Leading the way in immunotherapy
Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia
Investigators from Children's Mercy: Gary D. Myers, MD and Keith J. August, MD, MS
Background: In August of 2017, tisagenlecleucel (Kymriah) was approved for the treatment of children and adolescents with B-cell acute lymphoblastic leukemia (ALL) who have relapsed or not responded to chemotherapy. This breakthrough immunotherapy has revolutionized the treatment of relapsed ALL. Kymriah is a novel cellular immunotherapy that reprograms a patient’s own immune system to identify and kill leukemia cells. Kymriah is manufactured by harvesting the patient’s own T-cells using leukapheresis and engineering these cells to attack a specific target on leukemia cells, CD19. Once manufactured, these T-cells are returned to the patient. Children’s Mercy Hospital was one of the first hospitals in the country to offer this treatment to patients and was an integral part of the two clinical trials that paved the way for the approval of Kymriah. CMH is now one of only a handful of children’s hospitals treating patients on a clinical trail for newly diagnosed patients with B-cell ALL with a slower than expected response to treatment.
Study outcomes: An international phase 2 study treated 75 patients with relapsed or refractory B-cell ALL with Kymriah. The overall remission rate was 81%, with 50% of patients remaining leukemia free 1 year after treatment. Very few patients in this trial were treated with bone marrow transplant which had previously been the standard of care.
Citation: Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Veneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Valduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine. 2018; 378(5):439-448.
Funding Source: Novartis Pharmaceuticals
IRB Number: 14070317
- Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Veneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Valduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine. 2018; 378(5):439-448.
- Laetsch TW, Myers GD, Baruchel A, Dietz AC, Pulsipher MA, Bittencourt H, Beuchner J, De Moerloose B, Davis KL, Nemecek E, Driscoll T, Mechinaud F, Boissel N, Rives S, Bader P, Peters C, Sabnis HS, Grupp SA, Yanik GA, Hiramatsu H, Stefanski HE, Rasouliyan L, Yi L, Shah S, Zhang J, Harris AC. Patient-Reported Quality of Life After Tisagenlecleucel Infusion in Children and Young Adults with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia: A Global, Single-Arm, Phase 2 Trial. Lancet Oncology. 2018; 20(12):1710-1718.
- Mueller KT, Waldron E, Grupp SA, Levine JE, Laetsch TW, Pulsipher MA, Boyer MW, August KJ, Hamilton J, Awasthi R, Stein AM, Sickert D, Chakraborty A, Levine BL, June CH, Tomassian L, Shah SS, Leung M, Taran T, Wood PA, Maude SL. Clinical Pharmacology of Tisagenlecleucel in B-Cell Acute Lymphoblastic Leukemia. Clinical Cancer Research. 2018; 24(24):6175-6184.
- Stein AM, Grupp SA, Levine JE, Laetsch TW, Pulsipher MA, Boyer MW, August KJ, Levine BL, Tomassian L, Shah S, Leung M, Huang PH, Awasthi R, Mueller KT, Wood PA, June CH. Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells. CPT: Pharmacometrics & Systems Pharmacology. 2019; 8(5):285-295.
Targeting leukemia stem cells
Overcoming Wnt-β-Catenin Dependent Anticancer Therapy Resistance in Leukaemia Stem Cells
Investigators from Children's Mercy: John M. Perry, PhD, Ryan R. Reynolds, MD, Erin M. Guest, MD, Keith J. August, MD, MS and Alan S. Gamis, MD, MPH
Background: Dr. John Perry has identified molecular pathways in leukemia stem cells that play an important role in the development of resistance to chemotherapy. Leukemia stem cells make up a small portion of all leukemia cells but are more resistant to cancer therapy. The ability to eliminate these stem cells during treatment would improve our ability to treat and cure children with leukemia. Work done in Dr. Perry’s lab at Children’s Mercy Hospital has identified a potential treatment that would specifically target leukemia stem cells and early phase clinical trials are evaluating the effectiveness of targeted therapy at Children’s Mercy and at the University of Kansas Cancer Center. This research is born out of a collaboration between CMH, KUCC and the laboratory of Dr. Linheng Li at the Stowers Institute in Kansas City.
