Checkpoint Blockade in Hematology and Stem Cell ... · Hematology and Stem Cell Transplantation ......

©2015 MFMER | slide-1

Checkpoint Blockade in Hematology and Stem Cell

Transplantation

Saad S. Kenderian, MDAssistant Professor of Medicine and OncologyMayo Clinic College of Medicine

October 14, 2016


NoneDisclosures

Checkpoint blockade use in leukemia, lymphoma, and myeloma

Off Label use


Outline

- Overview of checkpoint blockade

- Activity and tolerability of checkpointblockade in hematological malignancies

- Checkpoint blockade after BMT


What are immune checkpoints?

©2012 MFMER |

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Nirschl, et. al. Clin Cancer Res 2013;19, 4917-4924

Antigen specificity

CD28

immune priming

Anergy/death—occurs primarily during immune attack

Ipilimumab

Nivolumab, MK-3475 (pembrolizumab)


Why should we block the immune checkpoints?

Keir ME. Annu Rev Immunol. 2008; 26:677-704Pardoll DM Nature Rev Cancer. 2012;12:252-64


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


CTLA-4 vs. PD-1

Ribas, NEJM 2012


Checkpoint blockade in solid tumors


Treatment with Checkpoint blockade is practice changing in many solid tumors


Unique Toxicities after checkpoint blockade


Outline





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


Signal of activity for Ipilimumab in non-Hodgkin lymphoma


Colitis is the most common AE after Ipilimumab treatment in lymphoma


Why Hodgkin lymphoma?

Ansell et al. NEJM 2015

1. 9p24.1 amplification leads to PDL1 over expression on RS cells


Chen et al. Clinc Cancer Res 2012

Why Hodgkin lymphoma?2. EBV infection leads to PDL1 over expression on RS cells


Nivolumab treatment results in major responses in Hodgkin Lymphoma


Nivolumab is well tolerated in Hodgkin Lymphoma


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


Pembrolizumab treatment results in major responses in Hodgkin Lymphoma


Pembrolizumab treatment is associated with expansion of T cells and NK cells


• 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


Nivolumab treatment is well tolerated in Hodgkin Lymphoma


Summary: Toxicities of PD1 blockade in Hodgkin Lymphoma• Fatigue 20%• Pneumonitis 10% • Hepatitis 10%• Pancreatitis 10%• SAE 20%• 1 death due to pneumonitis


Lesokhin et al. JCO 2016


Major responses in NHL, B & T cell lymphomaNo major responses in MM


Expected toxicity profile of nivolumab


Pidilizumab combination with rituximab in follicular lymphoma

Westin et al. Lancet 2014

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)


Checkpoint blockade in hematological malignancies: Improving response rates

Combination with chemotherapy

Combination with antibodies

Combination with small molecules


Pidilizumab combination with rituximab result in major responses in follicular lymphoma




Pidilizumab combination with rituximab in follicular lymphoma



Evidence of immune activation after Pidilizumab combination with rituximab


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


Outline





PD1 Blockade after autologous stem cell transplantation

Target minimal residual disease


Immune reconstitution after autologous transplantation

Rationale:



• 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%




PFS at 18 months: 72%PFS at 18 months is historic controls: 52%

Response rates in patients with PET+ disease: 51%




Stimulate graft versus leukemia effect


Worsening or activation of graft versus host effect

Rationale:

Risk:


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



• 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



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


Is PD1 blockade safe after allogeneic transplantation?


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AcknowledgmentsPenn TRP/CCICarl JuneSaar GillDavid PorterOlga SheshtovaMarco RuellaMiriam KimMichael Klichinsky

Mayo HematologyTait ShanafeltNeil KayStephen Russell Greg NowakowaskiAlex Wolanshyj

Mayo BMTMark LitzowWilliam HoganMrinal PatnaikShahrukh Hashmi

Hem LeadershipMartha LacyDennis GastineauThomas WitzigAngela Dispenzieri

CIMKeith StewartScott Beck

ImmunologyDiane JelinekDan BilladeeauLarry Pease

Predolin Foundation

Acknowledgments

ASBMT NP/PABrenda FryeAmy Witter

Checkpoint Blockade in Hematology and Stem Cell ... · Hematology and Stem Cell Transplantation ......

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