Expanding Uses of Umbilical Cord Blood: Duke Experience. Vinod K. Prasad, MD, MRCP (London) PBMT Division, Duke University Medical Center

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1 Expanding Uses of Umbilical ord Blood: Duke Experience Vinod K. Prasad, MD, MRP (London) PBMT Division, Duke University Medical enter

2 UBT - Record Umbilical cord blood contains sufficient numbers of stem and progenitor cells to rescue marrow after myeloablative therapy.

3 Unrelated Umbilical ord Blood Transplantation Duke August 24 th yr old (14.1 kg); relapse T-cell ALL No family or adult BM donor 4/6 ord blood unit from NYB; TN 4.6x10e7/Kg Engrafted Day +31 (AN >500) Severe Pulmonary Hemorrhage and died Day yr old infant leukemia Sept 93 4/6 BU; TN 4.86x10e7/kg Long term survivor

4 New Technique or Technology 1. Great hope and enthusiasm by some 2. Major skepticism from others 3. Slow acceptance by the community 4. Weaknesses and strengths better understood 5. Judicious application 6. New becomes common and routine 7. Desire and search for the next new B Transplants B Procurments

5 Pediatric Unrelated ord Blood Transplants at Duke August August 2008 Disease ategory Number of patients ALL 186 AML 129 Inherited Metabolic Disorder 187 Immune Deficiency 55 Bone Marrow Failure 28 MDS 22 ML 16 Lymphoma 9 Hemoglobinopathy 11 Osteopetrosis 8 Others 7 Total Transplants 719 Total Patients Transplanted 658 Some received more than one transplant

6 * * * * * * * * * * 13 Domestic ord Blood Banks 150,000 BU in USA 400,000 worldwide

7 The arolinas ord Blood Bank Established 1997 through OBLT (NHLBI) urrent inventory >20,000 units 8 collection sites in N with access to ~30,000 births Staff collection model Units listed and distributed through NMDP AR bank NMDP Member bank 2004 FAT accreditation 2005, 2008 NBI Bank 2006 Netcord Bank 2007

8 Unrelated Umbilical ord Blood Advantages Rich source of progenitor cells Rapid availability of banked units Non-invasive collection procedure Less precise HLA matching Donor access to larger and more diverse patient population Lower risk of graft vs. host disease Disadvantages Limited cell number May not be adequate for larger recipients Slower neutrophil and platelet engraftment Donor is not available for additional products (DLI, second transplant) Possibility of undetected genetic disease

9 ord Blood Advantages ord Blood Unit Marrow/PBS Donor All Black White Hispanic Asian/PI AI/AN Multi Median Time in Days From Initiating a Formal Search to Scheduling Transplant 4 of 6 5 of 6 6 of 6 Likelihood of finding unrelated BU

10 OBLT: Pediatric Hematologic Malignancy 191 subjects transplanted between HLA: Low-res A, B; High-res DRB1; Retrospective - High resolution. Hematological malignancies: no ML blast, ALL relapse No related donor Regimen: TBI 1350, y 120, eqatg 90 GvHD Prophylaxis: SA/Methylpred Age: 7.7 (1 18) yrs; Wt: 25.9 (8-118) kg Demographics: 61% Males; 58% White; 51% MV+; 77% High Risk TN: Median pre cryo: 5.2 x 10e7/kg D34: Median : 1.52 x 10e5/kg Primary Disease N (%) ALL 109 (57) AML 57 (30) MDS, ML, Others 15 (8) OVERALL SURVIVAL TN pre-cryo x 10e7/kg p= Kurtzberg et al Blood 2008

11 OBLT: Pediatric Hematologic Malignancy 191 subjects transplanted between Overall Survival: Probability Recipient MV Sero-status p < P< Months Post-Transplant Positive, N=98 Negative, N=92

12 OBLT: Pediatric Hematologic Malignancy 191 subjects transplanted between DISEASE FREE SURVIVAL Original HLA typing Retrospective HLA typing Low res -A and -B; Hi res DRB1 Hi resolution A, -B, and DRB1 p= p=0.3385

13 OBLT: Pediatric Hematologic Malignancy 191 subjects transplanted between The first prospective, multi-institutional study of cord blood transplantation. Standard treatment protocol, supportive care, and outcome definitions and assessments Low incidence of graft failure (10%) and engraftment correlated with nucleated cell dose, HLA match, and donor gestational age. Incidence of grade III/IV agvhd was 19%; cgvhd was 20% (70% limited) and GVHD caused death in 30% of fatalities. Incidence of relapse was 25% (77% of pts were high risk) Overall survival was 55%. Early engraftment, patient MV negative serology and male gender being favorable risk factors. Notably, level of HLA match (original or high resolution) and risk status at diagnoses did not impact survival. Ethnic minority had same outcomes as aucasians

14 Krabbe s Disease Deficiency of Galactocerebrosidase - accumulation of lipids in the NS resulting in demyelization. Incidence - 1/100,000 to 200,000 Age of onset - Early infantile Dead by 1-2 years of age Late infantile hildhood Autosomal recessive; Scandinavian descent Neurological: irritability, hypertonia, spasticity, peripheral neuropathy, seizures, optic atrophy, mental deterioration, death before age 3yr (early infantile) Deficiency of galactocerebrosidase - blood, skin biopsy and/or prenatal sampling MRI/T brain - attenuation of white matter Elevated SF protein Decreased nerve conduction studies

