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Cellular Therapies for Pediatric Acute Lymphoblastic Leukemia

Explore the evolving landscape of cellular therapies for pediatric acute lymphoblastic leukemia, covering presentation, treatment challenges, CART therapy outcomes, and hematopoietic cell transplantation benefits.

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Cellular Therapies for Pediatric Acute Lymphoblastic Leukemia

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  1. Cellular Therapies for Pediatric Acute Lymphoblastic Leukemia Larisa Broglie, MD MS Assistant Professor of Pediatric Blood and Marrow Transplantation Transplant and Cellular Therapy Meetings February 20, 2019

  2. Objectives • Review Acute Lymphoblastic Leukemia (ALL) – presentation, treatment, and outcomes • Discuss therapy for relapsed ALL and challenges in treatment • Discuss Chimeric Antigen Receptor T-cell therapy (CART) – outcomes and complications • Discuss the expanding landscape of cellular therapy for pediatric leukemias

  3. Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in children • Approximately 3,000 new cases per year • Clinical presentation: fever, fatigue, bruising/bleeding, bone pain • Categorized as precursor B-cell ALL (pre-B ALL), or T-cell ALL Pre B-ALL CD19 CD34 CD22 CD10 TdT CD13 Principles and Practice of Pediatric Oncology, Pizzo and Poplack 2015.

  4. Survival for Pediatric B-cell ALL has significant improved Hunger SP, Mullighan CG. N Engl J Med 2015

  5. Challenges remain for patients with relapsed or refractory disease • Almost all patients achieve remission after the first month of chemotherapy • Treatment continues for 3 years for boys and 2 years for girls • Approximately 15-20% of patients eventually relapse • Difficulty in complying with the prolonged, maintenance therapy • High risk features • Aggressive cytogenetic abnormalities

  6. Outcomes depend on location and timing of relapse • Location: • Bone Marrow • Central Nervous System (CNS) • Both • Timing: • Very Early = <18mo from diagnosis • Early = >18mo after diagnosis but <6mo from completion of chemotherapy • Late = >6mo after completing chemotherapy (>36mo from diagnosis) Isolated BM relapse Early Combined BM relapse Early Nguyen K et al. Leukemia. 2008

  7. Hematopoietic Cell Transplantation (HCT) improves outcomes for high risk, relapsed ALL • High risk patients: • very early BM or combined relapse • early BM relapse • Chemotherapy alone resulted in subsequent relapse or death in all patients • HCT improved outcomes with Event Free Survival (EFS) of almost 50% N=58, unrelated donor BMT N=53, chemotherapy Borgmann, A et al. Blood. 2003

  8. Outcomes improved if negative minimal residual disease (MRD) state can be achieved No relapses if MRD negative pre-HCT Survival improves if MRD negative pre-HCT Pulsipherer al. Blood. 2015

  9. Survival after HCT is dependent on remission status 1 CR1 CR2 or greater Induction Failure or Active Disease D'Souza A, Fretham C. CIBMTR Summary Slides, 2017

  10. ALL Summary • Most patients with pre-B ALL achieve sustained remission with chemotherapy • Approximately 15-20% relapse, requiring intensification of therapy and many benefit from stem cell transplantation • Greatest benefit from HCT is when patients have little disease remaining (MRD negative) • Challenges remain for some patients: • Refractory to upfront, standard therapies • Unable to achieve remission after relapse

  11. How do we manage patients with refractory disease?

  12. Immunotherapy – targeting the immune system against leukemia • Hematopoietic Cell Transplantation • Targeted Monoclonal Antibodies (Rituximab) • Bispecific T-cell Engagers (Blinatumomab, Inotuzumab) • Chimeric Antigen Receptor T-cell Therapy (CART) Brown, P. Blood. 2018

  13. What is CART? C • Chimeric • Antigen • Receptor • T-cell • T-cells elicit a cytotoxic response to foreign antigens • Leukemia persists because it evades detection by the immune system • CART harnesses the immune system to fight cancer • Autologous T-cells are manipulated to target leukemia • Primary target is CD19 – a marker on pre-B ALL cells A R T

  14. 30 years of progress to bring CART to the bedside 2013: 2 children with refractory ALL, achieve remission 1980-1990s: Altering T-cell receptor can lead to targeted cell killing 2000s: Second Generation CARTs – improved in vitro killing and persistence in mice 1990s: First Generation CARTs – slow tumor growth in mice 2012: Adult studies begin showing promise of CD19 CAR (Seattle, NCI, MSKCC, Penn) 2017: FDA Approves first CART product Grupp et al. New Eng J Med. 2013 Maude, S et al. New Eng J Med. 2014

  15. Creating autologous T-cells to target leukemia Infusion: Of CAR T-cells into patient Leukapheresis: Collect T-cells Growth: Of T-cells expressing the Chimeric Receptor Viral Transduction: Chimeric receptor transferred into T-cells Shubert et al, Human Gene Therapy. 2016; Frey, NV and Porter, DL. Am J Hematol. 2016

  16. The evolution of Chimeric T-cell Receptors Monoclonal Antibody Transmembrane Domain Co-stimulatory Domain CD3ζ Park JH and Brentjens RJ. Blood. 2015

