Managing Patients Undergoing CD19 CAR-T Therapy
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- Amberlynn Harris
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1 Managing Patients Undergoing CD19 CAR-T Therapy June 7, 2018 Dr. Ronan Foley, MD, FRCPC and Jennifer Wiernikowski, MN, NP-Adult, CON(C) Juravinski Hospital Hamilton ON
2 Speaker Disclosures Dr Foley: Advisory Boards: Roche, Lundbeck/TEVA, Sanofi, Celgene, Novartis, Janssen, Alexion Lectures: Roche, Lundbeck/TEVA, Sanofi, Celgene, Novartis, Janssen Funding: Roche Canada Juravinski Cancer Center and Foley (Site PI) Participation in Juliet CD19 CART Clinical Trial Data included in this presentation
3 Speaker Disclosures Jenn Wiernikowski: Advisory Boards: Celgene, Jazz Lectures: Lundbeck/TEVA, Celgene, Janssen, Jazz
4 Objectives Review the MOA of CAR T therapy and how CAR-T cells are made Share data to support CAR T therapy in DLBCL Managing AEs Specific to CAR T therapy Nursing assessment; recognizing early signs of trouble Nursing interventions Making sure we are ready: the logistics of providing CAR T treatment Who is eligible for CAR-T therapy? How do we decide? What does the interdisciplinary team look like? What are the roles of the team members?
5 Exploiting the Immune System in Cancer Treatment Several components of the immune system can be involved in response to cancer, harnessing the cytotoxic potential of T Cells has been a big focus T Cells can be manipulated to recognize and attack cancer cells via Vaccination (HPV, preventing cervical cancer) Monoclonal antibodies & BiTES (Rituximanb, Blinatumomab) Modification of T Cells Ex Vivo (CAR-T) CAR T cell tx involves genetically engineering receptors to recognize the cancer antigen & transducing them within the patients T Cells taking advantage of T Cell signaling and cytotoxic activity McGuirk, J. et al (2017). Cytotherapy 19/
6 OK lets get started.
7 Hematopoiesis naïv e B-lymphocytes Lymphoid progenitor T-lymphocytes Plasma cells Hematopoietic stem cell Myeloid progenitor Neutrophils Eosinophils Basophils Monocytes Platelets Red cells
8 Acute GVHD GVHD is an immune reaction following allosct in which the donor-derived immune cells view the recipient s body as foreign and attack the recipient s normal cells Donor-derived T cells respond to genetically defined proteins on host cells, mainly human leukocyte antigens (HLAs) 1 HLAs are expressed on almost all nucleated cells (class I HLA proteins) or on hematopoietic cells (class II HLA proteins) 1 GVHD is characterized by high levels of proinflammatory cytokines (eg, tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-6, or interferon [IFN]-γ), 1,2 which enhance activation and proliferation of effector T cells 3 1. Ferrara JL, et al. Lancet. 2009;373(9674): Spoerl S, et al. Blood. 2014;123(24): Spoerl S, et al. Blood. 2014;124(21) [abstract 3934]. Donor-derived immune cells are transferred to the recipient along with the hematopoietic stem cells (graft) Host cells are recognized as foreign and attacked
9 9 Acute GVHD Overview Acute GVHD occurs primarily in the skin, gastrointestinal tract, and liver 1 Patients present with a combination of inflammatory dermatitis, enteritis, and hepatitis 2 The skin is the most common affected tissue, and a maculopapular rash is usually the first manifestation Patients with acute GVHD of the gastrointestinal system may present with anorexia, nausea, vomiting, profuse watery diarrhea, or abdominal cramping Acute GVHD of the liver is preceded or accompanied by elevated serum aminotransferases and serum alkaline phosphatase; liver GVHD rarely occurs without other organ involvement From Ferrara JL, et al. Lancet. 2009;373(9674): Acute GVHD of the skin (grade 1) Acute GVHD of the duodenum (stage 4). Ulceration, exudates, and bleeding are seen From Velasco-Guardado A, et al. Rev Esp Enferm Dig. 2012;104(6): Ferrara JL, et al. Lancet. 2009;373(9674): Carpenter PA, Macmillan ML. Pediatr Clin North Am. 2010;57(1): Jagasia MH, et al. Biol Blood Marrow Transplant. 2015;21(3): e1.
