Emerging Considerations for Cord Blood Transplantation. Cord Blood Unit Panel Discussion

Transcription

1 Emerging Considerations for Cord Blood Transplantation Juliet Barker, MBBS Joanne Kurtzberg, MD Koen van Besien, MD, PhD Moderators: Janelle Olson, PhD, CHTC Elizabeth Beduhn, CHTC Cord Blood Unit Panel Discussion Juliet Barker Overview of CD34+ as a consideration in cord blood transplantation Joanne Kurtzberg Emerging uses of cords in non-malignant diseases Koen van Besien Use of dual haplo/cord blood transplants 2 1

2 12/4/2014 Using CD34+ Cell Dose in Cord Blood Unit Selection CSA/ MMF Juliet N. Barker, MBBS (Hons), FRACP Associate Attending Director, Cord Blood Transplant Program Memorial Sloan-Kettering Cancer Center Acknowledgements Laboratory Medicine Katherine Smith Richard Meagher Joann Tonon Adult & Pediatric BMT Duncan Purtill Cladd Stevens Doris Ponce Parastoo Dahi Andromachi Scaradavou Sergio Giralt CBT Program Research Marissa Lubin Emily Lauer Biostatistics Sean Devlin Search Coordinators Courtney Byam Eric Davis Jen Paulson Melissa Sideroff Debbie Wells 1

3 12/4/ yr DFS 8/8 & 7/8 URD-T or dcbt Probability of DFS P = N = 175. Adults dcbt (n = 55): 68% yrs. Acute leukemia 8/8 URD-T (n = 74): 59% or CML. 7/8 URD-T (n = 46): 40% dcbt: Inf. CD34+ dose x 10 5 /kg. 11% 7-8/8, 48% 5-6/8, 41% 2-4/8. Ponce et al, Months Post BMT dcbt: higher 3-year DFS than 7/8 URD-T. ASBMT 2014 Number of Patients Distribution of URD, CB & No URD / CB by Patient Ancestry (n = 884) Image unavailable due to copyright restrictions 8/8 URD 7/8 URD CB No URD/CB Patient Ancestry Dahi et al, ASBMT

4 12/4/2014 Patient Ancestry Europeans N = 605 Non-Europeans N = 279 African (n = 95) W. Hispanic (n = 59) Asian (n = 66) URD, CB & No URD / CB by Patient Ancestry (n = 884) 8/8 URD 7/8 URD dcb No 7-8/8 URD/ dcb 397/605 (66%) 97/605 (16%) 103/605 (17%) Image unavailable due to copyright restrictions 74/279 (26.5%) 10/95 (11%) 16/59 (27%) 20/66 (30%) 55/279 (20%) 24/95 (25%) 17/59 (29%) 8/66 (12%) 115/279 (41%) 37/95 (39%) 19/59 (32%) 37/66 (56%) 8/605 (1%) 35/279 (12.5%) 24/95 (25%) 7/59 (12%) 1/66 (1%) Only one quarter of Non-Europeans received 8/8 URD. Access for African ancestry patients most challenging. Dahi et al, ASBMT 2015 Relevance of CB? (beyond extending access if no 7-8/8 URD) Decreases need to allograft with mismatched 7/8 URD. Extends transplant access if no haplo. 3

5 12/4/2014 CB: Approaches to Reduce TRM Unit selection Conditioning Immune suppression & GVHD Speeding engraftment (beyond unit selection) Preventing infections How to Select Units? Dose (TNC, CD34+) & quality HLA-match RBC content (thaw & infusion) 4

6 12/4/2014 % Viable CD34+s % Viable CD34+s Post-Thaw by Bank (n = 366 units) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% NYBC (n=149) Median 94% (68-99) Median 89% (34-98) Other US (n=123) Median 92% (34-98) International (n=94) Variability in viability by unit & by bank: introduces unit quality as important variable in unit selection. PROBLEM: Delayed or failed engraftment increased TRM SOLUTIONS Improved unit selection* Ex vivo expansion 3rd party cells Facilitate homing 5

