Expanding Uses of Umbilical Cord Blood: Duke Experience

Vinod K. Prasad, MD, MRCP (London)PBMT Division, Duke University Medical Center

UCBT - Record

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

Unrelated Umbilical Cord Blood TransplantationDuke – August 24th 1993

• 3 yr old (14.1 kg); relapse T-cell ALL• No family or adult BM donor• 4/6 Cord blood unit from NYBC;

TNC – 4.6x10e7/Kg• Engrafted Day +31 (ANC >500)• Severe Pulmonary Hemorrhage and

died Day +61

• 1 yr old infant leukemia Sept 93• 4/6 CBU; TNC 4.86x10e7/kg• Long term survivor

New Technique or Technology1. Great hope and enthusiasm by some2. Major skepticism from others3. Slow acceptance by the community4. Weaknesses and strengths better understood5. Judicious application 6. ‘New’ becomes ‘common and routine’7. Desire and search for the next ‘new’

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CB Transplants CB Procurments

Pediatric Unrelated Cord Blood Transplants at DukeAugust 1993 - August 2008

Disease CategoryNumber of

patients

ALL 186AML 129Inherited Metabolic Disorder 187Immune Deficiency 55Bone Marrow Failure 28MDS 22CML 16Lymphoma 9Hemoglobinopathy 11Osteopetrosis 8Others 7

Total Transplants 719Total Patients Transplanted 658

Some received more than one transplant

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13 Domestic Cord Blood Banks

150,000 CBU in USA400,000 worldwide

The Carolinas Cord Blood Bank

• Established 1997 through COBLT (NHLBI)• Current inventory >20,000 units• 8 collection sites in NC with access to ~30,000 births• Staff collection model• Units listed and distributed through NMDP• ARC bank 1999-2001• NMDP Member bank 2004• FACT accreditation 2005, 2008• NCBI Bank 2006• Netcord Bank 2007

Unrelated Umbilical Cord 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

Cord Blood Advantages

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Median Time in DaysFrom Initiating a Formal Search

to Scheduling Transplant

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COBLT: Pediatric Hematologic Malignancy191 subjects transplanted between 1999-2003

Primary Disease N (%)

ALL 109 (57)

AML 57 (30)

MDS, CML, Others 15 (8)

• HLA: Low-res A, B; High-res DRB1; Retrospective - High resolution.• Hematological malignancies: no CML blast, ALL relapse• No related donor• Regimen: TBI 1350, Cy 120, eqATG 90• GvHD Prophylaxis: CSA/Methylpred• Age: 7.7 (1 – 18) yrs; Wt: 25.9 (8-118) kg• Demographics: 61% Males; 58% White;

51% CMV+; 77% High Risk

• TNC: Median pre cryo: 5.2 x 10e7/kg• CD34: Median : 1.52 x 10e5/kg

C C C

CCCCCCCCCCCC

CCCC

CCCCC

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CCC C C CCCC C C C C CCC

OVERALL SURVIVAL

TNC pre-cryo x 10e7/kgp=0.0367

Kurtzberg et al Blood 2008

COBLT: Pediatric Hematologic Malignancy191 subjects transplanted between 1999-2003

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Positive, N=98Negative, N=92

P<0.01

Overall Survival:

Recipient CMV Sero-status

p < 0.01

COBLT: Pediatric Hematologic Malignancy191 subjects transplanted between 1999-2003

DISEASE FREE SURVIVALOriginal HLA typing Retrospective HLA typing Low res -A and -B; Hi res –DRB1 Hi resolution –A, -B, and –DRB1

C C C

C C

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p=0.3385p=0.1874

COBLT: Pediatric Hematologic Malignancy191 subjects transplanted between 1999-2003

• 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 CMV

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 Caucasians

Krabbe’s Disease• Deficiency of Galactocerebrosidase - accumulation of lipids

in the CNS resulting in demyelization.• Incidence - 1/100,000 to 200,000• Age of onset -

– Early infantile – Dead by 1-2 years of age– Late infantile– Childhood

• 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/CT brain - attenuation of white matter• Elevated CSF protein• Decreased nerve conduction studies

CCC10

Unrelated UCBD-T for IMD: Demographics

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< 1 1-2 2-3 3-4 4-5 5-10 10-15 15-20 >20

