Checkpoint Blockade in Hematology and Stem Cell Transplantation Saad S. Kenderian, MD Assistant Professor of Medicine and Oncology Mayo Clinic College of Medicine October 14, 2016 2015 MFMER slide-1
Disclosures None Off Label use Checkpoint blockade use in leukemia, lymphoma, and myeloma 2015 MFMER slide-2
Outline - Overview of checkpoint blockade - Activity and tolerability of checkpoint blockade in hematological malignancies - Checkpoint blockade after BMT 2015 MFMER slide-3
What are immune checkpoints? immune priming Antigen specificity CD28 Ipilimumab Anergy/death occurs primarily during immune attack Nivolumab, MK-3475 (pembrolizumab) Nirschl, et. al. Clin Cancer Res 2013;19, 4917-4924 2012 MFMER slide-4 2015 MFMER slide-4
Why should we block the immune checkpoints? Keir ME. Annu Rev Immunol. 2008; 26:677-704 Pardoll DM Nature Rev Cancer. 2012;12:252-64 2015 MFMER slide-5
Regulation of T Cell Responses Via Multiple Co- Stimulatory and Inhibitory Interactions T cell response to antigen is mediated by peptide-mhc recognized by TCR (first signal specificity) B7 family of membrane-bound ligands bind both co-stimulatory and inhibitory receptors (second co-stimulatory signal) Pardoll DM Nature Rev Cancer 12, 252, 2012 2015 MFMER slide-6
CTLA-4 vs. PD-1 Ribas, NEJM 2015 MFMER 2012 slide-7
Checkpoint blockade in solid tumors 2015 MFMER slide-8
Treatment with Checkpoint blockade is practice changing in many solid tumors 2015 MFMER slide-9
Unique Toxicities after checkpoint blockade 2015 MFMER slide-10
Outline - Overview of checkpoint blockade - Activity and tolerability of checkpoint blockade in hematological malignancies - Checkpoint blockade after BMT 2015 MFMER slide-11
Ipilimumab in non-hodgkin lymphoma 18 patients with NHL: Follicular 14 patients DLBCL 3 patients Mantle cell lymphoma 1 patient Most were advance stage Prior regimens: 2(1-4) Cohort 1: 3 mg/kg first dose, then 1 mg/kg monthly x 3 doses Cohort 2: 3 mg/kg monthly x 4 doses Ansell et al. CCR 2009 2015 MFMER slide-12
Signal of activity for Ipilimumab in non- Hodgkin lymphoma 2015 MFMER slide-13
Colitis is the most common AE after Ipilimumab treatment in lymphoma 2015 MFMER slide-14
Why Hodgkin lymphoma? 1. 9p24.1 amplification leads to PDL1 over expression on RS cells Ansell et al. NEJM 2015 2015 MFMER slide-15
Why Hodgkin lymphoma? 2. EBV infection leads to PDL1 over expression on RS cells Chen et al. Clinc Cancer Res 2012 2015 MFMER slide-16
Nivolumab treatment results in major responses in Hodgkin Lymphoma 2015 MFMER slide-17
Nivolumab treatment results in major responses in Hodgkin Lymphoma 2015 MFMER slide-18
Nivolumab is well tolerated in Hodgkin Lymphoma 2015 MFMER slide-19
Pembrolizumab in Hodgkin Lymphoma 31 heavily pretreated patients All have failed prior brentuximab Most have >5 prior therapies Most (71%) failed prior ASCT Most (97%) were of mixed cellulrity Armand et al. JCO 2016 2015 MFMER slide-20
Pembrolizumab treatment results in major responses in Hodgkin Lymphoma 2015 MFMER slide-21
Pembrolizumab treatment results in major responses in Hodgkin Lymphoma 2015 MFMER slide-22
Pembrolizumab treatment results in major responses in Hodgkin Lymphoma 2015 MFMER slide-23
Pembrolizumab treatment is associated with expansion of T cells and NK cells 2015 MFMER slide-24
Phase II, multicenter Nivolumab 3 mg/kg every 2 weeks till progression or withdrawal 80 patients Median age = 37 Stage III or IV=86% Prior therapy 4-7 Younes et al. Lancet Oncology 2016 2015 MFMER slide-25
Nivolumab treatment results in major responses in Hodgkin Lymphoma 2015 MFMER slide-26
Nivolumab treatment results in major responses in Hodgkin Lymphoma 2015 MFMER slide-27
Nivolumab treatment results in major responses in Hodgkin Lymphoma 2015 MFMER slide-28
Nivolumab treatment is well tolerated in Hodgkin Lymphoma 2015 MFMER slide-29
Summary: Toxicities of PD1 blockade in Hodgkin Lymphoma Fatigue 20% Pneumonitis 10% Hepatitis 10% Pancreatitis 10% SAE 20% 1 death due to pneumonitis 2015 MFMER slide-30
Lesokhin et al. JCO 2016 2015 MFMER slide-31
Major responses in NHL, B & T cell lymphoma No major responses in MM 2015 MFMER slide-32