7 12/4/2014 Cell Dose Is infused viable CD34+ dose better than TNC dose? Analysis of dcbt Neutrophil Engraftment N = 129: Engraftment 95% Univariate Variable* HR P value Recipient Age (continuous, per decade) Dominant Unit Pre-freeze TNC 1.19 Dose: Bank Pre-freeze CD All < Dominant Unit Dose: Post-thaw Inf. TNC 1.28 Inf. Viable CD Inf. CFU Inf. Viable CD Multivariate analysis: only significant factor infused viable CD34+ cell dose of dominant unit: HR 1.95 (95%CI: ), p < * Diagnosis, CMV serostatus, prep. regimen intensity & HLA match: NS Purtill et al, Blood

8 12/4/2014 Cumulative Incidence MSKCC dcbt: Neutrophil Engraftment by Dominant Unit Infused Viable CD34+/kg (n = 129) > Winning unit infused viable CD34+ dose determines speed & success < 0.5 Inf. viable CD34+ cell dose < 0.50 (n = 32) 1.00 Ref (n = 32) (n = 32) 1.70 < > 1.4 (n = 33) 1.86 < Days Post-Transplant Purtill et al, Blood 2014 What Determines Infused Viable CD34+ Cell Dose & Can it be Predicted at Unit Selection? Analysis of 3 Factors in 402 Units Pre-freeze CD34+ count Post-thaw CD34+ recovery CD34+ viability* * Tested at MSKCC by flow cytometry & 7-AAD exclusion Purtill et al, Blood

9 12/4/2014 Pre- vs Post-Thaw CD34+ Cell Recovery (n = 402) Post-thaw total CD34+ cell count Bank pre-freeze total CD34+ cell count Post-thaw total CD34+ cell count Post-Thaw CD34+ Cell Recovery Overall correlation: r 2 = 0.73 Median recovery: 101% (range ) Low recovery (< 65%): 39 CB units (11%) Netcord-FACT accredited: 8% p < Non-Netcord-FACT accredited: 29% Bank pre-freeze total CD34+ cell count 8

10 12/4/2014 Post-thaw CD34+ Cell Recovery & Viability Post-thaw total CD34+ cell count Median viability: 92% (range 34-99%) < 75% viability: n = 33 (8%) < 75% viability Bank pre-freeze total CD34+ cell count Factors Associated with Low CD34+ Cell Viability N (%) < 75% Variable (N) CD34+ Viability Netcord-FACT accreditation OR* (95% CI) Yes (n = 350) 15 (4%) Reference No (n = 52) 18 (35%) 4.9 ( ) Cryopreservation year (n = 119) 17 (14%) 1.47 ( ) (n = 283) 16 (6%) Reference Cryopreservation volume per bag (ml) < 24.5 (n = 14) 5 (36%) 8.8 ( ) (n = 298) 8 (3%) Reference (n = 45) 7 (16%) 8.5 ( ) > 30.0 (n = 45) 13 (29%) 7.5 ( ) Processing method Manual (n = 187) 24 (13%) 2.3 ( ) Automated + semiautomated (n = 215) 9 (7%) Reference Multivariate p value <

11 12/4/2014 CD34+ Conclusions: Engraftment & Unit Quality Analysis Infused viable CD34+ cell dose of dominant unit is critical determinant of engraftment after dcbt. Post-thaw CD34+ recovery is Bank-dependent: Non-Netcord-FACT Banks associated with lower recovery. Post-thaw CD34+ viability is dependent on Banking practices: Non-FACT accredited < 24.5 ml or > 26 ml lower post-thaw viability CD34+ Conclusions: Relevance in Unit Selection Pre-freeze CD34+ cell dose can be used for unit selection: more reliable than TNC. Ideally > 1 x 10 5 /kg. Quality: another factor in unit selection: Netcord- FACT accreditation, processing & cryovolume. Applies to both units of double unit graft. Post-thaw testing (with back-up) warranted if low unit - esp. if single unit CBT. 10

