Introduction 6/7/2013. Umbilical Cord Blood Transplantation: Research and Clinical Applications

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1 Umbilical Cord Blood Transplantation: Research and Clinical Applications Omar Aljitawi, MD Hematology/Oncology Pathology and Laboratory Medicine University of Kansas Medical Center April 27, 13 Introduction 2 1

2 Probability of Having a Bone Marrow Donor No Donor The only option is an HSCT from a Matched sibling 3% Matched Unrelated Donor Unrelated Cord Blood Unit Mismatched family donor Haploidentical family donor 3 First Successful Cord Blood Transplant (1988) Umbilical cord blood extraction Since the 1 st successful UCB has been used as a graft source for > 25, patients with both malignant & non malignant diseases (Cutler et al, 12). Matthew Farrow (recipient) 4 2

3 Indications 5 How does UCBT fair in comparison to MUD or MMUD transplants? 6 3

4 Reduced Intensity Conditioning Transplantation in Acute Leukemia: The Effect of the Source Unrelated Donor Stem Cells on Outcomes Claudio Brunstein, Mary Eapen, Kwang Ahn, Frederick R. Appelbaum, Karen Ballen, Richard Champlin, Fangyu Kan, Mary J. Laughlin, Robert J. Soiffer, Daniel J. Weisdorf, Ann Woolfrey, Mary M. Horowitz and John E. Wagner on behalf of the Center for International Blood and Marrow Transplant Research 7 Patient Characteristics Variables MUD MMUD CB, TCF CB, other Number of patients P-value Age at transplant, years median (range) 59 (23-69) 58 (21-69) 55 (23-68) 48 (21-67) <.1 CMV Seropositive 174 (56) 67 () 82 (68) 31 (78).21 Performance score pretransplant < 9% 123 (39) 44 () 33 (27) 17 (43).36 Year of transplant (31) 29 (26) 25 (21) 3 ( 8) (69) 82 (74) 96 (79) 37 (93) Median (range) follow-up of survivors, months 35 (6-96) 25 (6-75) 25 (5-97) 25 (6-61) 8 4

5 Disease Characteristics Variables MUD MMUD CB, TCF CB, other Number of patients P-value Acute myeloid leukemia 294 (94) (9) 99 (82) 3 (75) <.1 Acute lymphoblastic leukemia 19 ( 6) 11 (1) 22 (18) 1 (25) CR1 165 (53) 53 (48) 74 (61) 1 (25) <.1 CR2 65 (21) 19 (17) 33 (27) 17 (43) CR3+ 9 ( 3) 6 ( 5) 7 ( 6) 2 ( 5) PIF, relapse 74 (24) 33 (3) 7 ( 6) 11 (28) 9 Leukemia-Free Survival 9 dcb other vs. dcb TCF ± ATG 1.3 ( ).216 MUD vs. dcb TCF ± ATG.89 ( ).368 MMUD vs. dcb TCF ± ATG 1.14 ( ).432 P=.17 9 Probability, % MUD vs. dcb other.68 (.47.99).46 MMUD vs. dcb other.88 ( ).518 CB, TCF: 26% 8/8 PBPC: 31% /8 PBPC: 25% 1 1 CB, other regimen: 9% Months 1 5

6 Conclusion These data support dcb after TCF for adults with acute leukemia where a transplant is indicated but a suitably HLA MUD donor is not available or when transplant is needed urgently. Are there any other competitors in the field? 12 6

7 Haploidentical transplant versus double umbilical cord blood transplantation

8 Hematopoietic Recovery 11 by American Society of Hematology Brunstein C G et al. Blood 11;118: GVHD 11 by American Society of Hematology Brunstein C G et al. Blood 11;118:

9 Long-Term Outcomes 11 by American Society of Hematology Brunstein C G et al. Blood 11;118: Haploidentical transplant versus double umbilical cord blood transplantation The answer: CTN#111 clinical trial 18 9