10 Activation of T cells T-cells have receptors Macrophages present fragments of broken down pathogens to T-cells through a HLA antigen This sensitizes the T-cell, which acquires specific receptors on its surface that enables them to recognize the invader The T-cell undergoes clonal expansion Cytotoxic T-cells secrete chemicals that kill infected cells Helper T-cells produce cytokines that stimulate B-cells Some T-cells become memory T-cells Expansion and persistence
11 Targeted Immunotherapy
12 CAR costimulatory domains Antigen- Binding Domain (scfv) Anti-CD19 Anti-CD19 Anti-CD19 Hinge and Transmembrane Domain CD8-alpha hinge Costimulatory Domain 4-1BB CD28 CD28 Signaling Domain CD3-ζ CD3-ζ CD3-ζ Tisagenlecleu cel(novartis) Axicabtagene Ciloleucel (Kite Pharma) Lisocabtagene Maraleucel (Juno Therapeutics) Vector Lentiviral 1-4 Retroviral 3-7 Retroviral 8-10 Persistence 4 years 30 days 30 days
13 CTL019 is a living drug designed to target CD19+ B cells Patient s T cell CTL019 cell Anti-CD19 CAR construct CD19 Tumor cell Dead tumor cell Native TCR Lentiviral vector Cytokine release CTL019 proliferation Ex vivo In vivo References: 1. Milone MC et al. Mol Ther. 2009;17: ; 2. Hollyman D et al. J Immunother. 2009;32: ; 3. Kalos M et al. Sci Transl Med. 2011;3:95ra73.
14 CD19 as the target The primary focus of CAR T trials to date This antigen is expressed on B Cell precursor cells, most mature B cells and several B cell malignancies yet not expressed on other vital tissues Studies to date have therefore focused on R/R heavily pre-treated pediatric ALL and R/R DLBCL R/R ALL pediatric trials have shown CR rates of up to 90% R/R DLBCL adult trials have shown CR rates of up to 50-70% McGuirk, J. et al (2017). Cytotherapy 19/
15 CD19: A rational target for therapy CD19 is expressed on B cells and B-cell precursors and is not expressed on bone marrow stem cells or other tissues Bone marrow Periphery Bone marrow Stem cell Pro-B cell Pre-B cell Native B cell Activated B cell Memory GC B cell Late plasmablast Plasma cell ALL MCL DLBCL WM CD19 MZL CLL FL FL: follicular lymphoma; GC: germinal center; MCL: mantel cell lymphoma; MZL: marginal zone lymphoma; WM: Waldstrom s macroglobulinemia. Adapted from Blanc V et al. Clin Cancer Res. 2011;17(20):
16 How is this going to work in the clinic? Answer it s a bit like a DLI
17 Overview of CTL019 Therapy in the Clinic Copyright Novartis Corporation 1.Leukapheresis: patient s T cells are collected T cells are genetically transduced ex vivo with a lentiviral vector encoding the anti- CD19 CAR 1,3 3.CTL019 cells undergo ex vivo expansion on magnetic antibodycoated beads Lymphodepleting chemotherapy: the patient may receive a preparative lymphodepleting regimen before T cell infusion CTL019 cells are infused into the patient Porter DL, et al. N Engl J Med. 2011;365: ; 2. Porter DL, et al. J Cancer. 2011;2: ; 3. Kalos M, et al. Sci Transl Med. 2011;3:95ra73. Image from Levine BL. Cancer Gene Ther. 2015;22:79-84.
18 Tisagenlecleucel process overview A multistep process Patient identification Collection & Cryopreservation Manufacturing Lymphodepleting chemotherapy Infusion Post-infusion monitoring Long-term monitoring Patient Selection Apheresis Team F/C DMSO Admission Disease stability/status Consents Family meeting Expectations Distance from institution Caregiver TD testing DLI Collection Peripheral access Stem Cell Lab Labels ISBT Bendamustine Infections Outpatient CRS Neurotoxicity TLS B-Cell Aplasia Disease progression
19 Tisagenlecleucel site setup process implicates many stakeholders Tisagenlecleucel therapy process Apheresis staff Cell-processing staff Infusion staff Pharmacy staff Legal Prescribing physicians Nurses Finance Procurement Transplant coordinators Non-CTL019 certified MDs and advanced practitioners Social workers/ care coordinators Intensive care unit/emergency department staff Commercial Team Apheresis Team Call Centre Clinical Team Medical Team Legal HPPA Support Functions