12 12/4/2014 If units can be selected based on likely post-thaw viable CD34+ dose are 2 units needed? What is an adequate single? MSKCC dcbt: Role of Non-Dominant Unit (n = 129 myeloablative dcbt) Graft Variable Multivariate HR (95%CI) p value Dominant unit viable 1.72 CD34+ Image cell dose unavailable (continuous) due to copyright ( ) restrictions< Dominant unit % viable CD34+ cells (by decile) 1.31 ( ) Non-dominant unit TNC dose (continuous) 1.19 ( ) Winner determines speed & success of engraftment, but non-dominant unit may have facilitation effect- role in overcoming allogeneic barrier to engraftment??? Purtill / Barker, ASH

13 12/4/2014 Recognition of HLA-Allele Mismatch Number of CB Units (CBU) 4/6 units: 2/8-6/8 8 Allele Donor-Recipient HLA-Match Selection based on high resolution typing now standard & selection of better matched units possible. Dahi et al, BMT

14 Novel Applications of Cord Blood Therapies Joanne Kurtzberg, MD Jerome Harris Distinguished Professor of Pediatrics Professor of Pathology Pediatric Blood and Marrow Transplant Program Carolinas Cord Blood Bank Julian Robertson Cell and Translational Therapy Program 1

15 Early Observations Cord blood could substitute for bone marrow as a donor for HSCT for all standard allogeneic indications Hematological malignancies, marrow failure, immunodeficiencies, hemoglobinopathies, certain inherited metabolic diseases Cell dose matters and single cord blood unit may be on the cusp or too small for larger individuals HLA matching also matters, but lesser matches can be utilized when higher cell doses are administered Immune reconstitution is delayed GvHD is decreased as compared to adult HSCT sources?relapse may be lower post CBT versus other HSCT sources 2

16 0501 Treatment Schema HLA <2 ag mm TNC >2.5 x 10 7 /kg UCB 1 HLA <3 ag mm TBI TBI TBI TBI UCB 2 HLA <2 ag mm TNC >1.5 x 10 7 /kg Flu 25 mg/m2 daily TBI 165 cgy twice daily Cy 60 mg/kg daily FLU FLU FLU CY CY REST G CSF CSA MMF TIME Overall Survival - Intent-to-Treat Single UCB: 71% (62-79) 80 Probability, % Double UCB: 65% (55 73) P= Months Number at risk Double UCB Single UCB

17 Engraftment (ANC 500) Partially Matched, Fresh (med = 13 days) NON matched, Cryopreserved (med = 19 days) Conventional CBT (med = 25 days) Expanded Unit CD34 Cell Dose Average: 12.5 million/kg Median: 8.3 million/kg Range: 0.9 to 49 million/kg Expanded Unit CD34 Cell Dose Average: 6.8 million/kg Median: 6 million/kg Range: 3.1 to 11.6 million/kg NiCord Product for BMT NiCord Cord Blood Unit CliniMACS separation: Enrichment of CD133 + cells Cultured fraction (CF) The CD133 positive cell fraction Cultured for 3 weeks using NAM technology + Non cultured fraction (NF) The CD133 negative cell fraction Kept frozen till the day of transplantation 4