10 Why I think UCBT is the eventual winner in this competition? 19 Advantages and limitations of umbilical cord blood transplantation UCB transplant can make MUD transplants history 1

11 UCB Stem Cell Biological Advantages 21 What has been done to improve UCBT outcomes? 22 11

12 Current efforts to overcome UCB limitations Increase UCB stem cell dose: A. Improve the harvest yield upon collecting cord blood units B. Infuse two cord units simultaneously double cord blood transplantation C. Expand the cord blood stem cells Ex Vivo, e.g: Notch mediated expansion (FHCRC), mesenchymal cell based expansion (MDACC) D. Prostaglandin E2 (PGE2) (Boston University) Unit selection Improve UCB stem cell homing: A. Direct intra bone cord blood infusion ( European experience) B. CD26 inhibitor (Indiana University) C. Prostaglandin E2 (PGE2) ( Boston University ) D. Surface fucosylation of cord blood stem cells E. Use of hyperbaric oxygen (KU s approach) Novel preparative regimens, e.g: reduced intensity 23 One versus Two UCBT 24 12

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14 UCBT/year in adults by type of graft* (n=3396)

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18 Current efforts to overcome UCB limitations Increase UCB stem cell dose: A. Improve the harvest yield upon collecting cord blood units B. Infuse two cord units simultaneously double cord blood transplantation C. Expand the cord blood stem cells Ex Vivo, e.g: Notch mediated expansion (FHCRC), mesenchymal cell based expansion (MDACC) D. Prostaglandin E2 (PGE2) (Boston University) Unit selection Improve UCB stem cell homing: A. Direct intra bone cord blood infusion ( European experience) B. CD26 inhibitor (Indiana University) C. Prostaglandin E2 (PGE2) ( Boston University ) D. Surface fucosylation of cord blood stem cells E. Use of hyperbaric oxygen (KU s approach) Novel preparative regimens, e.g: reduced intensity 35 Unit Selection for UCBT 36 18

19 Similar Survival in Patients with Acute Myeloid Leukemia Relapsing after Matched Related Donor and Umbilical Cord Blood Transplantation Parastoo Dahi, MD, Department of Medicine, Adult Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Doris Ponce, MD, Department of Medicine, Adult Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Katherine Evans, BA, Department of Medicine, Adult Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Marissa Lubin, BA, Department of Medicine, Adult Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Anne Marie Gonzales, BS, Department of Medicine, Adult Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Courtney Byam, BS, Department of Pediatrics, Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Rosanna Ferrante, BA, Department of Pediatrics, Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Melissa Sideroff, BA, Department of Pediatrics, Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Deborah Wells, MA, Department of Pediatrics, Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Sergio A. Giralt, MD, Department of Medicine, Adult Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Nancy Kernan, MD, Department of Pediatrics, Pediatric Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Andromachi Scaradavou, Department of Pediatrics, Pediatric Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY Juliet N. Barker, MBBS, (Hons), FRACP, Department of Medicine, Adult Bone Marrow Transplant, Memorial Sloan-Kettering Cancer Center, NY 37 Take home message: higher resolution HLA-match is frequently possible without significant compromise in graft dose 38 19

20 Does UCB unit selection matter that much? 39 Superior Survival after Umbilical Cord Blood Transplantation (UCBT) in Children with Hematological Malignancies Treated on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 51 Relative to the COBLT Study Kurtzberg J Carter SL, Mendizabal AM, Wall D, Schultz KR, Kernan NA, Eapen M and Wagner JE