  17. Are all CARTs created equal? • T-cell Targets • CD19 • Others (CD22, CD20, CD123, CD33, GD2) • Costimulatory Domains • 4-1BB • CD28 • Virus Transduction • Lentivirus • Retrovirus

  18. CAR T-cells induce targeted leukemia cell death T-cell Leukemia Chimeric T-cell Receptor CD 19 Apoptosis

  19. https://www.chop.edu/news/five-years-later-first-pediatric-recipient-car-t-cell-therapy-remains-cancer-freehttps://www.chop.edu/news/five-years-later-first-pediatric-recipient-car-t-cell-therapy-remains-cancer-free

  20. CART therapy leads to high rates of CR • N=30 children and adults with pre-B ALL • 80% of patients had detectable leukemia prior to infusion • 90% achieved complete remission • Only 7 of these patients later relapsed • 6 month EFS = 67%, OS = 78% 20 Maude, S et al. New Eng J Med. 2014

  21. Results were validated in an international study • International trial • N=75 received CART infusion • 81% of patients achieved remission • 59% relapse free survival at 12mo • 22 patients relapsed, 68% were CD19 negative at time of relapse Maude et al. NEJM. 2018

  22. Unique Complications of CART • Hypogammaglobulinemia (low IgG levels) • CD19 is a normal marker on B-cells • Can be a marker of CART persistence • Treatment with IV immunoglobulin • Cytokine Release Syndrome • Neurotoxicity (Immune Effector Cell-Associated Neurotoxicity Syndrome)

  23. Cytokine Release Syndrome • 10yo female receives CART infusion after she fails to respond to chemotherapy for her relapsed B-cell ALL • 3 days after CART infusion, she has a high fever to 40oC • She is started on antibiotics but her blood pressure becomes unstable. She is hypotensive with blood pressures of 70/30s • She is given IV fluid but requires escalating vasopressors • She now requires oxygen supplementation • Due to concern for Cytokine Release Syndrome, she is give a dose of Tocilizumab and she clinically improves

  24. CRS – potentially life threatening systemic inflammation • Due to a cytokine release, predominantly mediated by IL-6 • Approximately >75% of patients experience CRS • Severe, life threatening CRS occurs in 27-44% • Increased risk of severe CRS with: • higher CART cell doses • higher disease burden • concurrent infection • Treatment: • Supportive Care • Anti-IL6 therapy (Tocilizumab, Siltuximab) • Try to avoid steroids if possible as may impair CART cells Lee et al. ASBMT Consensus Guidelines. Biol Blood Marrow Transplant. 2018

  25. CRS Grading – ASBMT Consensus Guidelines Lee et al. ASBMT Consensus Guidelines. Biol Blood Marrow Transplant. 2018

  26. Immune Effector Cell-Associated Neurotoxicity • 13yo male received CART infusion 10 days ago for refractory B-cell ALL • He had CRS requiring a brief ICU stay but improved, and was preparing for discharge home • But, he began complaining of headaches • He worsened and was unable to answer questions or talk; he is less awake and less alert • He was monitored closely but had no seizure or evidence of cerebral edema • He gradual improved over the next weeks with supportive care and rehab

  27. Neurotoxicity can cause cerebral edema and death • Estimated to occur in 25-50% of patients • Headaches can be non-specific • Hallmark symptom is aphasia • Can progress to motor weakness, seizure, cerebral edema and death • The pathophysiology of neurotoxicity is not well understood. • Treatment remains supportive care Lee et al. ASBMT Consensus Guidelines. Biol Blood Marrow Transplant. 2018

  28. Neurotoxicity Grading – ASBMT Consensus Guidelines • Grading scales available for adults and children ≥12yo: • Level of consciousness • Motor findings • Seizure • Increased intracranial pressure • <12yo use Cornell Assessment of Pediatric Delirium: • Eye contact • Communication • Activity • Response to others Lee et al. ASBMT Consensus Guidelines. Biol Blood Marrow Transplant. 2018

  29. Relapse can occur after CART infusion • Relapse can still occur after CART • Relapse can be either: • CD19 positive • CD19 negative • CD19 positive relapse from poor persistence of CART • CD19 negative relapse from new mutations in the leukemia that is no longer recognized by CART

  30. FDA Approval of first 2 CART agents • Tisagenlecleucel • Aka Kymriah • Novartis • $475,000 • Approved for pediatric patients with of refractory or 2nd or later relapse of B-cell ALL • Axicabtagene • Aka Yescarta • Kite Pharma • $373,000 • Approved for adults with relapsed or refractory large B-cell lymphoma

  31. This is just the beginning Wells Fargo Securities Conference, November 2017

  32. More Than Just CARTs • Allogeneic CARTs • CARTs for solid tumors • Tumor specific T-cells • Natural Killer CARTs • And more…

  33. Thank you CIBMTR and the Cellular Therapy Forms Committee • Marcelo Pasquini • Bronwen Shaw • Janet Bruner-Grady • Tiffany Hunt • And more Patients and families Columbia University Pediatric Blood and Marrow Transplant • Prakash Satwani • Monica Bhatia • Diane George • Jim Garvin Data Managers and Research Support Staff

  34. Questions?

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