Pediatric Grand Rounds (RECORDING) Predicting Patient Outcomes from Single Cells in Childhood Cancer

This presentation is a recording of a Stanford Pediatric Grand Rounds Session.  World-renowned experts will present the latest research, practice guidelines, and treatment protocols to advance best practices in the care of pediatric patients. These online recordings will provide pediatricians and family physicians with up-to-date clinical information on a wide range of clinical issues encountered in daily pediatric practice. 

Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood and one of the deadliest despite impressive improvements in survival. The Davis lab uses single-cell, high-dimensional analysis to identify the most important cells, those that are resistant to standard and cutting-edge therapies, leading to relapse. By identifying and understanding these treatment resistant cells can we work to prevent relapse and cure more children and young adults with ALL.

  Release Date: June 15, 2022
  Expiration Date: June 15, 2023
  Estimated Time to Complete: 1.0 hour
  Registration Fee: FREE
 *Originally recorded 03/25/2022.

1. Recognize current clinical outcomes and challenges in childhood acute lymphoblastic leukemia.
2. Recognize developmental structure of B cell ALL.
3. Describe impact of single-cell approaches to identify clinically relevant cell populations in ALL.

In support of improving patient care, Stanford Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. 

Credit Designation 
American Medical Association (AMA) 
Stanford Medicine designates this Enduring Material for a maximum of 1.00 AMA PRA Category 1 Credits^TM.  Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Accessibility Statement
 Stanford University School of Medicine is committed to ensuring that its programs, services, goods and facilities are accessible to individuals with disabilities as specified under Section 504 of the Rehabilitation Act of 1973 and the Americans with Disabilities Amendments Act of 2008.  If you have needs that require accommodations, please contact the CME Conference Coordinator.

Cultural and Linguistic Competency
The planners and speakers of this CME activity have been encouraged to address cultural issues relevant to their topic area for the purpose of complying with California Assembly Bill 1195. Moreover, the Stanford University School of Medicine Multicultural Health Portal contains many useful cultural and linguistic competency tools including culture guides, language access information and pertinent state and federal laws.  You are encouraged to visit the Multicultural Health Portal: https://laneguides.stanford.edu/multicultural-health

References/Bibliography

Asnani, M., Hayer, K. E., Naqvi, A., et al. (2020). Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia 34, 1202–1207. https://doi.org/10.1038/s41375-019-0580-z

Bagashev, A., Sotillo, E., Tang, C. H., Black, K. L., Perazzelli, J., Seeholzer, S. H., Argon, Y.,

Barrett, D. M., Grupp, S. A., Hu, C. C., & Thomas-Tikhonenko, A. (2018). CD19 Alterations Emerging after CD19-Directed Immunotherapy Cause Retention of the Misfolded Protein in the Endoplasmic Reticulum. Molecular and cellular biology, 38(21), e00383-18. https://doi.org/10.1128/MCB.00383-18

Bendall, S. C., Davis, K. L., Amir, E., et al. (2014). Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Cell, 157(3), 714–725. https://doi.org/10.1016/j.cell.2014.04.005

Cain, D. W., & Cidlowski, J. A. (2017). Immune regulation by glucocorticoids. Nature reviews. Immunology, 17(4), 233–247. https://doi.org/10.1038/nri.2017.1

Chan, L., Chen, Z., Braas, D. et al. (2017). Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542, 479–483. https://doi.org/10.1038/nature21076

Churchman, M. L., Qian, M., Te Kronnie, G., Zhang, R., Yang, W., Zhang, H., Lana, T., Tedrick, P., Baskin, R., Verbist, K., Peters, J. L., Devidas, M., Larsen, E., Moore, I. M., Gu, Z., Qu, C., Yoshihara, H., Porter, S. N., Pruett-Miller, S. M., Wu, G., … Mullighan, C. G. (2018). Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell, 33(5), 937–948.e8. https://doi.org/10.1016/j.ccell.2018.03.021

Geng, H., et al. (2015). Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia. Cancer cell, 27(3), 409–425. https://doi.org/10.1016/j.ccell.2015.02.003

Gittins, R. (1933). Studies in the Anaemias of Infancy and Early Childhood: Part VIII Leukaemia (leucosis) in Children. Archives of Diseases of Childhood. https://adc.bmj.com/content/archdischild/8/47/291.full.pdf

Good, Z., Sarno, J., Jager, A., Samusik, N., Aghaeepour, N., Simonds, E. F., White, L., Lacayo, N. J., Fantl, W. J., Fazio, G., Gaipa, G., Biondi, A., Tibshirani, R., Bendall, S. C., Nolan, G. P., & Davis, K. L. (2018). Single-cell developmental classification of B cell precursor acute lymphoblastic leukemia at diagnosis reveals predictors of relapse. Nature medicine, 24(4), 474 483. https://doi.org/10.1038/nm.4505

Greaves, M. F. (1986). Differentiation-linked leukemogenesis in lymphocytes. Science (New York, N.Y.), 234(4777), 697–704. https://doi.org/10.1126/science.3535067

Hunger, S. P. & Mullighan, C. G. (2015). Acute Lymphoblastic Leukemia in Children. The New England Journal of Medicine 2015;373:1541-1552. https://doi.org/10.1056/NEJMra1400972

Inaba, H., & Mullighan, C. G. (2021). Pediatric acute lymphoblastic leukemia. Haematologica 2020;105(11):2524-2539. https://doi.org/10.3324/haematol.2020.247031

Jacoby, E., Nguyen, S., Fountaine, T., et al. (2016). CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nature Communications, vol. 7, 12320. https://doi.org/10.1038/ncomms12320