21 Background Cell dose has been identified as an important factor influencing: incidence and rate of hematopoietic recovery risk of transplant-related mortality probability of survival after UCBT. BMT CTN 51 asked whether increasing cell dose, using 2 cord blood units for a single transplant, would improve transplant outcomes and showed that increasing cell dose in this fashion did not result in superior outcomes. 41 Donor-Recipient HLA Match COBLT 191 Single UCB N = 111 HLA match grade* 6/6 17 (8.9%) 16 (14.4%) 5/6 58 (3.4%) 5 (45.%) 4/6 111 (58.1%) 44 (39.6%) 3/6 5 (2.6%) 1 (.9%) 5/6 + 6/6 75 (39.3%) 66 (59.5%) 3/6 + 4/6 P= (.7%) 45 (.5%) * HLA match criteria: HLA A and B at antigen level HLA DRB1 at allele level 42 21

22 Median Cell Doses COBLT N=191 Single UCB N = 113 TNC (cryo) x1 7 /kg 5.1 ( ) 4.8 ( ) TNC (thaw) x1 7 /kg 4. ( ) 3.9 ( ) CD34 (cryo) x1 5 /kg 2. ( ) 2. ( ) CD34 (thaw) x1 5 /kg* 1.5 ( ) 2. ( ) *p= Neutrophil Recovery Single Day 42: 89.2% (95% CI: %) Day : 79.6% (95% CI: %) Incidence, % p=.8* Days Number at risk COBLT Single *=multivariate analysis adjusted for HLA match and pre-cryo CD

23 Platelet Recovery Single Month 6: 76.2% (95% CI: %) Incidence, % month 6: 5.% (95% CI: %) P<.17* Months Number at risk COBLT Single *=multivariate analysis adjusted for HLA matching, pre-cryo CD34 and CIBMTR risk 45 Acute GVHD Grade II-IV Incidence, % Single Day : 58.6% (95% CI: %) Day : 42.% (95% CI: %) p=<.1* Days Number at risk COBLT Single *=multivariate analysis adjusted for HLA matching and Pre-cryo TNC 46 23

24 Acute GVHD Grade III-IV p=.25 Incidence, % Day : 18.9% (95% CI: %) Single Day : 13.5% (95% CI: %) Days Number at risk COBLT Single Chronic GVHD p=.7* Incidence, % Single Month 12: 3.5% (95% CI: %) month 12:.7% (95% CI: %) Months Number at risk COBLT Single *=multivariate analysis adjusted for CMV status and Pre-Cryo TNC 48 24

25 Treatment-related Mortality COBLT vs. Single 51: HR 1.72, p=.292* Other race vs. Caucasian: HR 1.96, p=.4 Incidence, % month 12: 29.5% (95% CI: %) Single Month 12: 19.8% (95% CI: %) Months Number at risk COBLT Single *=multivariate analysis adjusted for race 49 Relapse p=. Incidence, % Single Month 12: 12.1% (95% CI: %) month 12: 18.% (95% CI: %) Months Number at risk COBLT Single

26 Disease-free Survival Single Month 12: 67.5% (95% CI: %) Probability, % month 12: 52.5% (95% CI: %) COBLT vs. Single 51: HR 1.74, p=.86* Other race vs. Caucasian: HR 1.72, p=.5 Relapse vs. remission: HR 1.63, p=.5 CMV ( + ) vs. CMV ( - ): HR 1.83, p=.3 Months Number at risk COBLT Single *=multivariate analysis adjusted for race, risk status, CMV status 51 Overall Survival All Patients - Total pre-cryo nucleated cell dose - TNC > Month 12: 64.1% (95% CI: %) Probability, % TNC month 12: 38.9% (95% CI: %) p=.92 Months Number at risk TNC TNC >

27 Overall Survival Single Month 12: 71.2% (95% CI: %) Probability, % month 12: 57.3% (95% CI: %) COBLT vs. Single 51: HR 1.89, p=.39* Other race vs. Caucasian: HR 1.81, p=.3 CMV (+) vs CMV (-): HR 1.72, p=.1 Months Single 51 Number at risk COBLT Single *=multivariate analysis adjusted for race and CVM status 53 Conclusions Survival after single UCBT in children has significantly improved over the past decade. Other outcomes, including lower TRM, higher DFS and neutrophil engraftment have also improved

