Cellular Therapies for Pediatric Acute Lymphoblastic Leukemia Larisa
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
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 2
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 CD 34 CD 19 CD 22 CD 10 CD 13 Td. T Principles and Practice of Pediatric Oncology, Pizzo and Poplack 2015. 3
Survival for Pediatric B-cell ALL has significant improved Hunger SP, Mullighan CG. N Engl J Med 2015 4
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 5
Outcomes depend on location and timing of relapse • Location: • Bone Marrow • Central Nervous System (CNS) • Both Isolated BM relapse Early • Timing: • Very Early = <18 mo from diagnosis • Early = >18 mo after diagnosis but <6 mo from completion of chemotherapy • Late = >6 mo after completing chemotherapy (>36 mo from diagnosis) Combined BM relapse Early Nguyen K et al. Leukemia. 2008 6
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 7
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 Pulsipher er al. Blood. 2015 8
Survival after HCT is dependent on remission status 1 CR 2 or greater Induction Failure or Active Disease D'Souza A, Fretham C. CIBMTR Summary Slides, 2017 9
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 10
How do we manage patients with refractory disease? 11
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 12
What is CART? C A – Antigen R – Receptor T – T-cell – Chimeric • 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 CD 19 – a marker on pre-B ALL cells 13
30 years of progress to bring CART to the bedside 1980 -1990 s: Altering T-cell receptor can lead to targeted cell killing 1990 s: 2000 s: 2012: 2013: 2017: 2 children with Second Generation First Generation Adult studies begin refractory ALL, FDA Approves CARTs – improved CARTs – slow tumor showing promise of achieve remission first CART product in vitro killing and growth in mice CD 19 CAR (Seattle, persistence in mice NCI, MSKCC, Penn) Grupp et al. New Eng J Med. 2013 Maude, S et al. New Eng J Med. 2014 14
Creating autologous T-cells to target leukemia Infusion: Of CAR T-cells into patient Growth: Of T-cells expressing the Chimeric Receptor Leukapheresis: Collect T-cells Viral Transduction: Chimeric receptor transferred into T-cells Shubert et al, Human Gene Therapy. 2016; Frey, NV and Porter, DL. Am J Hematol. 2016 15
The evolution of Chimeric T-cell Receptors Monoclonal Antibody Transmembrane Domain Co-stimulatory Domain CD 3ζ Park JH and Brentjens RJ. Blood. 2015 16
Are all CARTs created equal? • T-cell Targets • CD 19 • Others (CD 22, CD 20, CD 123, CD 33, GD 2) • Costimulatory Domains • 4 -1 BB • CD 28 • Virus Transduction • Lentivirus • Retrovirus 17
CAR T-cells induce targeted leukemia cell death T-cell Chimeric T-cell Receptor Leukemia CD 19 Apoptosis 18
https: //www. chop. edu/news/five-years-later-first-pediatric-recipient-car-t-cell-therapyremains-cancer-free 19
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 20
Results were validated in an international study • International trial • N=75 received CART infusion • 81% of patients achieved remission • 59% relapse free survival at 12 mo • 22 patients relapsed, 68% were CD 19 negative at time of relapse Maude et al. NEJM. 2018 21
Unique Complications of CART • Hypogammaglobulinemia (low Ig. G levels) • CD 19 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) 22
Cytokine Release Syndrome • 10 yo 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 40 o. C • She is started on antibiotics but her blood pressure becomes unstable. She is hypotensive with blood pressures of 70/30 s • 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 23
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-IL 6 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 24
CRS Grading – ASBMT Consensus Guidelines Symptom Fever Grade 1 Grade 2 Grade 3 Grade 4 ≥ 38 o. C Requiring 1 vasopressor Requiring multiple vasopressors Requiring nonrebreather or high flow O 2 Requiring positive pressure ventilation With either: Hypotension None Not requiring vasopressors And/or: Hypoxia None Requiring nasal cannula for supplemental O 2 Lee et al. ASBMT Consensus Guidelines. Biol Blood Marrow Transplant. 2018 25
Immune Effector Cell-Associated Neurotoxicity • 13 yo 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 26
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 27
Neurotoxicity Grading – ASBMT Consensus Guidelines • Grading scales available for adults and children ≥ 12 yo: • • Level of consciousness Motor findings Seizure Increased intracranial pressure • <12 yo use Cornell Assessment of Pediatric Delirium: • • Eye contact Communication Activity Response to others Lee et al. ASBMT Consensus Guidelines. Biol Blood Marrow Transplant. 2018 28
Relapse can occur after CART infusion • Relapse can still occur after CART • Relapse can be either: • CD 19 positive • CD 19 negative • CD 19 positive relapse from poor persistence of CART • CD 19 negative relapse from new mutations in the leukemia that is no longer recognized by CART 29
FDA Approval of first 2 CART agents • Tisagenlecleucel • • Aka Kymriah Novartis $475, 000 Approved for pediatric patients with of refractory or 2 nd or later relapse of Bcell ALL • Axicabtagene • • Aka Yescarta Kite Pharma $373, 000 Approved for adults with relapsed or refractory large B-cell lymphoma 30
This is just the beginning Wells Fargo Securities Conference, November 2017 31
More Than Just CARTs • Allogeneic CARTs • CARTs for solid tumors • Tumor specific T-cells • Natural Killer CARTs • And more… 32
Thank you CIBMTR and the Cellular Therapy Forms Committee Columbia University Pediatric Blood and Marrow Transplant • Marcelo Pasquini • Prakash Satwani • Bronwen Shaw • Monica Bhatia • Janet Bruner-Grady • Diane George • Tiffany Hunt • Jim Garvin • And more Patients and families Data Managers and Research Support Staff 33
Questions? 34
- Slides: 34