18 NiCord Graft Processing and Transplantation Schema CD133 + CD34 + Fraction I. NiCord cultured fraction (CF) Day 21: Cultured with cytokines (FLT3, SCF, TPO, IL 6) + Nicotinamide in cultured bags for 21 days Day 0: Cells harvested, safety and quality tested Hand delivery to clinical site (18hr stability) TRANSPLANTATION I. NiCord CF Image unavailable due to copyright restrictions II. NiCord NF CD133 CD34 Fraction III. Unmanipulated CBU II. NiCord non cultured Fraction (NF) Day 21: cryopreserved CONDITIONING: Day 9 to 0 CONFIDENTIAL FOLLOW UP MMF Tacrolimus ARRIVAL OF NiCord NF TO CLINICAL SITE ARRIVAL OF NiCord CF TO CLINICAL SITE NiCord Rapid Engraftment Shortens Hospitalization CONFIDENTIAL Avg. hospitalization days Patients engrafted with NiCord : 23.5 (Day 14 post transplant discharge) Patients engrafted with the UM CBU: 40 (Day 31 post transplant discharge) Duke control cohort (n=17) average 36 (Day 24 post transplant discharge) Rapid PB WBC Reconstitution in Patients Engrafted with NiCord WBC ANC>500 ANC>500 ANC>500 Image unavailable (median) due to copyright restrictions (average) (median) Days post transplantation Horwitz M et al J Clin Invest. 2014;124(7): NiCord (n=8) UM (n=2) Cont. (n=17) 5

19 Stable Donor Derived Chimerism, Over Three Years, CONFIDENTIAL Provided by NiCord HSC s Image unavailable due to copyright restrictions Horwitz M et al J Clin Invest. 2014;124(7): NiCord Single Expanded Cord Blood Transplantation CONFIDENTIAL CD133+ Fraction I. NiCord cultured fraction (CF) Day 21: Cultured with cytokines (FLT3, SCF, TPO, IL 6) + Nicotinamide (2.5mM) in cultured bags for 21± 2 days Day 0: Cells harvested, safety and quality tested Hand delivery to clinical site (18hr stability) TRANSPLANTATION NiCord CF.I Image unavailable due to copyright restrictions NiCord NF.II CD133 Fraction Unmanipulated CBU.III II. NiCord non cultured Fraction (NF) Day 21: cryopreserved CONDITIONING: Day 9 to 0 FOLLOW UP MMF Tacrolimus ARRIVAL OF NiCord NF TO CLINICAL SITE ARRIVAL OF NiCord CF TO CLINICAL SITE 6

20 NiCord Phase I/II Study Single Cord Configuration First 5 SC Patients, Preliminary Results Myeloablative conditioning regimen: TBI/Flu, Cy optional GvHD prophylaxis: tacrolimus/mycophenolatemofetil Five patients enrolled to date ANC engraftment on day 9, 11 and 6, 7, 26 agvhd grade II in two patients CONFIDENTIAL Image unavailable due to copyright restrictions DC/NICORD Transplantation in patients with Sickle Cell Disease 5 patients ages 4 17 years Severe manifestations Bu/CY/ATG or Flu/BU/CY Median day to ANC 500 day +8 4 patients engrafted and surviving long term: 8 months 2 years 2 with unmanipulated unit, 1 nicord, 1 mixed nicord/umu How does SCT correct inborn errors of metabolism? Marrow and immunoablation Replacement with donor cells Donor leukocytes produce enzyme Enzyme distributed through blood circulation Cells migrate to brain, cross blood brain barrier, replace enzyme in brain Cellular Enzyme Replacement Therapy Non hematopoietic cell engraftment 7

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22 Differentiation of Donor Cells into Cardiac Myocytes A = troponin B = Stacking C = myosin A C B Engraftment of donor derived insulin expressing beta cells in a recipient of UCBT Donor derived islet in a 1.5 year old, MPS 1, female recipient of a male UCBT surviving 161 days post transplant Huang et al. Diabetologia (2011) 54:

23 SCT for Krabbe Disease: Early transplantation is critical! Newborn Screening: New York State 2008 Now 7 other states Escolar et al, NEJM, 2005 VP3 Some newborns with Krabbe Disease have sustained prenatal damage to their cortical spinal tracks M Escolar, CDL, NFRD, UNC-CH 10

24 Slide 20 VP3 all 2-3 DAYS OF AGE tierney, borrassa, Degan Miles; Cerebral pudencle - k4 and k6 are normal (yellow is myelination) Middle - Bourassa - less fibres, no myelin; the outcome of the motor function worse in the middle child. Vinod Prasad, 4/12/2007

