CAR T-Cell Therapy for Acute Lymphoblastic Leukemia: Identifying Appropriate Patients and Maximizing Outcomes. Shannon L.

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2 CAR T-Cell Therapy for Acute Lymphoblastic Leukemia: Identifying Appropriate Patients and Maximizing Outcomes Shannon L. Maude, MD, PhD

3 CTL019 cell Lentiviral vector Anti-CD19 CAR construct CD19 Native TCR Dead tumor cell CAR T-Cell Therapy for Acute Lymphoblastic Leukemia: Identifying Appropriate Patients and Maximizing Outcomes Shannon Maude, MD, PhD Cancer Immunotherapy Program Children s Hospital of Philadelphia The University of Pennsylvania School of Medicine BioAscend ASH Satellite Symposium November 30, 2018

4 Disclosures Consultancy Novartis: advisory boards, clinical trial steering committee CTL019 (now known as Kymriah, tisagenlecleucel) licensed by Novartis CTL119 (investigational product) licensed by Novartis

5 Pediatric Acute Lymphoblastic Leukemia (ALL) Survival for newly diagnosed ALL Survival for 2 nd relapse Hunger SP et al. JCO 2012;30: Resimuller et al. JPHO 2013 Outcomes remain poor for pediatric ALL that is refractory or in second or greater relapse

6 ELIANA Phase 2 Trial of CTL019 Maude SL et al. N Engl J Med 2018;378:

7 Duration of Remission, Event-free and Overall Survival Primary Endpoint: 61/75 CR/CRi (81%) Maude SL et al. N Engl J Med 2018;378: RFS: 59% (95% CI, 41 to 73) at 12 mo 8 underwent HSCT

8 First US FDA Approval of a CAR T-Cell Therapy August 30, 2017 The FDA approved the first CAR T-cell therapy, tisagenlecleucel, for children and young adults up to age 25 with B-ALL that is refractory or in second or greater relapse August 2018 EMA approval September 2018 Health Canada approval

9 Patient Selection Population: Patients with B-ALL in 2 nd or greater relapse or refractory Time from referral to treatment weeks Need to stabilize and maintain functional status Screen patients who have received prior CD19-directed therapy (eg, blinatumomab) for CD19 expression

10 Leukapheresis Planning At relapse Considerations: WBC count, blast count After chemotherapy Considerations: timing, type of chemotherapy, ALC After SCT Considerations: timing, GVHD, immunosuppression

11 Timing of Leukapheresis Known eligible: Multiply relapsed/refractory Relapsed after allo SCT Refractory to multiple intensive therapies Potentially eligible: High-risk disease Primary induction failure Early BM relapse High-risk cytogenetics

12 Timing of Leukapheresis Known eligible: Multiply relapsed/refractory Potentially eligible: High-risk disease Reserve for patients likely to need and benefit Better collection Better T-cell growth Intensive therapy may limit collection and T-cell expansion Usually minimal May delay therapy May be difficult to stabilize patient May not be used

13 Patient Stabilization Time from referral to treatment weeks Goals: Prevent rapid progression Avoid organ toxicity and infectious complications NOT to induce remission or reduce disease burden Additional considerations: If awaiting leukapheresis, need to consider chemotherapy carefully

14 Identifying Patients to Maximize Outcomes Identifying high-risk patients T-cell collection for future use may allow for Better T-cell product More rapid treatment Incorporating CAR T cells earlier in the course Identifying patients as soon as they meet indication (before they receive multiple intensive therapies) may allow for Better T-cell product Better outcome Less severe toxicity

15 Maximizing Outcomes Expanding the role Moving into upfront therapy for VHR subsets at high risk of relapse Planning trials in other VHR populations - Down Syndrome B-ALL in first relapse - Hypodiploid B-ALL - B-ALL with t(17;19)

16 What s Next for Cell Therapy in Pediatric Cancers? Expanding the role of CTL019 - While outcomes for pediatric ALL have improved significantly, there remain subgroups with poor outcomes - We have reached the limit of chemotherapy intensification Borowitz MJ et al. Blood 2015;126:

17 Maximizing Outcomes Overcoming relapse CD19+ relapse Due to short persistence Humanized anti-cd19 CAR (CTL119): NCT Checkpoint blockade CD19- relapse Due to antigen escape Alternative targets: anti-cd22 CAR: NCT , NCT , NCT

18 Maximizing Outcomes Expanding the potential Increase durable remission rates by preventing relapse through Improved persistence Dual targeting: NCT , NCT Combinations and innovative CAR designs may be needed

19 ALL Case Review and Panel Discussion

20 ALL Case 21-year-old male with relapsed B-ALL Diagnosed with standard-risk B-ALL as a child Late isolated testicular relapse 4 years from diagnosis, 10 months off therapy testicular irradiation and chemotherapy Second relapse - isolated BM, 4 years off therapy Refractory to reinduction Refractory to blinatumomab Refractory to moxetumomab Complications including HUS Referred for CD19-directed CAR T cells

21 ALL Case 21-year-old male with 2 nd relapse of ALL ALL History 2 nd relapse Refractory to reinduction, blinatumomab, moxetumomab Timing Month -1 Month -1 Week -1 Day -1 Key notes T cells collected Received maintenance chemo and VP/AraC Peripheral blasts - Received lymphodepleting chemotherapy (fludarabine/cyclophosphamide) Disease evaluation showed >90% blasts in BM, no peripheral blasts

22 ALL Case 21-year-old male with 2 nd relapse of ALL Day

23 ARS: What is the recommended dose of tocilizumab for patients with CRS and are at or above 30 kg weight? 1. 4 mg/kg 2. 8 mg/kg mg/kg mg/kg