20 So why all the fuss about CART?
21 DLBCL Treatment Algorithm Stage III/IV or II with bulk RCHOP(21d)x6 +/- IFR IT/HD Mtx for high risk sites Stage I/II non bulky RCHOP(21d)x3-4 +IFR PET pos +2 RCHOP +IFR Progression ASCT Eligible Ineligible Salvage GDP/ICE HD-ASCT Progression Palliation Gemcitabine, Ifosfamide, Etoposide, Len Relapsed/Refractory DLBCL OS 5-11 mos, CR rates <10% Crump et al., (2017) Blood; Oct 19; 130(16)
22 Primary Analysis of JULIET: a Global, Pivotal, Phase 2 Trial of Tisagenlecleucel (CTL019) in Adult Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma Stephen J. Schuster, Michael R. Bishop, Constantine S. Tam, Edmund K. Waller, Peter Borchmann, Joseph P. McGuirk, Ulrich Jäger, Samantha Jaglowski, Charalambos Andreadis, Jason R. Westin, Isabelle Fleury, Veronika Bachanova, Stephen Ronan Foley, P. Joy Ho, Stephan Mielke, John M. Magenau, Harald Holte, Koen van Besien, Marie José Kersten, Takanori Teshima, Kensei Tobinai, Paolo Corradini, Özlem Anak, Lida Pacaud, Christopher del Corral, Rakesh Awasthi, Feng Tai, Gilles Salles, Richard T. Maziarz On behalf of the JULIET study investigators
23 JULIET: Primary Endpoint Was Met, ORR 53% Response Rate, % Best Overall Response Rate (N = 81) Response at 3 Months (N = 81) Response at 6 Months (n = 46) ORR (CR + PR) 53 a CR PR * P <.0001 (95% CI, 42%-64%). Null hypothesis of ORR 20%. CR, complete response; ORR, overall response rate; PR, partial response. Juliet (submitted) Schuster et al, submitted
24 JULIET: ORR Consistent Across Subgroups Null hypothesis of ORR 20% ORR n/n (%) [95% CI] All patients 43/81 (53.1) [ ] Age, years < 65 32/64 (50.0) [ ] 65 11/17 (64.7) [ ] Sex Female 18/29 (62.1) [ ] Male 25/52 (48.1) [ ] Prior antineoplastic therapy 2 lines 22/41 (53.7) [ ] > 2 lines 21/40 (52.5) [ ] Cell of origin a Nongerminal center 19/34 (55.9) [ ] Germinal center 19/41 (46.3) [ ] Rearranged MYC/BCL2/BCL6 Double/triple hits 5/12 (41.7) [ ] Other 38/69 (55.1) [ ] a Data from 6 patients are missing ORR, overall response rate. Schuster et al, submitted
25 High Durable CR Rates in R/R Aggressive B-NHL Treated with JCAR017 (lisocabtagene maraleucel; liso-cel) (TRANSCEND NHL 001): Defined Composition CD19-Directed CAR T Cell Product Allows for Dose Finding and Definition of Pivotal Cohort Jeremy S. Abramson, 1 M. Lia Palomba, 2 Leo I. Gordon, 3 Matthew Lunning, 4 Jon Arnason, 5 Michael Wang, 6 Andres Forero- Torres, 7 David Maloney, 8 Tina Albertson, 9 Jacob Garcia, 9 Daniel Li, 9 Benhuai Xie, 9 Tanya Siddiqi 10 1 Massachusetts General Hospital Cancer Center, Boston, MA; 2 Memorial Sloan Kettering Cancer Center, New York, NY; 3 Northwestern University Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; 4 University of Nebraska Medical Center, Omaha, NE; 5 Beth Israel Deaconess Medical Center, Boston, MA; 6 University of Texas MD Anderson Cancer Center, Houston, TX; 7 University of Alabama at Birmingham, Birmingham, AL; 8 Fred Hutchinson Cancer Research Center, Seattle, WA; 9 Juno Therapeutics, Seattle, WA; 10 City of Hope National Medical Center, Duarte, CA
26 JCAR017 (lisocabtagene maraleucel; liso-cel) CD19-Directed Defined Cell Product Tumor cell Patient s PBMCs Tumor antigen Epitope Immunomagnetic selection Transmembrane domain scfv Spacer Lentivirus transduction Expansion Formulated at specified composition of CD4 + and CD8 + CAR + T cells T cell Intracellular costimulatory domain Signaling sequence Administered at precise doses of CD4 + and CD8 + CAR + T cells CAR + CD8 + CD8 + (targets tumor) EF1p CD19 scfv murine monoclonal FMC63 Spacer Transmembrane domain Signaling domain VL linker VH CD28tm 4-1BB CD3ζ T2A Transduction marker huegfrt 3 LTR CD4 + (targets tumor, supports persistence) Other PBMC Cell Types 27 CAR + CD4 + Abramson et al