Diagnosis N (%)Adrenoleukodystrophy

(ALD)13 8.2%

GM1 Gangliosidosis 1 0.6%Hunter’s Syndrome 6 3.8%Hurler’s Syndrome 45 28.3%

I-cell disease 1 0.6%Krabbe disease 36 22.6%

Lesch-Nyhan disease 4 2.5%Metachr Leukodystrophy

(MLD)15 9.4%

Others 4 2.5%Neiman-Pick B 2 1.3%PMD 1 0.6%Sandhoff disease 3 1.9%Sanfillipo Syndrome 19 11.9%

Tay Sachs 9 5.7%Alpha manosidosis 1 0.6%

DUMC Aug 1995 – April 2007

TOTAL PATIENTS – 159Age – Median (range) 1.5 yrs (0.05 – 26.25)

Prasad et al Blood 2008

Diapositiva 15

CCC10 -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 Comprehensive Cancer Center; 09/12/2007

E

How does UCBT correct IMD?• Cytoreduction or conditioning• Donor derived hematopoietic

nzyme could be transported from normal cells to deficient cells

1976 PNAS Neufeld

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

Muentzer NEJM 2007

Substance AEnzyme

Substance B

x

Unrelated UCB-T for IMD: Demographics

Median Range

Cell Dose x 10e7/kg Cryopreserved 9.73 (2.24 – 50.37)

Cell Dose x 10e7/kg Reinfused 7.57 (1.49 – 32.40)

CD34 x 10e5/kg Reinfused 2.14 (0.26-104.75)

CFU x 10e4/kg Reinfused 5.74 (0.00 – 105.30)

• Total Pts: 159• Males: 61%• CMV +Pt: 19.5%• PS<80: 41.5%• ABO mismatch: 44.7% • Ethnic mismatch: 25.2%• Sex mismatch: 49.1%

HLA Match N (%)

3/6 4 3.2%

4/6 73 46.5%

5/6 75 45.8%

6/6 7 4.5%

Duke Evaluation to cytoreduction – 34.5 daysDiagnosis to cytoreduction – 87 days

Prasad et al Blood 2008

VP17

Diapositiva 17

VP17 some of the data on Krabbe and Hurler publishedALD coming out in BBMTSanfillipo presented at meetingVinod Prasad; 04/05/2007

Unrelated UCB-T for IMD: Overall Survival

Patients with all Performance statusDuration Overall Survival 95% CI

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 80-100Duration Overall Survival 95% CI

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

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

• UCBT 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 CFUs.• UCBT is effective in treatment of children with Lysosomal

and Peroxisomal Storage Disorders and should be considered for all patients in need of transplantation therapy.

UCB-T for IMD: Conclusions

GALC Levels Post Transplant

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MRI changes post transplant

1. UCB cells are immunologically tolerant and can be successfully transplanted across partially mismatched allogeneic HLA barriers.

UCBT: Record

2. UCBT has been used to treat a variety of malignant and non-malignant disorders affecting bone marrow

3. UCB 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. UCB 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

Private UCB 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: CP, congenital hydrocephalus, other brain injuries

Autologous UCBT at Duke

• CP, HIE, congenital hydrocephalus, other brain injuries

• Hypotheses: – UCB contains anti-inflammatory cells that

could inhibit the inflammatory response after acute injury

– UCB contains neural cell progenitors that could facilitate repair and regeneration.

– UCB cells cross the blood brain barrier

How is cord blood used now and in the future?

• Current applications:Treatment of patients with malignancies, marrow failure, congenital immunodeficiency, metabolic diseases (cellular ERT), hemoglobinopathies

• Future applications:Fetal transplant therapyCellular repair and regeneration

brain, heart, pancreas, liver, bones, vascular insufficiency

Stimulate autologous cellsReplacement by allogeneic cellsSuppression of inflammation

• Children and their families

• Joanne Kurtzberg• PBMT Program at Duke• RN, Coordinators, NP,

SW, PT, OT, ST, stem cell laboratory

• Nancy Kernan, John Wagner, LeeAnn Baxter-Lowe and Other COBLT collaborators

• EMMES: Adam Mendizabal, Shelly Carter

Acknowledgements