15 10 Number Unrelated UBD-T for IMD: Demographics < >20 DUM Aug 1995 April 2007 Diagnosis N (%) TOTAL PATIENTS 159 Age Median (range) 1.5 yrs ( ) Age at Transplantation in Years Adrenoleukodystrophy (ALD) % GM1 Gangliosidosis 1 0.6% Hunter s Syndrome 6 3.8% Hurler s Syndrome % I-cell disease 1 0.6% Krabbe disease % Lesch-Nyhan disease 4 2.5% Metachr Leukodystrophy (MLD) % Others 4 2.5% Neiman-Pick B 2 1.3% PMD 1 0.6% Sandhoff disease 3 1.9% Sanfillipo Syndrome % Tay Sachs 9 5.7% Alpha manosidosis 1 0.6% Prasad et al Blood 2008

16 Diapositiva many of the younger patients are siblings of patients who were initially diagnosed and were too advanced to transplant -many were diagnosed in utero -a number of siblings transplanted omprehensive ancer enter; 09/12/2007

17 How does UBT correct IMD? Muentzer NEJM 2007 ytoreduction or conditioning Donor derived hematopoietic and immune system engraftment Donor leukocytes produce enzyme Microglia in the brain derived from the donor cells Enzyme helps defective cells by cross-correction Non-hematopoietic cell engraftment Substance A Substance B x Enzyme Enzyme could be transported from normal cells to deficient cells 1976 PNAS Neufeld

18 Prasad et al Blood 2008 VP17 Unrelated UB-T for IMD: Demographics Total Pts: 159 Males: 61% MV +Pt: 19.5% PS<80: 41.5% ABO mismatch: 44.7% Ethnic mismatch: 25.2% Sex mismatch: 49.1% HLA Match N (%) 3/ % 4/ % 5/ % 6/ % Duke Evaluation to cytoreduction 34.5 days Diagnosis to cytoreduction 87 days Median Range ell Dose x 10e7/kg ryopreserved 9.73 ( ) ell Dose x 10e7/kg Reinfused 7.57 ( ) D34 x 10e5/kg Reinfused 2.14 ( ) FU x 10e4/kg Reinfused 5.74 ( )

19 Diapositiva 17 VP17 some of the data on Krabbe and Hurler published ALD coming out in BBMT Sanfillipo presented at meeting Vinod Prasad; 04/05/2007

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21 Unrelated UB-T for IMD: Overall Survival

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23 Patients with all Performance status Duration Overall Survival 95% I 1 year 71.80% 64.7%-78.9% 3 year 62.70% 54.8%-70.5% 5 year 58.20% 49.7%-66.6% Patients with Performance status Duration Overall Survival 95% I 1 year 88.40% 79.6%-97.1% 3 year 83.50% 73.0%-94.1% 5 year 79.50% 66.9%-92.1% 97.9% achieved donor chimerism of >90% All but 4 achieved and sustained normal enzyme levels

24 Functional Outcomes Better outcomes were seen in patients: Transplanted as neonates Juvenile (less rapidly progressive) disease With high PS at transplant Poor outcomes were seen in patients: With lower PS Progressive early infantile disease Progressive symptoms at transplant Escolar NEJM 2007; Staba NEJM 2005; Beam BBMT 2007

25 UB-T for IMD: onclusions UBT is uniquely suited for children with IMD. Readily available (Time to transplant 41 days) >95% chance of finding a matched donor (>4/6 match) Early therapy is associated with improved outcomes Incidence of acute and chronic GvHD was low. Overall survival was 72% at 1 year and 58% at 5 years In patients with favorable PS, overall survival was 88% at 1 year and 80% at 5 years. Higher overall survival was most influenced by performance status and infused FUs. UBT is effective in treatment of children with Lysosomal and Peroxisomal Storage Disorders and should be considered for all patients in need of transplantation therapy.

26 GAL Levels Post Transplant Months Since Transplant Untreated Treated ontrols MRI changes post transplant erebellar Ped erebral Ped Basal Ganglia Thalamus Post Limb I Genu of Splenium of Frontal WM Occi-pariet WM orona Radiata en Semiovale (nmol/hr Leukocyte Ga /mg of protien) lactocerebrosidase

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28 UBT: Record 1. UB cells are immunologically tolerant and can be successfully transplanted across partially mismatched allogeneic HLA barriers. 2. UBT has been used to treat a variety of malignant and nonmalignant disorders affecting bone marrow 3. UB cells can be used for transplantation in patients with inherited metabolic diseases where the primary defect does not involve bone marrow or hematopoiesis. 4. Almost 14,000 umbilical cord blood transplants of which >10,000 from unrelated donors have been performed worldwide. 5. UB cells contain pluri-potent elements and have the ability of trans-differentiation into non-hematopoietic lineages including brain, muscle, liver, cartilage and bone. Kogler et al JEM 2004

29 Private UB Transplantation In the US, ~500,000 units stored, <100 transplanted Applications: Siblings with malignancies, aplastic anemia, sickle cell anemia, thalassemia, inborn errors, immunodeficiencies In trials: P, congenital hydrocephalus, other brain injuries

30 Autologous UBT at Duke P, HIE, congenital hydrocephalus, other brain injuries Hypotheses: UB contains anti-inflammatory cells that could inhibit the inflammatory response after acute injury UB contains neural cell progenitors that could facilitate repair and regeneration. UB cells cross the blood brain barrier

31 How is cord blood used now and in the future? urrent applications: Treatment of patients with malignancies, marrow failure, congenital immunodeficiency, metabolic diseases (cellular ERT), hemoglobinopathies Future applications: Fetal transplant therapy ellular repair and regeneration brain, heart, pancreas, liver, bones, vascular insufficiency Stimulate autologous cells Replacement by allogeneic cells Suppression of inflammation

32 hildren and their families Joanne Kurtzberg PBMT Program at Duke RN, oordinators, NP, SW, PT, OT, ST, stem cell laboratory Nancy Kernan, John Wagner, LeeAnn Baxter- Lowe and Other OBLT collaborators EMMES: Adam Mendizabal, Shelly arter Acknowledgements