27 High Rates of Response in FULL DLBCL Population FULL By B-NHL Subtype DLBCL, NOS tfl tcll/mzl FL3B/PMBCL BOR, n a ORR, % (95% CI) 74 (63, 83) 74 (60, 85) 84 (60, 97) 50 (19, 81) 100 (16, 100) CR, % (95% CI) 52 (41, 63) 51 (37, 64) 63 (38, 84) 30 (7, 65) 100 (16, 100) 3-mo f/u, n b mo ORR, % (95% CI) 53 (41, 65) 54 (39, 69) 67 (38, 88) 22 (3, 60) 50 (1, 99) 3-mo CR, % (95% CI) 44 (33, 57) 43 (29, 59) 60 (32, 84) 22 (3, 60) 50 (1, 99) 6-mo f/u, n c mo ORR, % (95% CI) 35 (23, 49) 35 (20, 53) 50 (19, 81) 0 (0, 46) 50 (1, 99) 6-mo CR, % (95% CI) 31 (20, 46) 32 (18, 50) 40 (12, 74) 0 (0, 46) 50 (1, 99) BOR, best overall response; NOS, not otherwise specified. Homogeneous CORE patient population identified and will move forward in pivotal trial a Includes patients with event of PD, death, or 28-day restaging scans. Two patients did not have restaging scans available. b The denominator is number of patients who received JCAR017 3 months ago, prior to data snapshot date, with an efficacy assessment at month 3 or prior assessment of PD or death. c The denominator is number of patients who received JCAR017 6 months ago, prior to data snapshot date, with an efficacy assessment at month 6 or prior assessment of PD or death. Abramson et al
28 JCAR017 Shows High Durable ORR in Poor-Risk DLBCL Subgroups Population CORE Patient Population a tfl DLBCL NOS Double/triple hit or double expressor Double/triple hit Double expressor Never in CR Chemosensitive Chemorefractory Relapse <12m from ASCT SD/PD to last chemo Stage 3/4 Stage 1/2 IPI 3-5 IPI 0-2 ORR (95% CI) 65.4 (50.9, 78) 76.9 (46.2, 95) 61.5 (44.6, 76.) 83.3 (58.6, 96.4) 84.6 (54.6, 98.1) 80 (28.4, 99.5) 73.1 (52.2, 88.4) 66.7 (38.4, 88.2) 64.9 (47.5, 79.8) 84.6 (54.6, 98.1) 54.2 (32.8, 74.4) 62.2 (44.8, 77.5) 76.9 (46.2, 95) 42.1 (20.3, 66.5) 80.6 (62.5, 92.5) n Month 3 ORR (95% CI) a Includes all DLBCL patients treated at all dose levels in CORE. Abramson et al
29 Long-Term Follow-Up of ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (axi-cel; KTE-C19) in Patients With Refractory Aggressive Non-Hodgkin Lymphoma Sattva S. Neelapu, MD 1* ; Frederick L. Locke, MD 2* ; Nancy L. Bartlett, MD 3 ; Lazaros J. Lekakis, MD 4 ; David B. Miklos, MD 5 ; Caron A. Jacobson, MD 6 ; Ira Braunschweig, MD 7 ; Olalekan O. Oluwole, MBSS, MPH 8 ; Tanya Siddiqi, MD 9 ; Yi Lin, MD, PhD 10 ; John Timmerman, MD 11 ; Eric Jacobsen, MD 6 ; Patrick M. Reagan, MD 12 ; Adrian Bot, MD PhD 13 ; John Rossi, MS 13 ; Lynn Navale, MS 13 ; Yizhou Jiang, PhD 13 ; Jeff Aycock 13 ; Meg Elias, RN, BSN 13 ; Jeffrey S. Wiezorek, MD, MS 13 ; and William Y. Go, MD, PhD 13 1 The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Moffitt Cancer Center, Tampa, FL; 3 Washington University, St. Louis, MO; 4 University of Miami Health System, Sylvester Comprehensive Care Center, Miami, FL; 5 Stanford University, Stanford, CA; 6 Dana-Farber Cancer Institute, Boston, MA; 7 Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; 8 Vanderbilt-Ingram Cancer Center, Nashville, TN; 9 City of Hope National Medical Center, Duarte, CA; 10 Mayo Clinic, Rochester, MN; 11 UCLA David Geffen School of Medicine, Los Angeles, CA; 12 University of Rochester School of Medicine, Rochester, NY; 13 Kite, a Gilead Company, Santa Monica, CA *Drs. Neelapu and Locke contributed equally to this work. Neelapu SS, et al. ASH abstr:578.