Study outcomes: High-throughput drug screening identified doxorubicin as an inhibitor of the Akt-β-catenin interaction that is specific to leukemia stem cells. Targeted treatment with doxorubicin at low doses reduced Akt-activated β-catenin levels in chemoresistant leukemia stem cells. These findings suggest a potential strategy for overcoming cancer therapy resistance.
Funding Source: Midwest Cancer Alliance (now known as Masonic Cancer Alliance)
IRB Number: 13100340
- Perry JM, Tao F, Roy A, Lin T, He XC, Chen S, Lu X, Nemechek J, Ruan L, Yu X, Dukes D, Moran A, Pace J, Schroeder K, Zhao M, Venkatraman A, Qian P, Li Z, Hembree M, Paulson A, He Z, Xu D, Tran TH, Deshmukh P, Nguyen CT, Kasi RM, Ryan R, Broward M, Ding S, Guest E, August K, Gamis AS, Godwin A, Sittampalam GS, Weir SJ, Li L. Overcoming Wnt-β-Catenin Dependent Anticancer Therapy Resistance in Leukaemia Stem Cells. Nature Cell Biology. 2020; 22: 689-700.
Improving outcomes for children with AML
Gemtuzumab Ozogamicin in Children and Adolescents with de novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results from the Randomized Phase III Children’s Oncology Group Trial AAML0531
Investigators from Children's Mercy: Alan S. Gamis, MD, MPH
Background: Acute myeloid leukemia (AML) is the second most common type of leukemia diagnosed in children. Treatment for AML is aggressive and still fails to cure 40% of children. An international clinical trial for pediatric AML, AAML0531, directed by Dr. Alan Gamis, led to the FDA approval of a targeted therapy, gemtuzumab ozogamicin. Gemtuzumab ozogamicin is a conjugated monoclonal antibody that targets the CD33 protein, which is present on the surface of AML leukemia cells. Gemtuzumab ozogamicin attaches directly to AML cells and is ingested. Once inside the cell, the chemotherapy agent is then released leading to leukemia cell death. The administration of gemtuzumab ozogamicin to standard chemotherapy for AML led to improved outcomes in pediatric AML without an increase in toxicity. Gemtuzumab ozogamicin is now considered the standard of care for all children with AML.
Study outcomes: Over 1,000 children and adolescents with AML were randomized to receive standard chemotherapy with or without gemtuzumab ozogamicin (GO), an antibody drug conjugate, targeting CD33 on leukemia cells. Patients that received GO as part of their chemotherapy had a significantly improved 3-year EFS of 53.1% compared to 46.9% (p=0.04) a decreased relapse rate 32.8% compared to 41.3% (p=0.006). GO is now a standard part of chemotherapy for younger patients with AML.
Funding Source: NIH/Children’s Oncology Group
IRB Number: 06 08-134
- Gamis AS, Alonzo TA, Meschinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab Ozogamicin in Children and Adolescents with de novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results from the Randomized Phase III Children’s Oncology Group Trial AAML0531. J Clinical Oncology. 2014; 32(27): 3021-3032.
At the forefront of precision medicine
Single-Cell Multiomics Reveals Increased Plasticity, Resistant Populations and Stem-Cell-Like Blasts in KMT2A-Rearranged Leukemia
Investigators from Children's Mercy: Midhat Farooqi, MD, PhD and Erin M. Guest, MD
Background: Precision medicine is a rapidly developing field that is already having a major impact on the treatment of children with leukemia and lymphoma. Children’s Mercy Hospital provides access to one of the top centers for Genomic Medicine in the country. With Dr. Midhat Farooqi as Director of Molecular Oncology and Dr. Erin Guest as Director of the Cancer Genomics Program, all children diagnosed with leukemia and lymphoma have genetic testing done on their cancer cells. In some cases, this information can have a significant impact on diagnosis, prognosis and even guide treatment using targeted therapies. We expect cancer genomics to play a major role in improving leukemia and lymphoma outcomes for children and Children’s Mercy is poised to be a leading institution in this medical revolution. Dr. Farooqi and Dr. Guest are committed to focusing on rare, higher risk subsets of pediatric ALL such as infants, T-cell ALL, and Hispanic children with ALL.
