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Engineering an Immunity to Cancer: A New Era of Adoptive Cellular Therapy with Tisagenlecleucel (Kymriah) in Pediatric ALLDiana Schreier, Pharm.D., M.B.A.Pharmacy Grand RoundsOctober 17, 2017
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Objectives• Define Chimeric Antigen Receptor (CAR) T-Cell
Therapy and its role in the treatment of pediatric ALL
• Describe the process of engineering, administering and monitoring tisagenlecleuceltreatment
• Review complications and management strategies for treatment-related adverse effects
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Patient case• JM is a 6 year old male brought in by his
mother. She is very concerned that JM has been looking very pale recently and is covered in bruises.
• Upon further evaluation, JM’s workup shows the following: lymphadenopathy, Hgb 7.4, leukocytes 6.3, plt 87, > 20% lymphoblasts on bone marrow biopsy
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Question• JM was diagnosed with ALL. What is the first
line therapy for treating JM’s leukemia?
1. Tisagenlecleucel (Kymriah)2. Intensive chemotherapy followed by HSCT3. HSCT without chemotherapy4. Clinical trial
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Phases of Pediatric ALL Treatment• Remission induction:
• Achieve remission• Consolidation/intensification:
• Eradicate remaining cancerous cells • Extracompartment therapy:
• CNS-directed• Maintenance:
• Suppress re-emergence
Cooper et al. Pediatr Clin North Am. 2015; 62(1): 61-73.National Comprehensive Cancer Network. Acute Lymphoblastic Leukemia (Version 4.2017). https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed October 6, 2017.
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Relapsed Pediatric ALL Treatment• Relapses occur most frequently within 2 years of
treatment completion• Oftentimes patients undergo re-induction and
consolidation to achieve 2nd complete response• Followed by allogeneic hematopoietic stem cell
transplant (HSCT)• Cure rate of 30%-50% after chemotherapy and
allogeneic HSCT
Cooper et al. Pediatr Clin North Am. 2015; 62(1): 61-73.Inaba et al. Lancet. 2013;381(9881): 1943-55.Locatelli et al. Blood. 2012; 12(14): 2807-16.
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Immuno-oncology• Hallmark of cancer:
• Ability to avoid immune destruction
• Immunosurveillance• Host recognizes and eliminates immunogenic
tumors
• Novel therapies in immuno-oncology• Check point antibodies (PDL-1, CTLA-4 inhibitors)• Cytokine therapy (interleukins, interferons)• Chimeric Antigen Receptor (CAR) T-cells
Hanahan et al. Cell. 2011;100:57-70.Finn et al. Ann Oncol. 2012;23(8): vii6-vii9.
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Immuno-oncology
• Unregulated tumor growth occurs when tumor subverts immune response
1. Loss of immunogenicity2. Microenvironment with immunosuppressive cells
Cancer cell
Cancer cell
1 2
Cancer cell
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Immunosurveillance mechanismExpansion and differentiation
T cell
Cancer cell
Cytokine signaling
Cytotoxicity
Kymriah® [package insert]. Novartis Pharmaceuticals Corporation. New Hanover, NJ; 2017.
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Tisagenlecleucel mechanism• Chimeric Antigen Receptor (CAR) T cells
• Autologous T-cells that have been genetically altered to express a disease-associated antigen
Eshhar, Z et al. Proc Natl Acad Sci USA. 1993; 90(2):720-724.
Tisagenlecleucel
ALL B cell
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Dahan R, Reiter Y. Expert Rev Mol Med. 2012; 14: e6.Kochenderfer JN et al. J Immunother. 2009; 32(7): 689-702.
