall survival 0.0 0.2 0.4 0.6 0.8 1.0 Donor No donor p<0.001 Survival probability 12 24 36 48 60 Months Sarina B, et al. Blood 2010;115:3671–7

Response-adjusted Transplantation: Restoring Intensity UCLH – single centre series Salvage (n=61) FDG-PET < Metabolic CR Non-progressive Metabolic CR Progressive Salvage FDG-PET SD or better Progressive Autologous Transplant (BEAM) Allogeneic Transplant (BEAM-C) n=28 n=25 n=8 Thomson KJ, et al. Leukaemia. 2013

Transplant Outcomes Autologous Transplant Allogeneic Transplant Non relapse-related mortality 1 (4%) 2 (8%) Relapse 3 (11%) 5 (21%) Autologous Transplant Allogeneic Transplant OS: 92% OS: 88% PFS: 85% cPFS: 84% PFS: 71% Thomson et al., Leukaemia 2013

Reduced Intensity Conditioning Allotransplant following Brentuximab Vedotin for Relapsed cHL n=18, prior ASCT - 17 Median # of BV cycles - 7 Median time from BV to alloSCT - 62 days (24-276d) Best response to BV - CR 7, PR 8, SD 2, PD1 Type of transplant - 7 MRD, 8 MUD, 3 haplo Acute GVHD 27.8% Chronic GVHD 56.3% Median F/U – 12 mo PFS – 92% Chen R et al. Blood 119: 6379: 2012.

Treatment Options for Continue Brentuximab: Second Auto Transplant Limited Durability Toxicity Second Auto Transplant Allo Transplant Highly effective Well tolerated if implemented before multiple treatment failures and with adequate GVHD prophylaxis

Scenario of HL Failure MS SK SG SC Age, PMH 49, CAD, Stents, MI, HTN, HCHOL 34 39 24, ADD, Obesity Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM NS, IIA NS, II B NS, IV B (liver) R1 ABVD x6 + IT MTX: PR PD ABVDx4 +XRT CT  Rel 9 m ABVD x6 PRPD ABVD x6 PRPD R 2 DICE x3: PR PD DICE x 2 + BUVP Auto: CR  Rel 6 m DICE x2: SD ICE x2:PD R3 Brentuximab x3: PR PD Brentuximab x9: CR  PD GND  CBV Auto (pul tox): CR Rel 6 m Brentuximab x2:PD R4 PEPC: PD R5+R6 Brentuximab x 5: PR  PD , Brent + GN x1 Donor Cond+GVH Current Status

Scenario of HL Failure MS SK SG SC Age, PMH 49, CAD, Stents, MI, HTN, HCHOL 34 39 24, ADD, Obesity Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM NS, IIA NS, II B NS, IV B (liver) R1 ABVD x6 + IT MTX: PR PD ABVDx4 +XRT CT  Rel 9 m ABVD x6 PRPD ABVD x6 PRPD R 2 DICE x3: PR PD DICE x 2 + BUVP Auto: CR  Rel 6 m DICE x2: SD ICE x2:PD R3 Brentuximab x3: PR PD Brentuximab x9: CR  PD GND  CBV Auto (pul tox): CR Rel 6 m Brentuximab x2:PD R4 Benda x 2: CR PEPC: PD R5+R6 Brentuximab x 5: PR  PD , Brent + GN x1 Donor Haplo Cord Cond+GVH Flu Mel ATG Tacro MMF Current Status 6 mo post TX No GVHD NED

Scenario of HL Failure MS SK SG SC Age, PMH 49, CAD, Stents, MI, HTN, HCHOL 34 39 24, ADD, Obesity Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM NS, IIA NS, II B NS, IV B (liver) R1 ABVD x6 + IT MTX: PR PD ABVDx4 +XRT CT  Rel 9 m ABVD x6 PRPD ABVD x6 PRPD R 2 DICE x3: PR PD DICE x 2 + BUVP Auto: CR  Rel 6 m DICE x2: SD ICE x2:PD R3 Brentuximab x3: PR PD Brentuximab x9: CR  PD GND  CBV Auto (pul tox): CR Rel 6 m Brentuximab x2:PD R4 XRT Pelvis Benda x 2: CR PEPC: PD R5+R6 Brentuximab x 5: PR  PD , Brent + GN x1 Donor MRD Haplo Cord Cond+GVH BEAM-CAMPATH-Tacro Flu Mel ATG Tacro MMF Current Status 1 yr post Tx- No GVH NED 6 mo post TX No GVHD NED

Scenario of HL Failure MS SK SG SC Age, PMH 49, CAD, Stents, MI, HTN, HCHOL 34 39 24, ADD, Obesity Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM NS, IIA NS, II B NS, IV B (liver) R1 ABVD x6 + IT MTX: PR PD ABVDx4 +XRT CT  Rel 9 m ABVD x6 PRPD ABVD x6 PRPD R 2 DICE x3: PR PD DICE x 2 + BUVP Auto: CR  Rel 6 m DICE x2: SD ICE x2:PD R3 Brentuximab x3: PR PD Brentuximab x9: CR  PD GND  CBV Auto (pul tox): CR Rel 6 m Brentuximab x2:PD R4 XRT Pelvis Benda x 2: CR PEPC: PD R5+R6 Brentuximab x 5: PR  PD , Brent + GN x1 Donor MRD Haplo Cord Cond+GVH BEAM-CAMPATH-Tacro Flu Mel ATG Tacro MMF Flu Mel Campath Tacro Current Status 1 yr post Tx- No GVH NED 6 mo post TX No GVHD NED 18 mo post TX cGHV skin resolved

Scenario of HL Failure MS SK SG SC Age, PMH 49, CAD, Stents, MI, HTN, HCHOL 34 39 24, ADD, Obesity Hist/Ext NS. IVB (Lung, spleen, bone, epidural, BM NS, IIA NS, II B NS, IV B (liver) R1 ABVD x6 + IT MTX: PR PD ABVDx4 +XRT CT  Rel 9 m ABVD x6 PRPD ABVD x6 PRPD R 2 DICE x3: PR PD DICE x 2 + BUVP Auto: CR  Rel 6 m DICE x2: SD ICE x2:PD R3 Brentuximab x3: PR PD Brentuximab x9: CR  PD GND  CBV Auto (pul tox): CR Rel 6 m Brentuximab x2:PD R4 XRT Pelvis Benda x 2: CR PEPC: PD Gem Ox: PD R5+R6 Brentuximab x 5: PR  PD , Brent + GN x1 Benda x3: PR Donor MRD Haplo Cord Cond+GVH BEAM-CAMPATH-Tacro Flu Mel ATG Tacro MMF Flu Mel Campath Tacro Current Status 1 yr post Tx- No GVH NED 6 mo post TX No GVHD NED 18 mo post TX cGHV skin resolved ND

Conclusions Responses to Brentuximab are rarely durable in HL Allogeneic transplant is an excellent treatment option and overcomes disease resistance. With current supportive care and GVHD prophylaxis, the incidence of cGVHD is limited. We have a donor for all