UPDATED IN HEMATOLOGIC MALIGNANCIES

UPDATED IN HEMATOLOGIC MALIGNANCIES EKAPUN KAROOPONGSE MD DIVISION OF HEMATOLOGY, MEDICINE MAHIDOL UNIVERSITY

TREATMENT IN HEMATOLOGIC MALIGNANCIES Chemotherapy Immunotherapy Monoclonal antibody therapies Antibody-drug conjugates Immune checkpoint inhibitor Bispecific T cell engages (BITES) Chimeric Antigen Receptor (CAR) T cells

TREATMENT IN HEMATOLOGIC MALIGNANCIES Chemotherapy Immunotherapy Monoclonal antibody therapies : Multiple Myeloma Antibody-drug conjugates : Hodgkin lymphoma Immune checkpoint inhibitor : Hodgkin lymphoma Bispecific T cell engages (BITES) Chimeric Antigen Receptor (CAR) T cells : B-ALL

MONOCLONAL ANTIBODY Monoclonal Antibody in Hematologic malignancies Rituximab : B cell Non Hodgkin lymphoma Obinutuzumab : B cell Non Hodgkin lymphoma Daratumumab : Multiple Myeloma

DARATUMUMAB First in class, fully human IgG monoclonal antibody, target cell surface protein CD38 https://www.linkedin.com/pulse/voice-johan-frencken

DARATUMUMAB AS A FIRST LINE ALCYONE trial Phase III, RCT in 706 patients with newly diagnosed multiple myeloma, ineligible for stem cell transplantation Compare between VMP and Daratumumab-VMP MV Mateos NEJM Dec 2016

DARATUMUMAB AS A FIRST LINE Median F/U 16.5 (0.1-28) months MV Mateos NEJM Dec 2016

DARATUMUMAB INTERFERENCE Daratumumab interference with laboratory testing Interfere serum protein electrophoresis (SPEP) and Immunofixation (IFE) Interfere with antibody screens and panreactivity on blood compatibility antibody screens MV Mateos NEJM Dec 2016

ANTIBODY-DRUG CONJUGATION Brentuximab Vedotin FDA approved for relapse/refractory Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL) A CD30-directed monoclonal antibody conjugated to microtubule polymerization monomethyl auristatin E (MMAE)

Advanced and Relapsed/Refractory Hodgkin Lymphoma: What Has Been Achieved During the Last 50 Years - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/mechanism-of-action-of-sgn-35-the-antibody-drug-conjugate-binds-to- CD30-molecules-on-the_fig1_236059930 [accessed 20 Aug, 2018]

ROLE OF BRENTUXIMAB IN HL Consolidation after ASCT (AETHERA trial) In relapsed/refractory Hodgkin Lymphoma Monotherapy in R/R after ASCT (phase II) Combination with bendamustine As frontline treatment in advance stage Hodgkin lymphoma (ECHELON-1)

PHASE II : BRENTUXIMAB IN PATIENT WITH R/R POST ASCT Younes A, JCO 2012

94% of patient achieved tumor reduction 75% achieved ORR, 34% achieved CR Younes A, JCO 2012

PHASE II : BRENTUXIMAB IN PATIENT WITH R/R POST ASCT Younes A, JCO 2012 \

AETHERA TRIAL Used as consolidation therapy after ASCT in high risk for relapse after ASCT Refractory to frontline Relapse < 12 mo after frontline Relapse > 12 mo after frontline with extranodal disease Phase III, randomized, double-blind multicenter study Prolonged PFS, reduce the risk of disease progression or death Moskowitz Blood PC, 2014 Lancet 124:673 2015

AETHERA TRIAL n 329 BV 1.8 mg/kg q 3 wk for up to 16 cycles Median number of treatment cycles was 15 28% progress, 19% AE The estimate 2-year PFS was 54% and 2- year OS was 88% Moskowitz PC, Lancet 2015

AETHERA TRIAL : LONG TERM RESULT Moskowitz ] PC, Lancet 2015

IMMUNE ESCAPE OR IMMUE EDITTING

IMMUNE ESCAPE : THE CONCEPT Immune system is a critical regulator to support or inhibitor tumor development, growth, in action and metastasis Major player : cytotoxic T cells

IMMUNOTHERAPY : CHECK POINT INHIBITOR

IMMUNOTHERAPY OF LYMPHOMA AND MULTIPLE MYELOMA Using host immune system to combat cancer Target immune checkpoint signaling pathway, enhance T cell cytotoxic activity and induce tumor cell lysis Immune check point inhibitor

IMMUNE CHECKPOINT Signals regulate an immune response https://www.extremetech.com/extreme/250126-designer-virus-created-tells-immune-system-fight-cancer

IMMUNE CHECKPOINT Immune responses by T cells are balanced by co-stimulators and inhibitory signals Coana TRMOME-1046 2015