Structure of tisagenlecleucel CAR
scFv
Anti-CD19Transmembrane domain
Costimulationsignaling domain 41BB (CD137)
CD3ʓ signaling domain
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Treatment process
Leukapheresis Administration
Transport to manufacturer
Transduction
Final product
Lymphodepleting chemotherapy
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Tisagenlecleucel preparation• Preparation and transduction with lentiviral vector
• The vector is self-inactivating• Has not demonstrated signs of genotoxicity
Lentiviral transduction with anti-CD19 CAR
transgene
Li et al. Transl Med. 2010;8:104.Tisagenlecleucel (CTL019). FDA Advisory Committee Briefing Document. 2017
Cavazzana et al. Hum Gene Ther. 2016;27: 108-116.Hacein-Bey-Abina et al. JAMA. 2015; 313: 1550-1563.Heinrich et al. Mol Ther. 2013;21:1160-1168.
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Cellular Expansion• Utility of lymphodepletion
• Inhibits endogenous T cells that secrete regulatory cytokines
• Facilitates the expansion of transferred cells
Tisagenlecleucel
Porter D, et al. Sci Transl Med. 2015; 7(303):303ra139.Ramos et al. Cancer J. 2012;20(2): 112-118.
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Lymphodepleting chemotherapy• Infuse tisagenlecleucel 2 to 14 days after
completion of lymphodepleting therapy
• Fludarabine 30 mg/m2 IV daily for 4 days; AND• Cyclophosphamide 500 mg/m2 IV daily for 2 days
starting with the first dose of fludarabine
Porter D, et al. Sci Transl Med. 2015; 7(303):303ra139.Ramos et al. Cancer J. 2012;20(2): 112-118.
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Patient case• After JM’s first course of treatment he achieved
complete remission. It was determined that JM’s ALL had cytogenetic abnormalities that increased his risk of relapse, so after achieving remission he also underwent an allogeneic HSCT.
• After 12 months in remission JM returns to his 1 year follow-up appointment. Unfortunately it is determined that JM’s ALL has relapsed and he needs additional treatment.
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Patient case• JM is started on tisagenlecleucel. After his
infusion he develops a high fever, difficulty breathing, chills, severe nausea and hypotension. Which of the following is the most likely cause of this reaction?
1. Neurological toxicity2. Febrile neutropenia3. Cytokine release syndrome4. Hypofibrinoginemia
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CAR-T Toxicities
Challice L Bonifant, published online. 20 April 2016. doi:10.1038/mto.2016.11
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Tisagenlecleucel REMS• Enroll in the Risk Evaluation and Mitigation
Strategy (REMS) program• Created to mitigate the risk of cytokine release
syndrome (CRS) and neurotoxicity• Ensures that facilities and prescribers have
appropriate training and access to management medications
Risk Evaluation and Mitigation Strategy (REMS): Cytokine release syndrome and neurological toxicities. Novartis Pharmaceuticals Corporation. 2017.
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Treatment of CRS
CRS severity ManagementProdromal syndrome:
low-grade fever, fatigue, anorexia
Observe, exclude infection, administer antibiotics if neutropenic
Overt CRS (> 1 of the following)
- High fever- Hypoxia- Mild hypotension
Administer antipyretics, oxygen, IV fluids and/or vasopressors as needed
Kymriah® [package insert]. Novartis Pharmaceuticals Corporation. New Hanover, NJ; 2017.
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Treatment of CRSCRS severity ManagementSevere or Life-Threatening CRS (> 1 of the following):
- Refractory hemodynamic instability
- Worsening respiratory distress
- Rapid clinical deterioration
Administer vasopressors, oxygen, mechanical ventilation
Administer tocilizumab
Resistant CRS
No clinical improvement in 12 to 18 hours, or worsening despite management
Administer methylprednisolone
Repeat tocilizumab
Kymriah® [package insert]. Novartis Pharmaceuticals Corporation. New Hanover, NJ; 2017.
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Management of CRS in B2202
CRSmanagement
Total n = 53; [n(%)]
Systemic Anticytokine given 26 (49)
Tocilizumab• 1 dose• 2 doses• 3 doses
26 (49)16 (30)7 (13)
Siltuximab 5 (9)Corticosteroids 14 (26)Other 2 (4)
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting. BLA 125646: 2017.Lee et al. Blood. 2014; 124(2): 188-195.Sebba et al. Am J Health Syst Pharm. 2008; 65(15):1413-8.
