Pl I enary Tr T anslational Medicine April 30, 2015
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1 Plenary I Translational Medicine April 30, 2015
2 HBO in Hematopoietic Stem Cell Transplantation: Lessons Learned Omar Aljitawi, MD Hematology/Oncology Hematology and Transplantation (HAT) Laboratory Pathology and Laboratory Medicine University ofkansas Medical Center Bioengineering, University of Kansas
3 The problem we are trying to fix Clinical HSC transplantation HSC infusion Conditioning Neutropenia Engraftment Biologically Prolonged/ delayed in UCB Impaired in UCB HSC BM homing (Abbreviation: UCB: Umbilical cord blood transplantation; HSC: Hematopoietic stem cells; BM: Bone marrow.)
4 Hematopoietic stem cell (HSC) homing to bone marrow Homing is transient; hours to less than 72 hours
5 HSC homing and erythropoietin (EPO) SCF FLT 3 ligand EPO Circulating HSCs after birth Bone marrow homing markers (3 hours): Increased L selectin Decreased CXCR4 Gonzalez S, Amat L, Azqueta C, et al. Factors modulating circulation of hematopoietic progenitor cells in cord blood and neonates. Cytotherapy 2009;11: (Modified)
6 Hypothesis: EPO might play a role in HSC homing Epo Homing UCB stem cells Mobilization Epo Question: How do we lower blood EPO level?
7 Hyperbaric oxygen (HBO) Involves inhalation of 100% oxygen intermittently under a pressure greater than 1 atmospheric pressure (ATM) Results in: a. Mechanical effects related to increased pressure. b. Physiologic effects related to hyperoxia. HBO lowers EPO in healthy volunteers Balestra C et al. J Appl Physiol 2006;100:
8 HBO effects on EPO and UCB CD34+ cell homing/engraftment tin a transplant tmurine model dl Bone marrow engraftment EPO EPO + cells man CD34+ % Hum Bone marrow homing 3 hours HBO reduces blood EPO levels at time of HSC infusion HBO improves early bone marrow homing of HSC HBO improves HSC bone marrow engraftment Aljitawi et al, Unpublished data Aljitawi et al, BCMD (2013)
9 From bench to bedside
10 Clinical Study Schema UCB or PBSC infusion Hyperbaric oxygen (2.5 atmosphere absolutes and 100% oxygen for 2 hours) is given 6 hours prior to stem cell infusion.
11 Correlative studies: EPO Myeloablative Reduced intensity Median EPO serum level i in mu/ml Median EPO serum leve el in mu/ml Hours from HBO therapy *Lowest EPO level 8 hours from the start of HBO *EPO rebound noticed 24 hours later Hours from HBO therapy Aljitawi et al, ASH 2014
12 Blood Count Recovery and Engraftment HBO (n=8) Historic (n=31) Median time to neutrophil recovery (Days) 15 (6-25) 18 (5-41) Median time to platelet recovery (Days) 33 (30-84) 38(0-161) Aljitawi et al, ASH 2014 Aljitawi et al, ASH 2014
13 Would this concept apply to other types of hematopoietic stem cell transplantation? Autologous peripheral blood stem cell transplantation
14 Goals To determine the safety of HBO in autologous stem celltransplantation transplantation. To determine HBO efficacy in reducing timeto to neutrophil and platelet recovery.
15 Tolerability 20 patients treated to date. Only one patient was unable to complete the planned therapy. No treatment limiting toxicity was observed.
16 Comparison to historic data: Neutrophil hlrecovery N=12 Da ays until ne eutrophil re ecovery HBO and HC matched groups HBO Historic control *Neutrophil recovery was shorter in HBO by an average of 0.3 days. Aljitawi et al, ASBMT 2015
17 Comparison to historic data: Platelet Recovery N=12 covery Days until platelet rec HBO and HC matched groups HBO Historic control *Platelet recovery shorter in the HBO by an average of 3 days. Aljitawi et al, ASBMT 2015
18 Summary HBO in HSC transplantation: 1. Well tolerated. 2. Might ihimprove time to neutrophil and platelet count recovery. Phase II studies are planned to further investigate HBO effects on HSC engraftment.
19 Lessons learned EPO reduction is followed by EPO rebound. Future laboratory studies will focus on: a. Timing i of HBO b. Frequency of HBO Can we lower EPO throughout the period of HSC homing? Would this lead to further improvement in engraftment?
20 Concluding Remarks New concept: EPO targeting in HSC transplantation. We just scratched the tip of the iceberg! Novel approach to improving HSC engraftment: HBO modulates the host microenvironment Biology Timing Stay tuned! Correlatives
21 Thanks Mentorship/Support/Collaboration: /C i Technical Help: Preclinical: Hal Broxmeyer, PhD Linheng Li, PhD Buddhadeb Dawn, MD Jeff Radel, PhD Bruce Kimler, PhD George Vielhauer, PhD Tara Lin, MD Soumen Paul, PhD Thomas Yankee, PhD Mary Markiewicz, PhD Clinical: Joseph McGuirk, DO Tara Lin, MD Sunil Abhyankar, MD Sid Ganguly, MD Dennis Allin, PhD Chris Lominska, MD Anurag Singh, MD Leyla Shune, MD Mary aylaughlin, MD Peter Van Veldhuizen, MD - Patients Funding support: Nikhil Parelkar Megan Swink Yinghua Xiao HAT Lab: Tara Lin, MD Amanda Wise (Lab manager) Dandan Li, Pathology PhD student Cancer Center Clinical Trial Research Office Robert K. Dempski Cord Blood Research Fund Office of Scholarly, Academic and Research Mentoring (OSARM) - Frontiers Pilot and Collaborative Studies Funding Program - Robert K. Dempski Cord Blood Research Fund - SWOG/Hope Foundation
22 Plenary I Translational Medicine April 30, 2015
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MP 7.01.38 Placental/Umbilical Cord Blood as a Source of Stem Cells Medical Policy Section Surgery Issue 12:2013 Original Policy Date 12:2013 Last Review Status/Date Reviewed with literature search/12:2013
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SAVE A LIFE... BY GIVING LIFE! FOLLOW US ON: HÉMA-QUÉBEC PUBLIC CORD BLOOD BANK www.hema-quebec.qc.ca Scan this code with your smart phone to access the page Register to the Public Cord Blood Bank on the
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