Study outcomes: Single-Cell Multiomics Analyses were used to identify a stem cell-like population in the blood of very young patients that interacting in a suppressive fashion to impact other immune cells. These observations offer a compelling explanation for the ability of infant leukemia cells to evade chemotherapy and immune surveillance.
Funding Source: Department of Defense Health Program, Peer Reviewed Cancer Research Program, Translational Team Science Award
IRB Number: 00001243
- Chen C, Yu W, Alikarami F, Qiu Q, Chen CH, Flournoy J, Gao P, Uzun Y, Fang L, Davenport JW, Hu Y, Zhu Q, Wag K, Libbrecht C, Felmeister A, Rozich I, Ding YY, Hunger SP, Felix CA, Wu H, Brown PA, Guest EM, Barrett DM, Bernt KM, Tan K. Single-Cell Multiomics Reveals Increased Plasticity, Resistant Populations and Stem-Cell-Like Blasts in KMT2A-Rearranged Leukemia. Blood. 2021 Dec 5:blood.2021013442. doi: 10.1182/blood.2021013442. Online ahead of print.
- Burke MK, Kostadinov R, Sposto R, Gore L, Kelley SM, Rabik C, Trepel JB, Lee MJ, Yuno A, Lee S, Bhojwani D, Jeha S, Chang BH, Sulis ML, Hermiston ML, Gaynon P, Huynh V, Verma A, Gardner R, Heym KM, Dennis RM, Ziegler DS, Laetsch TW, Oesterheld JE, Dubois SG, Pollard JA, Glade-Bender J, Cooper TM, Kaplan JA, Farooqi MS, Yoo B, Guest E, Wayne AS, Brown PA. Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia; A TACL Pilot Study. Clin Cancer Res. 2020; 26(10): 2297-2307.
Circulating leukemia cells as a biomarker of response in ALL
Microfluidic Device for On-Chip Immunophenotyping and Cytogenetic Analysis of Rare Biological Cells
Investigators from Children's Mercy: Keith J. August, MD, MS
Background: One of the most important advances in pediatric leukemia in recent years has been the development of minimal residual disease (MRD) measurement in the bone marrow to identify patients that require more aggressive treatment to improve their chances of survival.
Children’s Mercy Hospital has an ongoing collaboration with Dr. Steven Soper and his lab in Lawrence, KS. Dr. Soper’s lab has expertise the design and development of microfluidic devices. These devices include tiny channels that filter blood and are used to detect rare circulating tumor cells in samples from patients with cancer. The collaboration with the Soper lab is evaluating the utility of using a specially designed microfluidic device to identify circulating leukemia cells in children with precursor B-cell acute lymphoblastic leukemia. By identifying rare cells in the blood, this project is striving to utilize this new technology to reduce the need for bone marrow testing and to help predict relapse before it is detected clinically.
Study Outcomes: A microfluidic device was developed to identify and characterize circulating leukemia cells in the peripheral blood of children with B-cell acute lymphoblastic leukemia. By identifying rare circulating leukemia cells, this novel technology may aid in the assessment of treatment response and minimal residual disease.
Funding Source: Masonic Cancer Alliance
IRB Number: 16060438
- Weerakoon-Ratnayake KM, Vaidyanathan S, Larkey N, Dathathreya K, Hu M, Jose J, Mog S, August K, Godwin AK, Hupert ML, Witek MA, Soper SA. Microfluidic Device for On-Chip Immunophenotyping and Cytogenetic Analysis of Rare Biological Cells. Cells. 2020, 9, 519; doi:10.3390/cells9020519.