IMMUNE CHECK POINT INHIBITOR IN MALIGNANCIES TREATMENT Drugs Mechanism Indications Ipilimumab Anti-CTLA-4 antibody Advanced melanoma Pembrolizumab Nivolumab Anti-PD-1 Melanoma, metastatic NSCL, H&N SCCA, urothelial carcinoma, gastric adenocarcinoma, classical Hodgkin lymphoma Plus hepatocellular carcinoma, renal cell carcinoma Atezolizumab Anti-PD1-L1 Urothelial cancer, NSCLC

IMMUNE DEFICIENCY/INVASION IN HL T-cell qualitative defect T-cell quality defect : decrease proliferation and decrease IL-2 secretion Defect in T cell-mediated antitumor immune response Increase expression of programmed cell death-1 ligand 1 (PD-L1), and PD-L1 receptor on T cells

IMMUNOTHERAPY OF LYMPHOMA AND MULTIPLE MYELOMA Nivolumab Approved for refractory classical Hodgkin lymphoma 2016 Pembrolizumab FDA approved for RR HL after > 3 regimens 2017

NIVOLUMAB IN RR HL Trial N included refractory to BV Case series 75 response 64%, CR 22%, Multicenter phase II 243 18 mo follow up Response 69%, Median PFS 14.7 Median duration of response 16.6.mo Nivolumab + Brentuximab Phase I 80 100% ORR, CR 62.5% H. Bekoz Annals of oncology 2017, Armand P. JCO 2018, Armand P Blood 2016, Diefenchah CS, Blood 2016

PEMBROLIZUMAB IN RR HL Trial N Pembrolizumab alone 1b 75 response 65%, CR 16%, Include failed BV Phase II 210 Response 69%, CR 22% Armand P JCO 2016, Chen R JCO 2017

IMMUNOTHERAPY : COMPLICATIONS Related to mechanism of action : immune-related adverse effect (iraes) Rash/inflammatory dermatitis/bullous dermatoses Colitis/Hepatitis Pneumonitis Inflammatory arthritis Nephritis Myasthenia gravis/peripheral neuropathy/encephalitis

BISPECIFIC T-CELL ENGAGES (BITES)

BITE Recombinant bispecific protein, two linked scfvs from two antibodies different One targeting a cell-surface molecule on T cells and the other targeting antigens on the surface of malignant cells

BLINATUMOMAB (AMG103) Antibody construct direct against the pan-b cell antigen CD19 and the CD3 Frankel SR, Current opinion in chemical biology 2013

BLINUTUMUMAB IN RRDLBCL Phase I trial with indolent, mantle cell and diffuse large B cell lymphoma 4-8 weeks continuous IV 5 ug/m 2 /d first week, 15 ug/m 2 /d second week than 60 ug/m 2 /d first week 5/9 patients showed objective clinical response (4CR/CRu, 1 PR) Median response duration +182 days, longest current duration +428 days Viardot A. Blood 2011

BLINUTUMUMAB IN ALL Phase III multi-institutional trial, RCT in RRALL Compare between blinutumumab and CMT 34% vs 16% CR, 6-month event free survival were 31 vs 12% Kantarjian H. NEJM 2017

BLINUTUMUMAB IN ALL Kantarjian H. NEJM 2017

CYTOKINES RELEASE SYNDROME Unique toxicity for immune-based therapy Reported after BiTEs and CAR-T cell treatment Associated with increasing production of IL-6 and interferon gamma S&S : fever + rigor, myalgia, arthalgias, rash, N&V, tachypnea, hypoxemia, hypotension, bleeding, renal failure, liver injury, delirium, confusion, seizure

CHIMERIC ANTIGEN RECEPTOR T CELL (CAR-T CELL)

CHIMERIC ANTIGEN RECEPTOR T CELLS T cell-based adoptive immunotherapy Antibody single-chain fragment (scfv) Costimulatory signal (Complete T cell activation process) CD3z signaling signal

Zhao Z, acts pharmaceutica sinica 2018

http://www.takara-bio.com/medi_e/car.html

CHIMERIC ANTIGEN RECEPTOR T CELLS Kochenderfer JN. Blood 2012

APPLICATIONS IN HEMATOLOGIC MALIGNANCIES CAR-T cell in ALL and CLL FDA approved for refractory B-cell ALL in 2017 Diffuse large B cell lymphoma in 2017

ELIANA TRIAL (GLOBAL PHASE II) In 68 children and young adult relapsed/refractory ALL Median f/u 6.2 months Tisagenlecleucel (KYMRIAH) was present in the blood and bone marrow and persisted beyond 2 years Cost 475,000 USD

JULIET TRIAL (GLOBAL PHASE II) Relapse/refractory DLBCL and DLBCL after tranformation from follicular lymphoma Single-arm multicenter, phase II, n = 68 50% response, 32% complete response Schuster SJ, ASH abstract 2017

ONGOING TRIALS OF CART-19 T CELLS High-risk multiple myeloma Chronic lymphocytic leukemia or small lymphocytic lymphoma Advanced lymphoid malignancies Relapsed and Refractory B cell Non-Hodgkin lymphoma

Q & A