30 ZUMA-1: Objective Response Phase 2 Primary Analysis N = 101 Phase 1 and 2 Updated Analysis N = 108 Median follow-up, mo ORR CR ORR CR Best objective response, % Ongoing, % % of patients in phase 1 obtained a CR In the updated analysis, 23/60 patients with either a PR (11/35) or SD (12/25) at the first tumor assessment (1 mo post axi-cel) subsequently achieved CR up to 15 months post-infusion without additional therapy - Median (range) time to conversion from PR to CR = 64 (49 424) days Response was evaluated by investigator assessment. CR, complete response; ORR, objective response rate; PR, partial response; SD, stable disease. Neelapu et al ASH Neelapu SS, et al. ASH abstr:
31 ZUMA-1: Duration of Response by Best Objective Response 11.1 (3.9 NR) NR (NR NR) 1.9 ( ) Median duration of CR has not been reached 3/7 (43%) phase 1 patients have ongoing CR at 24 months CR, complete response; NR, not reached; PR, partial response. Neelapu SS, et al. ASH abstr:578. Neelapu et al ASH
32 Overall Survival Median OS, a mo (95% CI) ZUMA-1 Updated Analysis 1 Propensity Score Analysis N = 513 N = 108 CAR T Non-CAR T NR 16.4 (11.5 NR) 5.4 ( ) 12-mo rate, % (95% CI) 59 (49 68) 73 (48 97) 26 (21 32) 18-mo rate, % (95% CI) 52 (41 62) 47 (0 72) 23 (19 29) Treatment difference, HR (95% CI) 0.28 ( ) (72% reduction in the risk of death) Similar results were observed from the 8-covariate analysis that additionally accounted for IPI and disease stage HR, hazard ratio; NR, not reached. a Kaplan-Meier estimate with median duration of follow up of 15.4 months. 1. Neelapu SS, et al. ASH abstr:
33 ELIANA: Eligibility and endpoints ELIANA is a single-arm, multicenter phase 2 study of CAR-T cell therapy The study includes 25 sites in 11 countries using a global supply chain and central manufacturing Key eligibility criteria 3 years of age at screening and 21 years of age at diagnosis Primary refractory disease Second or greater bone marrow (BM) relapse Ineligible for allogeneic SCT No prior anti-cd19 therapy Grade 2 to 4 acute or extensive chronic graft-vs.-host disease No active CNS involvement Endpoints Overall remission rate (CR + CRi) within 3 months) 4-week maintenance of remission Independent review committee assessment Secondary endpoints: Rate of CR/CRi with undetectable MRD (< 0.01%), DOR, EFS, OS, Cellular kinetics, Safety a Defined as not achieving complete remission (CR) after 2 cycles of a standard chemotherapy regimen, or chemorefractory, defined as not achieving CR after 1 cycle of standard chemotherapy for relapsed leukemia. b For relapsed patients. Reference: 1. Maude SL et al. N Engl J Med. 2018;378:
34 ELIANA efficacy: Primary endpoint Response rates Patients (N = 75) ORR (CR + CRi) within 3 months, n (%) a 61 (81) 95% CI, % BOR, n (%) CR 45 (60) CRi 16 (21) No response, n (%) 6 (8) Unknown, n (%) 8 (11) The response of 8 patients (11%) was unknown: 2 patients died before assessment (ALL and cerebral hemorrhage) 1 patient with remission at the day 28 assessment died prior to the 3-month assessment (encephalitis) 1 patient died with indeterminate bone marrow remission (systemic mycosis) 1 patient with unconfirmed remission proceeded to allohsct 2 patients achieved bone marrow remission but did not have a cerebral spinal fluid assessment by lumbar puncture post-infusion 1 patient showed an absence of marrow blasts by pathology but marrow and blood differentials were not available a In patients infused with tisagenlecleucel 3 months prior to data cutoff. allohsct: allogeneic hematopoietic stem cell transplant; Cri: CR with incomplete blood count recovery. Reference: 1. Maude SL et al. N Engl J Med. 2018;378: Source in speaker notes Maude SL et al. N Engl J Med. 2018;378:
35 Probability ELIANA efficacy: Event-free and overall survival Patients at risk OS EFS Event-free survival Event-free survival (EFS): Month 6: 73% (95% CI, 60-82) Month 12: 50% (95% CI, 35-64) Median EFS was not reached Months Since Tisagenlecleucel Infusion Overall survival (OS): Month 6: 90% (95% CI, 81-95) Month 12: 76% (95% CI, 63-86) Median OS, 19.1 months Overall survival EFS, event-free survival defined as the time from infusion to the first of the following: no response, relapse before 28 days or relapse after achieving CR/CRi; OS, overall survival defined as the time from infusion to death for any reason. Source in speaker notes Maude SL et al. N Engl J Med. 2018;378:
36 OK Jenn; How is this going to work
37 Leukopheresis Target cells are mononuclear cells, non mobilized T Cells (example CD 3+, CD4+ CD8+) Collection is often faster than stem cells (CD34+ mobilized cells collected for stem cell transplant), a single collection of 2-3 hrs In the Juliet trial the goal for collection was minimum absolute lymphocyte count of 500 cells/µl, CD3+ cell count of 150 cells/µl
38 Factors Affecting Collection & Timing Prior cycles of cytotoxic chemotherapy Previous stem cell transplant Immunosuppressive therapy should be stopped and no s/s of active GVHD at the time of collection Collection of T Cells in clinical trials require at least 3 months between allo SCT and pheresis because of the risk of collecting allo reactive T Cells (which mediate GVHD) Stop cytotoxic chemotherapy 2 weeks before collection, L Asp 4 weeks before collection, therapeutic steroids 72 hrs before collection
39 Chemotherapy Post Pheresis Bridging Chemotherapy Pts are often in active relapse or with tenuous remission therefore bridging chemotherapy is often given to maximize response while waiting for the CAR T to be ready. Maximize dx response, minimize organ toxicity Lymphodepleting chemotherapy Making room for auto T Lymphocytes (CARs) & reduces the number of circulating lymphocytes in the patient to upregulate cytokines to help promote expansion of the CAR Ts 7-10 days prior to CAR T infusion Fludarabine/cyclo/Bendamustine/EPOCH Outpatient chemo with supportive care per usual Infections, proph anti infectives, irradiated blood products
40 Infusion Day Cryopreserved product with DMSO Thawed at the bedside and administered by gravity Premeds and lemon drops Ronan any cautions re viability, time to infuse? FACT check lists to complete Documentation D/C Home if care plan in place to support
41 Nursing Assessment Daily History/physical/S&S infection Attention to signs and symptoms of Cytokine Release Syndrome and neurological changes Myalgias TLS markers Clinical evaluation of palpable disease Share your findings! Consistency of approach is essential Small changes in clinical assessment matter
42 Cytokine Release Syndrome A systemic inflammatory response secondary to high levels of circulating inflammatory cytokines driven by T Cell activation and proliferation Can be mild and self limiting (pyrexia, myalgias, arthralgias, anorexia, fatigue) to severe and life threatening (persistent high fever, hypotension, capillary leak, hypoxia, cytopenia, coagulopathy) HLH (Hemophagocytic Lymphohistiocytosis), MCA (Mast Cell Activation Syndrome) have also been described with marked elevation of CRP and ferritin TLS risk is also real and needs to be monitored
43 44 JULIET: Cytokine Release Syndrome Patients (N = 99) Time to onset, median (range), days a,b 3 (1-9) Duration, median (range), days a 7 (2-30) Hypotension that required intervention, % 28 High-dose vasopressors 6 Intubated, % 8 Anticytokine therapy, % 16 Tocilizumab 15 Corticosteroids 11 a Calculated based only on patients who had cytokine release syndrome (n = 57), excluding 1 patient who had onset on day 51. b Cytokine release syndrome was graded using the Penn scale and managed by a protocol-specific algorithm Porter DL, et al. Sci Transl Med. 2015;7(303):303ra139.