Liu, Y., Davis, K., et al. (2021). Inhibition of Pre-BCR Signaling Mediates a Metabolic Switch in B-Cell Progenitor Acute Lymphoblastic Leukemia. American Society of Hematology, vol. 138 (1:615). https://doi.org/10.1182/blood-2021-145956

Maude, S. et al. (2018). Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. The New England Journal of Medicine 2018;378:439-48. https://doi.org/10.1056/NEJMoa1709866

Mullighan, C. G., Miller, C. B., Radtke, I., Phillips, L. A., Dalton, J., Ma, J., White, D., Hughes, T. P., Le Beau, M. M., Pui, C. H., Relling, M. V., Shurtleff, S. A., & Downing, J. R. (2008). BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature, 453(7191), 110–114. https://doi.org/10.1038/nature06866

Mullighan, C. G., Su, X., Zhang, J., Radtke, I., Phillips, L. A., Miller, C. B., Ma, J., Liu, W., Cheng, C., Schulman, B. A., Harvey, R. C., Chen, I. M., Clifford, R. J., Carroll, W. L., Reaman, G., Bowman, W. P., Devidas, M., Gerhard, D. S., Yang, W., Relling, M. V., … Children's Oncology Group (2009). Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. The New England Journal of Medicine, 360(5), 470–480. https://doi.org/10.1056/NEJMoa0808253

Nguyen, K., Devidas, M., Cheng, S. C., La, M., Raetz, E. A., Carroll, W. L., Winick, N. J., Hunger, S. P., Gaynon, P. S., Loh, M. L., & Children's Oncology Group. (2008). Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia, 22(12), 2142–2150. https://doi.org/10.1038/leu.2008.251

Sotillo, E., Barrett, D. M., Black, K. L., Bagashev, A., Oldridge, D., Wu, G., Sussman, R., Lanauze, C., Ruella, M., Gazzara, M. R., Martinez, N. M., Harrington, C. T., Chung, E. Y., Perazzelli, J., Hofmann, T. J., Maude, S. L., Raman, P., Barrera, A., Gill, S., Lacey, S. F., … Thomas-Tikhonenko, A. (2015). Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer discovery, 5(12), 1282–1295. https://doi.org/10.1158/2159-8290.CD-15-1020

Sun, W. et al. (2018). Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study. Leukemia,
32(11), 2316–2325. https://doi.org/10.1038/s41375-018-0094-0

Tsuchida, M., Ikuta, K., Hanada, R., Saito, T., Isoyama, K., Sugita, K., Toyoda, Y., Manabe, A., Koike, K., Kinoshita, A., Maeda, M., Ishimoto, K., Sato, T., Okimoto, Y., Kaneko, T., Kajiwara, M., Sotomatsu, M., Hayashi, Y., Yabe, H., Hosoya, R., Nakazawa, S. (2000). Long-term follow-up of childhood acute lymphoblastic leukemia in Tokyo Children's Cancer Study Group 1981-1995. Leukemia, 14(12), 2295–2306. https://doi.org/10.1038/sj.leu.2401937

Van Zelm, M. et al. (2010). CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. The Journal of Clinical Investigation. https://doi.org/10.1172/JCI39748

For CME general questions, please contact 
     Email: [email protected]

Mitigation of Relevant Financial Relationships

Stanford Medicine adheres to the Standards for Integrity and Independence in Accredited Continuing Education. 

There are no relevant financial relationships with ACCME-defined ineligible companies for anyone who was in control of the content of this activity, except those listed in the table below. All of the relevant financial relationships listed for these individuals have been mitigated.

Faculty Member Information

Role in activity

Name of Ineligible Company(s) / Nature of Relationship(s)

Alan Ross Schroeder, MD
Clinical Professor
Stanford University

Co-Course Director and Reviewer

Nothing to disclose

Kara Lynn Davis, DO
Assistant Professor
Stanford University

Faculty

Grant or research support-Jazz Pharmaceuticals (Relationship has ended)|Membership on Advisory Committees or Review Panels, Board Membership, etc.-Novartis AG (Relationship has ended)

Debra Babcock, MD
Stanford Childrens (PCHA)

Planner

Nothing to disclose

Caitlin Billingham, MD, MPH
Chief Resident
Stanford Pediatrics

Planner

Nothing to disclose

Lisa Jo Chamberlain, MD
Associate Professor of Pediatrics – General Pediatrics
Stanford Children's Health

Planner

Nothing to disclose

Olja Marsenic Couloures, MD
LPCH

Planner

Nothing to disclose

Lane Francis Donnelly, MD
Chief Quality Officer, Packard Childrens Hospital at Stanford
Stanford University

Planner

Nothing to disclose

Baraka Dechelle Floyd, MD, MSc
Clinical Assistant Professor and Associate Chair for Diversity, Equity, and Inclusion
Stanford University School of Medicine

Planner

Nothing to disclose

Ingrid Garnica, BA
Stanford Pediatrics

Planner

Nothing to disclose

Charles Gawad, MD, PhD
Associate Professor
Stanford

Planner

Ownership-BioSkryb Genomics

Allison Guerin, EdD
Stanford

Planner

Nothing to disclose

Mary Beth Leonard, MD, MSCE
Professor and Chair, Department of Pediatrics
Stanford Medicine

Planner

Nothing to disclose

Stephen J Roth, MD, MPH
Attending, Cardiovascular ICU
Lucile Packard Children's Hospital Stanford

Planner

Nothing to disclose

Sarina Tom, BA
Education Operations Manager
Stanford Pediatrics

Planner

Nothing to disclose

Ke-You Zhang, MD
Stanford University

Planner

Nothing to disclose