25 Donor Cells engraft in the brain after IV UCBT DUOC 01 DUOC 01 Initial Description E Tracy, J Aldrink, J Panosian, D Beam, J Thacker and M Reese and J Kurtzberg, Isolation of oligodendrocyte like cells from, human umbilical cord blood, Cytotherapy (2008) 10, ET Tracy, CY Zhang, T Gentry, KW Shoulars and J Kurtzberg, Isolation and expansion of oligodendrocyte progenitor cells from cryopreserved human umbilical cord blood, Cytotherapy (2011)13, Completed preclinical toxicology, biodistribution, animal toxicology, validation of manufacturing, stability, development of release criteria, clinical protocol for IND submission 11

26 Robertson CT 2 Stem Cell Lab CCBB GMP Clinical Trials RP2 CT 2 Regulatory / QSU 100 employees GMP Cell Manufacturing Facility Flexible manufacturing spaces. Three class 10,000 (ISO class 7) suites available Aseptic processing, fill, and finish for cellular product cgmp sample storage Controlled receipt, storage and release of raw materials and supplies Environmental monitoring using industry standard equipment with quality audit and trending

27 DUOC 01 Manufacturing (GMP) More than Minimally Manipulated Thaw 20% fraction of licensed CBU, wash Deplete RBC Culture, NCS proliferation conditions, demidepleting non adherent cells in feeding Differentiation medium d14 17 Trypsinize, wash d21 Formulate for IT injection in syringe Release: viability, sterility, endotoxin, flow E. Tracy, T. Gentry, GMP Lab Tissue distribution of DUOC 01 cells Brain frequency pg hudna/reaction Total hudna (ng/tissue) day 1 4 of pg ng day 14 4 of pg ng day 28 3 of pg ng day 56 2 of pg ng Image unavailable due to copyright restrictions Spine frequency pg hudna/reaction Total hudna (ng/tissue) day 1 5 of pg ng day 14 4 of pg ng day 28 4 of pg ng day 56 1 of 2 1 pg 0.56 ng R. Storms RP2 Lab 13

28 LSD enzyme production Activity* of 11 lysosomal enzymes in 5 cgmp batches of DUOC 01 UCB Number Enzyme MEAN SD β galactosidase β mannosidase α L fucosidase α mannosidase β glucuronidase Image unavailable due to copyright restrictions β N acetyl glucose sulfatidase arylsulfatase A galactocerebrosidase sphingomyelinase glucocerebrosidase α L iduronidase *nmol/h/mg protein Analysis done by Lysosomal Disease Testing Laboratory, Jefferson Medical College D. Wenger Cytokines secreted by DUOC 01 in response to TNF α Image unavailable due to copyright restrictions A Balber RP2 lab 14

29 Myelin basic protein expression one week after return to normal diet and treatment with DUOC-01 or Ringer s solution Ringers DUOC 01 Anti-MBP 72 tiled images of representative section A. Saha RP2 Lab DUOC 01 First in Humans Trial Design 21 days IT 1-5 X10 6 cells DUOC-01 CBT provides enzyme permanently IND 9/2014 Cells from CBT in CNS 15

30 Our Roadmap Allo UCBT in IMD What about an allo cordderived product for Brain Injury? Donor cells engraft in brain What about auto cells for brain injury? Further injury prevented, some repair Autologous UCBT at Duke Safety HIE Study Babybac Cooling +/ UCB infusion Auto UCB infusion (volume reduced, fresh CB) Congenital Hydrocephalus HLHS/ECMO Cryopreseved cord blood CP ages 1 6 Cryopreserved cord blood Autism 16