44 Grading CRS Porter et al., J Hematol Oncol, 11
45 Management of CRS Supportive care for comfort: Antipyretics Antiemetics IV Fluids Hypotension IV Fluid bolus Vasopressor support Coagulopathy FFP or cryoprecipitate Hypoxia O2, CPAP, BiPAP, intubation Anticytokine Tx Tocilizumab Interlukin 6 blockade 4mg/kg IV over 1 hr Repeat in 24hrs if no clinical improvement Steroids solumedrol Avoid, last resort for life threatening CRS Shortest course possible to minimize the impact on long term durability of the CARs.
46 ICU at the ready! CRS Treatment Algorithm Example Grade I Fever, nausea, headache, malaise Out pt management (< 45 min, r/0 neutropenic fever (ANBX) Admit, Tylenol, IVF, daily ferritin and CRP CRS U Penn Staging Days 3-9 post infusion Grade II Organ toxicity/renal, liver, hypotension, desaturation Grade III Hypotension, coagulopathy, hypoxemia, organ failure Telemetry, IVF boluses (2L) escalate to pressors if no response, O2 Norepinephrine, dopamine, epinephrine Consider dose #1 Tociliuzumab Telemetry, IVF boluses (2L) as above and switch to pressors if no response, O2 Norepinephrine, dopamine, epinephrine, HD Tociliuzumab dose #2, FFP, Cryo, fibrinogen concentrates Grade IV Coagulopathy, hypoxemia, organ failure, ventilation Intubation ventilation, HD, high dose steroids (solumedrol 1gm daily x 3) ATG, CAMPATH
47 49 JULIET: Impact of CTL019 Dose on Response, Safety, & Exposure Response (tumor response at month 3) No apparent relationship Responses observed across full range of doses Dose ( CAR- positive viable T cells) a a 1 patient received a dose < CAR-positive viable T cells. Safety (CRS and neurological events) Exposure (maximal expansion from qpcr data) No relationship observed between dose and neurological events Higher probability of CRS with higher doses CRS is manageable per algorithm Dose and exposure were independent No expansion (AUC 0-28d and C max )- response relationship observed 1. Awasthi A, et al. Blood. 2017;130(23):[abstract 5211]. CRS, cytokine release syndrome.
48 Neurotoxicity Pathophysiology is not well understood In patients receiving CD19 specific CAR T treatment this has been reported. Early signs may be word finding difficulty, attention troubles, trouble with complex commands (counting backward by 7, handwriting) Confusion, delirium, expressive aphasia, clonus, seizures Watch for s/s of increased ICP, steroids may be needed in neurotoxicity Imaging with CT/MRI, neuro consult,?lp if suspect infection/dx
49 It takes a committed team In order to provide CAR-T therapy you need Hematologists trained in cellular therapy provision Apheresis Nurses Laboratory Staff Pathology department with flow cytometry expertise Cellular Therapy Nurses (I used to call us transplant nurses but I guess that is changing ) Pharmacists Social workers Administrators and managers ICU physicians and nurses are part of this team! ED physicians and nurses are part of this team! Strongly consider a CAR-T Coordinator much like you may have in stem cell transplant
50 Communication and Education Education: Patients/families, nursing staff, Emergency/ICU staff, & pharmacy Focus on early identification and management of AEs (esp CRS) Coordination Pre CAR T tx screening and a new list meeting Pheresis timing relative to recent chemo/ist Coordination with the lab/manufacturing site/clinical team to convey when product will be ready and connect that to any needed bridging chemo/ld chemo that is planned Pharmacy SOPs for LD chemotherapy Tociliuzumab on site,?siltuximab on site. Aim for administration of Toci within 2 hrs of being ordered McGirk, Cytotherapy vol 19.
51 ZUMA-1: Representative Immunohistochemistry of B Cell and Immune-Related Molecules Patient Summary CD19 at Baseline CD19 at PD PD-L1 at PD BOR: PR BL: CD19+ PD: CD19 PD-L1+ BOR: PR BL: CD19+ PD: CD19+ PD-L1+ All images at 40 magnification. Scale bar indicates 60 µm. BL, baseline; BOR, best objective response; PD, progressive disease; PD-L1, programmed cell death-ligand 1.
52 QUESTIONS?
R/R DLBCL Treatment Landscape
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