28 Current efforts to overcome UCB limitations Increase UCB stem cell dose: A. Improve the harvest yield upon collecting cord blood units B. Infuse two cord units simultaneously double cord blood transplantation C. Expand the cord blood stem cells Ex Vivo, e.g: Notch mediated expansion (FHCRC), mesenchymal cell based expansion (MDACC) D. Prostaglandin E2 (PGE2) (Boston University) Unit selection: cell dose and degree of HLA match Improve UCB stem cell homing: A. Direct intra bone cord blood infusion ( European experience) B. CD26 inhibitor (Indiana University) C. Prostaglandin E2 (PGE2) ( Boston University ) D. Surface fucosylation of cord blood stem cells E. Use of hyperbaric oxygen (KU s approach) Novel preparative regimens, e.g: reduced intensity 55 Novel ex vivo expansion mechanism 56 28

29 Nicord Expanded Hematopoietic Progenitor Cells (HPC) Are Capable of Outcompeting the Unmanipulated (UM) Cord Blood Unit and of Prolonged Myeloid and Lymphoid Engraftment Following Myeloablative Dual Umbilical Cord Blood (UCB) Transplantation Mitchell E. Horwitz, M.D., Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center Patrick J Stiff, MD, Loyola Univ Medical Center, Maywood, IL Nelson J. Chao, MD, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC David Rizzieri, M.D., Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC Gwynn Long, M.D., Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center Keith Sullivan, M.D., Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC Cristina Gasparetto, M.D., Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC John Chute, M.D., Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC Ashley Morris, PharmD, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center Carolyn McDonald, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center Steven Wease, EMMES Corporation, Rockville, MD David Snyder, Gamida Cell Ltd., Jerusalem, Israel Einat Galamidi Cohen, Gamida Cell Ltd., Jerusalem, Israel Hadas Shoham, Gamida Cell Ltd., Jerusalem, Israel Efrat Landau, Gamida Cell Ltd., Jerusalem, Israel Etty Friend, Gamida Cell Ltd., Jerusalem, Israel Joanne Kurtzberg, MD, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC Tony Peled, Gamida Cell Ltd., Jerusalem, Israel 57 A pilot study of myeloablative dual UCB transplantation where one UCB unit is expanded ex vivo using NiCord technology has completed accrual. The NiCord UCB graft: expanded CD133+ and an unexpanded CD133 T cell fraction. Preparative regimen: TBI (135cGy), fludarabine 1mg/m2 cyclophosphamide 1mg/kg (n=2). GvHD prophylaxis consisted of tacrolimus and MMF. Eleven patients (med. age 45; range 21 61) High risk malignancies received NiCord and an UM graft Both units were comparably HLA matched with the recipient. However, the UM unit contained a larger pre cryopreserved cell dose (3 x 17/kg [range ] vs. 2.5 x 17/kg [range ]). After expansion (CD133+ fraction), NiCord contained a median TNC and CD34+ cell dose of 2.7 x 17/kg (1. 6.4) and 3.5 x 16/kg ( ), respectively

30 TITLE? (Ask OMAR) 59 Results Eight patients engrafted with NiCord (one of which is a mixed donor chimera) and two with the UM graft. One patient experienced primary graft failure. The median time to neutrophil engraftment was 12.5 days (7 26) for the entire cohort, and 1.5 (7 18) days for those engrafting with NiCord. No safety concerns were raised. The estimated day treatment related mortality is 1%. With a median follow up of 8 months, the progression free and overall survival are both 9%. 3