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Cytokine release syndrome in the B2202 Trial• CRS occurred in 79% of patients
• Grade 3 or 4 CRS occurred in 49% (33/68) of patients
• Median time to onset was 3 days• Range 1 to 22 days
• Time to grade 3 or 4 onset• Within 6 days
• Median time to resolution was 8 days• Range 1 to 36 days
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting. BLA 125646: 2017.
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Cytokine release syndrome in the B2202 Trial (n=68)• No correlation between tisagenlecleucel dose and CRS
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting. BLA 125646: 2017.
Morbidity ConsequenceFever 49 (72%) of subjects had fevers lasting for a mean of 8 days
with a range of 1 to 36 daysRenalimpairment
Seven subjects (10%) required dialysis for a mean of 11 days
Respiratory 10 subjects (15%) required ventilatory support for a mean of 8.5 days (range 4 to 19 days)
ICU admission 31 subjects (46%) were admitted to an ICU with a mean LOS of 11 days (range 1 to 34 days)
Coagulopathy Hypofibrinoginemia grade 3: 14 subjects; grade 4: 18 subjects.One death due to intracranial hemorrhage
Tumor burden Trend toward a correlation between higher tumor burden and CRS
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B2202 CRS-Related Adverse Events
0%
10%
20%
30%
40%
50%
60%
70%
80%
Fever Renalimpairment
ICU admission Coagulopathy
Adverse Event Frequency
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting. BLA 125646: 2017.
72%
10%
46% 47%
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Neurotoxicity in the B2202 trial• Reported in 44% (n=30) subjects
• Neurotoxicity was generally related to CRS development• In 6 patients neurotoxicity occurred after CRS
resolution
• Supportive treatment• Maintain airway• Seizure prophylaxis• Corticosteroids
• Study had 1 death due to respiratory failure
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting. BLA 125646: 2017.
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Prolonged Cytopenias• Cytopenias can occur for several weeks following
lymphodepleting chemotherapy and tisagenlecleucelinfusion
• Myeloid growth factors are not recommended
• Prolonged cytopenias are associated with infection
• Grade 3 and 4 cytopenias:
Cytopenia (n=52) Day 28 Day 56Neutropenia 40% 17%
Thrombocytopenia 27% 12%
Kymriah® [package insert]. Novartis Pharmaceuticals Corporation. New Hanover, NJ; 2017.
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Serious Infections• Infection prophylaxis prior to tisagenlecleucel
administration should follow local guidelines
• Types of infections in B2202• Unknown source: 41%• Viral: 26%• Bacterial: 19%• Fungal: 13%
Infection Incidence (n=68)All grades 40 (59%)
Grade 3 or 4 24 (35%)Fatal 2 (3%)
Kymriah® [package insert]. Novartis Pharmaceuticals Corporation. New Hanover, NJ; 2017.
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Post-Infusion Deaths in B2202 trial• ALL: 7
• Infections: 2• Respiratory tract infection• Systemic mycosis• Encephalitis CSF positive for HHV6B
• Cerebral hemorrhage: 1
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting. BLA 125646: 2017.
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Tisagenlecleucel Efficacy
Results N=63CR/CRi N=52, (83%)
95% confidence interval (71% to 91%)P < 0.0001
CR N=40 (63%)CRi N=12 (19%)CR or CRi with MRD-negative bone marrow
52 (83%)95% confidence interval (71% to 91%)P < 0.0001
Duration of remission N=52 (not reached)
Kymriah® [package insert]. Novartis Pharmaceuticals Corporation. New Hanover, NJ; 2017.
CR: Complete responseCRi: Complete response with incomplete blood count recovery
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Balancing Risk and Benefit
Tisagenlecleucel benefit
Adverse effects
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Summary• Tisagenlecleucel is a novel CAR-T therapy that
uses a patient’s own T cells to treat ALL• The process of engineering, administering and
monitoring tisagenlecleucel is complex and requires a well-coordinated team
• Despite clinical efficacy, tisagenlecleucelexhibits multiple serious and life-threatening toxicities
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Questions & Discussion