31 HIE (babybac) Pilot Study Mike Cotten, Ron Goldberg, Amy Murtha, STCL, CCBB Term Newborns with HIE meeting diagnostic criteria for moderate to severe encephalopathy Eligible for cooling Collected autologous cord blood Cooled per SOC Informed consent Given autologous CB infusions at <24 and <48 hours of age Followed for infusional toxicity, survival and functional outcomes at 1 and 2 years of age Cotton et al, J Peds, 2014 Survival with 1 yr Bayley III scores > 85 in 3 domains *Survived to 15 months Survival with all 3 Bayley domain scores > 85 Cells N = 18 Cooled only N = (89) 35 (76) (72) 19 (41) 0.05 p NEXT STEPS: PHASE II RANDOMIZED TRIAL: 240 patients, 8-10 centers ~$5-6M? Standard Rx vs Placebo (RBC pellet) or 1 versus multiple (and later) infusions 17

32 CP AC (IND) Jessica Sun, Allen Song, Anne Fitzgerald, Colleen Mclaughlin Randomized, placebo controlled trial of autologous CB in children with spastic CP Ages 1 6 yrs Eligible cord blood GMFM level (II IV) Blinded/cross over design Baseline, 1 yr, 2yrs Evaluations by exam, neurocog/fxnl testing, MRI (functional in older pts), TMS, CB microarrays, QOL Primary Endpoint: >30% increase in predicted GMFM score at 1 year Activated 7/2010; completed accrual 2/2013 First analysis planned 3/2015 Phone screen CBU screen and shipment to duke Qualifiying visit *Placebo = TC % DMSO 18

33 Assessing Change in Changing Subjects Graham HK. Classifying cerebral palsy. J Pediatr Orthop. 2005;25:128 Assumptions: Mean increase of 6 points/year without intervention ~30% additional increase (7.8 total points/year) would be clinically significant. GMFCS Level I GMFM 66 Percentiles by Age GMFCS Level II GMFCS Level III Hanna SE, et al. Tabulated reference percentiles for the 66 item Gross Motor Function Measure for use with children having cerebral palsy, April 2008, available at GMFCS Level IV GMFCS Level V 19

34 Longitudinal Assessment (Left Hemiplegia) Year 0 Year 2 Age = 1yr4mo, GMFCS = 2 Total Streamline Count = Total Tract Voxel Count = WM Fraction = 26.88% Age = 3yr4mo, GMFCS = 1 Total Streamline Count = Total Tract Voxel Count = A Song BIAC WM Fraction = 30.61% R L R L R L cp010 (T(Left UE)) cp011 (H(Lh)) cp009 (H(Rh)) R L R L R L GMFM change < 10 GMFM change >= 10 Increased normalized connection volume Decreased normalized connection volume cp025 (Q) cp002 (Q) cp005 (Q) 20

35 Cell therapies for brain diseases Genetic Diseases Allogeneic cells Permanent engraftment Including brain Enzyme replacement Requires chemotherapy Acquired Brain Injuries Autologous cells Transient presence Paracrine/trophic effects Signaling of endogenous cells No chemotherapy What about allogeneic cells for treatment of brain injuries? Allogeneic cells for Acquired brain injuries and other cellular therapies? Most patients do not have their cord blood banked. A donor derived, readily available product is needed: Administration without chemotherapy. Will immunosuppression be needed? Should the product be HLA matched? Therapeutic effects through paracrine signaling Durable engraftment not necessary 21

36 The Marcus Foundation Grant JK and Geri Dawson Cord blood derived cellular therapies for treatment of autism, stroke, CP Autologous and allogeneic products Non homologous use Minimally manipulated and more than minimally manipulated cells Preclinical development, animal models, INDs, 11 clinical trials FDA LICENSURE hematopoietic reconstitution after myeloablative chemotherapy 22

37 Acknowledgements Pediatric Blood and Marrow Transplant Team MDs, APNs, NCs, SC, SW, FA, FSP Stem Cell Laboratory Carolinas Cord Blood Bank CT2: Andy Balber and team Allen Song and Jim Provenzale Jessica Sun/Mohamad Mikati/Gordon Worley Katie Gustafson/Laura Case and ND Team Amy Murtha, Haywood Brown Sid Tan, Mike Cotten, Ron Goldberg, Ricki Goldstein Geri Dawson and team NHLBI, HRSA, NMDP, The EMMES corp The Julian Robertson Foundation The Legacy of Angels Foundation The Katz Foundation The Marcus Foundation Our Patients and their parents and families 23