31 Conclusions NiCord expanded HPC's were capable of out competing those from the UM unit and predominate in the majority of patients. NiCord expanded HPC's reduced the time to hematopoietic recovery and are capable of long term (>22 months) neutrophil and T cell engraftment. Stem cell transplantation using NiCord is feasible, and may provide a potent cord blood graft enabling transplantation of a single expanded unit, without co infusion of UM cells 61 Current efforts to overcome UCB limitations Increase UCB stem cell dose: A. Improve the harvest yield upon collecting cord blood units B. Infuse two cord units simultaneously double cord blood transplantation C. Expand the cord blood stem cells Ex Vivo, e.g: Notch mediated expansion (FHCRC), mesenchymal cell based expansion (MDACC) D. Prostaglandin E2 (PGE2) (Boston University) Unit selection Improve UCB stem cell homing: A. Direct intra bone cord blood infusion ( European experience) B. CD26 inhibitor (Indiana University) C. Prostaglandin E2 (PGE2) ( Boston University ) D. Surface fucosylation of cord blood stem cells E. Use of hyperbaric oxygen (KU s approach) Novel preparative regimens, e.g: reduced intensity 62 31

32 UCB Stem Cell Biological Disadvantages Homing defects: a. UCB cells express lower levels of CXCR4 b. Low ex vivo transmigratory ability compared to BM HSCs (other studies have observed greater migratory activity in UCB derived CD34(+) cells). c. UCB cells have defects in fucosylation of the ligands that facilitate the adhesion to the vessels in the BM Human cord blood stem cell seeding efficiency in NOD/SCID mice was found to be less than that of bone marrow (4.4% versus %). Yahata et al. A highly sensitive strategy for SCIDrepopulating cell assay by direct injection of primitive human hematopoietic cells into NOD/SCID mice bone marrow. Blood 3;11: Is there another homing disadvantage? UCB cell dose is on average one log less than grafts, accordingly, if UCB cells get distracted, the bone marrow homing efficiency will be less compared to other grafts 64 32

33 Pre-Clinical Study Design CD34+ UCB stem cells transduced with lentivirus carrying luciferase gene BLOOD, 15 NOVEMBER 3 VOLUME 12, NUMBER

34 In vivo images: 3-hours post UCB CD34+ cell infusion 67 Early Bone Marrow Homing 68 34

35 In vivo images: month 3 post-transplant 69 Late Engraftment 7 35

36 Summary of results 71 Future Plans Pilot study to investigate the safety and potential efficacy of HBO in clinical UCB transplantation 72 36

37 HBO in Clinical UCB Transplantation Safe Simple Affordable Already approved for several indications Easy to translate to clinical use Novel approach to improve engraftment Supporting preliminary data 73 Study Protocol Design: pilot study End points: Primary: safety Secondary: efficacy in improving time to count recovery Exploratory: HBO effects on cytokines (EPO and TNF alpha) post UCB transplant Inclusion/exclusion criteria: broad Preparative regimen: RIC and myeloablative Cord units: 1 or 2 based on cell dose 74 37

38 Concluding Comments UCB transplantation is an acceptable alternative to MUD transplant when MUD is not available or when transplant is urgent. Improvement in pediatric UCB transplantation outcomes in the past decade as a result of better unit selection. Efforts are ongoing to improve UCB transplantation outcomes with signs of success in improving time to engraftment. 75 Many Thanks Technical Help: a. Jeff Eskew, PhD b. Nikhil Parelkar c. Yinghua Xiao d. Megan Swink e. Dandan Li Mentorship/Support/Co-I: a. Peter Van Veldhuizen, MD b. Joseph McGuirk, DO c. Sally Rigler, MD d. Hal Broxmeyer, PhD e. Linheng Li, PhD f. Kenneth Peterson, PhD g. Sunil Abhyankar h. Tara Lin, MD i. Sid Ganguly, MD Collaborators: a. Jeff Radel, PhD b. Bruce Kimler, PhD c. George Vielhauer, PhD d. Da Zhang, MD Cord Blood Research Fund Robert K. Dempski Cord Blood Research Fund 76 38

39 FIN! 77 39