Major responses in NHL, B & T cell lymphoma No major responses in MM 2015 MFMER slide-33
Expected toxicity profile of nivolumab 2015 MFMER slide-34
Pidilizumab combination with rituximab in follicular lymphoma 30 patients Rituximab sensitive (prior CR or PR) Measurable disease Intermediate to high risk follicular lymphoma Prior regimens (1-4) Pidilizumab 3 mg/kg every 4 weeks for 4 infusions Rituximab 375 mg/m2 weekly for 4 infusions (starting 17 days post Pidilizumab) Westin et al. Lancet 2014 2015 MFMER slide-35
Checkpoint blockade in hematological malignancies: Improving response rates Combination with chemotherapy Combination with antibodies Combination with small molecules 2015 MFMER slide-36
Pidilizumab combination with rituximab result in major responses in follicular lymphoma Westin et al. Lancet 2014 2015 MFMER slide-37
Pidilizumab combination with rituximab in follicular lymphoma Westin et al. Lancet 2014 2015 MFMER slide-38
Evidence of immune activation after Pidilizumab combination with rituximab Westin et al. Lancet 2014 2015 MFMER slide-39
Combination of PD1 inhibitor with lemalidomide Double hit lymphoma, refractory to multiple lines Combination of: Pembrolizumab q 3 wks Lenalidomide 15 mg daily CR after 3 cycles Chan et al. Ann Hematol 2016 2015 MFMER slide-40
Outline - Overview of checkpoint blockade - Activity and tolerability of checkpoint blockade in hematological malignancies - Checkpoint blockade after BMT 2015 MFMER slide-41
PD1 Blockade after autologous stem cell transplantation Rationale: Target minimal residual disease Immune reconstitution after autologous transplantation Armand et al. JCO 2013 2015 MFMER slide-42
PD1 Blockade after autologous stem cell transplantation 66 patients: De-novo DLBCL: 49 patients PMBCL: 6 patients Transformed low grade FL: 20 patients High dose chemo ASCT Pidilizumab Most have more than 2 prior regimens Most had high risk disease Status after transplantation: CR: 50% Non-CR: 50% Armand et al. JCO 2013 2015 MFMER slide-43
PD1 Blockade after autologous stem cell transplantation PFS at 18 months: 72% PFS at 18 months is historic controls: 52% Response rates in patients with PET+ disease: 51% Armand et al. JCO 2013 2015 MFMER slide-44
PD1 Blockade after autologous stem cell transplantation 2015 MFMER slide-45
PD1 Blockade after autologous stem cell transplantation 2015 MFMER slide-46
PD1 Blockade after autologous stem cell transplantation Rationale: Stimulate graft versus leukemia effect Risk: Worsening or activation of graft versus host effect Armand et al. JCO 2013 2015 MFMER slide-47
PD1 Blockade after allogeneic stem cell transplantation 29 patients: HL: 14 patients MM: 6 patients Others (AML, CML, CLL, NHL): 9 patients Allogeneic HSCT relapse ipilimumab All relapsed after allogeneic HSCT Most had RIC (80%) Bashey et al. JCO 2013 2015 MFMER slide-48
PD1 Blockade after allogeneic stem cell transplantation GVHD: Three patients developed limited cgvhd One patient developed mild acute GHVD Toxicities: Grade III or IV Pneumonitis: 10% Grade III or IV Hepatitis: 5% Grade III arthritis: 5% Responses: 2 patients had CR One patient had PR Bashey et al. JCO 2013 2015 MFMER slide-49
PD1 Blockade after allogeneic stem cell transplantation Bashey et al. JCO 2013 2015 MFMER slide-50
Is PD1 blockade safe after allogeneic transplantation? 22 year old female Multiply relapsed HL Status post allogeneic transplantation Post-transplant relapse Treated with nivolumab ~ 1 year after transplant Chad et al. Pediatric blood cancer 2016 2015 MFMER slide-51
Is PD1 blockade safe after allogeneic transplantation? 2015 MFMER slide-52
Acknowledgments Acknowledgments Mayo BMT Mark Litzow William Hogan Mrinal Patnaik Shahrukh Hashmi ASBMT NP/PA Brenda Frye Amy Witter Mayo Hematology Tait Shanafelt Neil Kay Stephen Russell Greg Nowakowaski Alex Wolanshyj Hem Leadership Martha Lacy Dennis Gastineau Thomas Witzig Angela Dispenzieri CIM Keith Stewart Scott Beck Penn TRP/CCI Carl June Saar Gill David Porter Olga Sheshtova Marco Ruella Miriam Kim Michael Klichinsky Immunology Diane Jelinek Dan Billadeeau Larry Pease Predolin Foundation 53 2015 MFMER slide-53