38 Koen van Besien, MD, PhD NYP WCMC New York, NY U Chicago Hong Tao Liu Andy Artz John Cunningham Lucy Godley Elizabeth Rich Justin Kline Richard Larson Vu Nguyen Toyosi Odenike Wendy Stock Amittha Wickrema Thanks to: WCMC Tsiporah Shore Usama Gergis Sebastian Mayer Melissa Cushing Transplant Unit Staff Research Coordinator RN, PA, Pharm D Rehab Medicine Biostatistics Chimerism HLA 1

39 8/8 Allele, Available-Match Rates in the Adult Donor Registry NATIONAL MARROW DONOR PROGRAM Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry 3 HAPLO VS UCB (CTN PARALLEL TRIALS) Hematooietic Recovery Outcome Age <70 (med 58 UCB, 48 Haplo) AL in CR Chemosens Agg Lymphoma Foll Lymphoma >2 chemo Brunstein C G et al. Blood 2011;118:

40 Cord Blood Graft % Donor Chimerism Haplo- identical Graft CD34-Selected Fernandez, Exp Hematology 31, 535, 2003 Magro et al, Haematologica 91, 540, 2006, Liu et al, Blood 118, 6438, 2011 Time CliniMACS Plus Cell Separation System 3

41 FLUDARABINE MELPHALAN ATG Flu-Mel Fludarabine* (30mg/m 2 /day) Melphalan (140 mg/m 2 ) *Thymo 1.5 mg/kg Tacrolimus Mycophenolate ( ) TBI 2Gray (X X) d 2-d 180 d 0-d 28/60 Decrease ATG dose for patients over 50 Decrease MMF TBI for selected patients Day CHIMERISM UNFRACTIONATED CD3 4

42 PATIENT COURSE 66 YO WM Refractory AML ANC d10, Plt d 30 D50: Unfrac: 100% UCB D50: CD3: 100% UCB 65 YO WM Transformed Follicular ANC d10, Plt d14 D50: CD33 100% Haplo D50: CD3 66% Haplo, 33% UCB 36 YO BF Hx Cadaveric Kidney Tx, CRF T- MDS ANC d10, Plt d42 D50: CD33 100% UCB D50: CD3 100% UCB WBC/ALC Pt 7 Counts Days after Transplant Pt 7 Unf r actionated chimer ism WBC PLT WBC PLT Days af ter tr ansplant HAPLOCORD VS DOUBLE UCB CASES REPORTED TO CIBMTR Haplo Cord Double UCB P N Age % Minority Advanced Disease 44% 23% < Year of Tx % 50% < % 50% Control Selection (Propensity Score Matching) Match 1 Case with up to four controls matched for: age, gender, race, disease type, disease stage pre-transplant, KPS and years within 2 years Presented by: Koen van Besien, MD 5

43 CASE CONTROL:HAPLOCORD VS DUCB MATCHED COHORT Haplo Cord DUCB P N Median Age Median Weight 80 (41-136) 78 (40-155) 0.32 %male % Minority % AML % Advanced Disease KPS < Year of Tx % 23% % 77% Follow up of survivors (median) 14 mo 22 mo 0.19 Presented by: Koen van Besien, MD ENGRAFTMENT OUTCOMES Haplo Cord DUCB P Neutrophil d30 91% 72% < d60 96% 86% Platelets d30 54% 6% < d60 78% 54% < Presented by: Koen van Besien, MD, PhD 6