24 ARS: What is the recommended dose of tocilizumab for patients with CRS and are at or above 30 kg weight? 1. 4 mg/kg 2. 8 mg/kg mg/kg mg/kg *Max dose 800 mg **Pediatric dosing for under 30kg is 12 mg/kg

25 CRS Management Algorithm CTL019 Infusion Prodromal syndrome: low-grade fevers, fatigue, anorexia (hours to days) Management: Observation, rule out infection (surveillance cultures); antibiotics per local guidelines (febrile neutropenia); symptomatic support Prodromal syndrome: low-grade fevers, fatigue, anorexia (hours to days) Management: Observation, rule out infection (surveillance cultures); antibiotics per local guidelines (febrile neutropenia); symptomatic support Symptom progression: High fevers, hypoxia, mild hypotension First-Line Management: Oxygen, fluids, low-dose vasopressor support, antipyretics; monitor/manage complications of TLS First manifestation of CRS: Flu-like symptoms starting within Further symptom progression Hemodynamic instability despite IV fluids and moderate- to high-dose a vasopressor support OR Worsening respiratory distress, including pulmonary infiltrates increasing oxygen requirement including high-flow oxygen and/or need for mechanical ventilation OR 24 hours to 7-14 days Rapid clinical deterioration Second-Line Management Tocilizumab: IV infusion over 1 hour (patient weight < 30 kg: 12 mg/kg IV; patient weight 30 kg: 8 mg/kg IV [maximum dose 800 mg]) Hemodynamic and respiratory support Treat symptomatically a See definition of high-dose vasopressors.

26 CRS Management Algorithm CTL019 Infusion Prodromal syndrome: low-grade fevers, fatigue, anorexia (hours to days) Management: Observation, rule out infection (surveillance cultures); antibiotics per local guidelines (febrile neutropenia); symptomatic support Symptom progression: High fevers, hypoxia, mild hypotension First-Line Management: Oxygen, fluids, low-dose vasopressor support, antipyretics; monitor/manage complications of TLS Symptom progression: High fevers, hypoxia, mild hypotension First-Line Management: Oxygen, fluids, low-dose vasopressor support, antipyretics; monitor/manage complications of TLS Further symptom progression Hemodynamic instability Progression despite IV fluids and of moderate- CRS: to high-dose a vasopressor support OR Worsening respiratory distress, including pulmonary infiltrates increasing oxygen requirement including high-flow oxygen and/or need Vascular for mechanical leak ventilation starting OR 2-5 days after Rapid clinical deterioration Second-Line Management fever onset leading to hypotension Tocilizumab: IV infusion over and 1 hour fluid (patient overload weight < 30 kg: 12 mg/kg IV; patient weight 30 kg: 8 mg/kg IV [maximum dose 800 mg]) Hemodynamic and respiratory support a See definition of high-dose vasopressors. Fluids (limited), oxygen Unstable hypotension, not immediately responsive to fluids: Start low-dose pressors, consider toci

27 CRS Management Algorithm CTL019 Infusion Further Prodromal symptom syndrome: progression low-grade fevers, fatigue, anorexia (hours to days) Management: Observation, rule out infection (surveillance cultures); antibiotics per local guidelines (febrile neutropenia); Hemodynamic instability despite IV fluids and moderate- to high-dose a symptomatic support vasopressor support OR Worsening Symptom progression: respiratory distress, including pulmonary infiltrates increasing High fevers, hypoxia, mild hypotension oxygen requirement including high-flow oxygen and/or need for mechanical First-Line Management: Oxygen, fluids, low-dose vasopressor support, antipyretics; monitor/manage complications of TLS ventilation OR Rapid clinical deterioration Second-Line Management Tocilizumab: IV infusion over 1 hour (patient weight < 30 kg: 12 mg/kg IV; patient weight 30 kg: 8 mg/kg IV [maximum dose 800 mg]) Hemodynamic and respiratory support Further symptom progression Hemodynamic instability despite IV fluids and moderate- to high-dose a vasopressor support OR Worsening respiratory distress, including pulmonary infiltrates increasing oxygen requirement including high-flow oxygen and/or need for mechanical ventilation OR Rapid clinical deterioration Second-Line Management Tocilizumab: IV infusion over 1 hour (patient weight < 30 kg: 12 mg/kg IV; patient weight 30 kg: 8 mg/kg IV [maximum dose 800 mg]) Hemodynamic and respiratory support a See definition of high-dose vasopressors. Further progression despite supportive care: Escalation of pressor or respiratory support Tocilizumab

28 ALL Case 21-year-old male with relapsed B-ALL Experienced grade 4 CRS Entered MRD-negative remission Remained in remission for 2 years with few long-term complications, on few medications, with good quality of life Relapsed with CD19-negative disease

29 Maximizing Outcomes As CAR T cells become more readily available Can earlier incorporation when patient meets indication Decrease toxicity severity? Improve chance of durable remission?

30 Penn CCI Carl June Anne Chew Regina Young CVPF Bruce Levine Don Siegel Andrew Fesnak Penn Statistics Pamela Shaw Ann Tierney TCSL Simon Lacey Jeff Finklestein Farzana Nazimuddin Vanessa Gonzalez CHOP Cancer Immunotherapy Program Stephan Grupp Shannon Maude Amanda DiNofia Lisa Wray Sue Rheingold Colleen Callahan Diane Baniewicz Amy Barry Penn Clinical David Porter Noelle Frey Grupp Lab David Barrett David Teachey Alix Seif CHOP Nursing CTO/IND Office CHOP Stem Cell Lab Yongping Wang CHOP Vector Core Frasier Wright Adaptive TcR Patients and Families Novartis David Lebwohl Tetiana Taran Patricia Wood Jennifer Brogdon