44 NEUTROPHIL AND PLATELET ENGRAFTMENT Presented by: Koen van Besien, MD, PhD HAPLOCORD VS DOUBLE UCB MATCHED COHORT Haplo Cord Double UCB P Conditioning Intensity <0.001 RIC or NMA Conditioning 100% 55% GVHD prophylaxis CNI+ MMF 100% 89% < ATG 100% 24% < Total Nucleated Cell Doses 1.93 ( ) 4.1 ( ) < (x10^7/kg) Median (range) Degree of Mismatch* < None (6/6) 10% 2% (4%) One Mismatch (5/6) 65% 19% (30%) Two Mismatches (4/6) 25% 41% (65%) Three Mismatches (3/6) 0% 1% (2%) Data not available 36% Patients who are missing CB match or cell dose data are excluded from Computation Presented by: Koen van Besien, MD 7

45 EXAMPLES x Age Weight Comorb UCB TNC/kg Match Out of 8 ANC 500 PLT 20 AGVHD CGVH D Current Status SC HL Ref ADD NO A&W 17 Mo EXAMPLES x Age Weight Comorb UCB TNC/kg Match Out of 8 ANC 500 PLT 20 AGVHD CGVH D Current Status SC HL Ref ADD NO A&W 17 Mo CS Tr L SD A fib Sleep apnea NO A&W 10 Mo 8

46 EXAMPLES x Age Weight Comorb UCB TNC/kg Match Out of 8 ANC 500 PLT 20 AGVHD CGVH D Current Status SC HL Ref ADD NO A&W 17 Mo CS Tr L SD A fib Sleep apnea DP AML PIF DM Arterial clot NO A&W 10 Mo NO A&W 12 Mo EXAMPLES x Age Weight Comorb UCB TNC/kg Match Out of 8 ANC 500 PLT 20 AGVHD CGVH D Current Status SC HL Ref ADD NO A&W 17 Mo CS Tr L SD A fib Sleep apnea DP AML PIF DM Arterial clot MS AML CR1 +PV + CLL Prostate ca TIA Glauco ma NO A&W 10 Mo NO A&W 12 Mo A&W 4 MO 9

47 HAPLOCORD VS DOUBLE UCB MATCHED COHORT Haplo Cord Double UCB P Conditioning Intensity <0.001 RIC or NMA Conditioning 100% 55% GVHD prophylaxis CNI+ MMF 100% 89% < ATG 100% 24% < Total Nucleated Cell Doses 1.93 ( ) 4.1 ( ) < (x10^7/kg) Median (range) Degree of Mismatch* < None (6/6) 10% 2% (4%) One Mismatch (5/6) 65% 19% (30%) Two Mismatches (4/6) 25% 41% (65%) Three Mismatches (3/6) 0% 1% (2%) Data not available 36% Patients who are missing CB match or cell dose data are excluded from Computation Presented by: Koen van Besien, MD RELATION BETWEEN MINIMAL UCB CELL DOSE AND HR HLA MATCH PROBABILITY OF 5/6 UCB UNIT AAFA KOREAN EURCAU 10

48 HAPLOCORD VS DOUBLE UCB MATCHED COHORT Haplo Cord Double UCB P Conditioning Intensity <0.001 RIC or NMA Conditioning 100% 55% GVHD prophylaxis CNI+ MMF 100% 89% < ATG 100% 24% < Total Nucleated Cell Doses 1.93 ( ) 4.1 ( ) < (x10^7/kg) Median (range) Degree of Mismatch* < None (6/6) 10% 2% (4%) One Mismatch (5/6) 65% 19% (30%) Two Mismatches (4/6) 25% 41% (65%) Three Mismatches (3/6) 0% 1% (2%) Data not available 36% Patients who are missing CB match or cell dose data are excluded from Computation Presented by: Koen van Besien, MD INCIDENCE OF ACUTE AND CHRONIC GVHD 11

49 PFS AND OS HAPLO CORD VS CONTROL GROUP CONCLUSION: HAPLO CORD TRANSPLANT Reliable and fast Neutrophil and Platelet Recovery Ability to use smaller, better matched UCB grafts Low rates of acute and chronic GHVD without increases in relapse rates Use of ATG? Better HLA matching? Excellent option for Patients with limited UCB options Older patients Rapid hematopoietic Recovery Low rates of cgvhd Long term survival improved 12