Unrelated Umbilical Cord Blood Transplantation for Severe Aplastic Anemia and Hypo-plastic MDS Using CordIn(TM), Umbilical Cord Blood-Derived Ex Vivo Expanded Stem and Progenitor Cells to Expedite Engraftment and Improve Transplant Outcome

Severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS) are life-threatening bone
marrow disorders. For SAA patients, long term survival can be achieved with immunosuppressive
treatment. However, of those patients treated with immunosuppressive therapy, one quarter to
one third will not respond, and about 50% of responders will relapse.

Combined haplo-cord transplant as an alternative to cord or haploidentical donor alone
transplantation has recently been shown to be a viable transplant option for SAA patients
lacking an HLA matched donor. In our ongoing protocol 08-H-0046, we have utilized this
approach in 25 patients with SAA with 23/25 patients having sustained engraftment and
long-term disease free/transfusion free survival. However, engraftment patterns have varied
substantially and in some patients, cord engraftment was profoundly delayed or never
occurred. A number of strategies to expand hematopoietic progenitor cells (HPC) in vitro to
improve engraftment and prevent graft rejection have recently been studied. Nicotimanide
(NAM) expanded umbilical cord blood/unrelated cord blood (UCB) can be successfully engrafted
in NOD/SCID mice (1) and humans (2) where they appear to have long-term repopulating
potential. CordIn(TM) is a cryopreserved stem/progenitor cell-based product of purified
CD133+ cells composed of ex vivo expanded allogeneic UCB cells. CordIn(TM) comprises: 1) Ex
vivo expanded, umbilical cord blood-derived hematopoietic CD34+ progenitor cellsU (
(CordIn(TM) cultured fraction (CF)); and 2) the non-cultured cell fraction of the same CBU
(CordIn(TM) Non-cultured Fraction (NF)) consisting of mature myeloid and lymphoid cellsU.
Both fractions, i.e. CordIn(TM) CF and CordIn(TM) NF are kept frozen until they are infused
on the day of transplantation.

This research protocol is therefore designed to evaluate the safety and effectiveness of
transplantation with ex vivo expanded UCB (CordIn(TM)) to overcome the high incidence of
graft rejection associated with conventional UCB for aplastic anemia, where graft rejection
occurs in up to 50% of subjects. We believe, based on preliminary data, that transplantation
of CordIn(TM) will not only lead to rapid engraftment, but will also lead to sustained
hematopoiesis, expedited immune recovery, and will reduce the chance of cord graft failure in
this setting, potentially obviating the need for co-transplanting haploidentical CD34+ cells
as a stem cell back-up. This phase II study is designed to have two cohorts: cohort 1 is
intended to establish (in as safe a manner as possible) preliminary pilot data to support the
capacity for the CordIn unit to engraft in patients with SAA in the presence of haplo CD34+
cells. For cohort 1, three to six subjects will be conditioned then will be transplanted with
the thawed CordIn(TM) unit (consisting of the cultured fraction and the non-cultured fraction
of the same CBU) and approximately 3 x 106 CD34+ cells/kg from a haploidentical donor which
will serve as a backup stem cell source should cord graft failure occur. If 3 of the first 3
to 4 subjects or 4 of 6 subjects achieve early and sustained engraftment (defined as ANC >500
cells/ul by day 26 and a calculated cord ANC >500 cells /ul by day 42 sustained at day 100),
the study will move to cohort 2 where up to 23 subsequent subjects will be transplanted with
the CordIn(TM) unit alone.

The primary objective of the Phase II study is to evaluate the ability of the CordIn(TM) unit
to achieve sustained early engraftment. Secondary endpoints will include 100 day and 200 day
treatment related mortality (TRM), and standard transplant outcome variables such as
non-hematologic toxicity, incidence and severity of acute and chronic GVHD, and relapse of
disease. Health related quality of life will also be assessed as secondary outcome measure.

-INCLUSION CRITERIA - RECIPIENT:

1. Diagnosed with severe aplastic anemia characterized by all of the following:

- Bone marrow cellularity <30% (excluding lymphocytes)

- Transfusion dependence for platelets and/or RBCs

- Neutropenia [(absolute neutrophil count <= 1000 cells/ uL) OR for patients
receiving granulocyte transfusions, absolute neutrophil count <= 1000 cells/ uL
before beginning granulocyte transfusions]. OR History of severe aplastic anemia
transformed to MDS that meet the following criteria: a) International Prognostic
Scoring System (IPSS) risk category of INT-1 or greater, b) < 5% myeloblasts and
< 30% of cellularity in the bone marrow on screening morphologic analysis.

2. Intolerance of or failure to respond to standard immunosuppressive therapy.

3. Identification of at least one HLA- haploidentical (i.e. greater than or equal to 5/10
and less than or equal to 8/10 HLA match) related donor (HLA-A, B, C, DR, and DQ loci)
who is available to serve as a haploidentical stem cell donor for a salvage
haplo-transplant in the event that the Cordin unit has been rejected (cohort 1 only).

4. Availability of at least one 5/8 HLA-matched (HLA-A, B, C, and DR loci) cord blood
unit from the National Marrow Donor Program (NMDP).

5. The cord blood unit must contain a minimum TNC of at least 1.8 x 10^9 and at least
1.8x10^7/kg TNC and at least 8 x 10^6 CD34+ cells (all doses prior to thawing). The
CBU will have undergone volume reduction (both plasma and red blood cell depletion)
prior to cryopreservation. All CBUs should be procured from public banks that meet
local applicable regulations.

6. Ages 4-55 years inclusive.

7. Ability to comprehend the investigational nature of the study and provide informed
consent. The procedure will be explained to subjects aged 4-17 years with formal
consent being obtained from parents or legal guardian.

EXCLUSION CRITERIA - RECIPIENT (ANY OF THE FOLLOWING):

1. Availability of an HLA identical or 9/10 HLA matched (HLA A, B, C, DR, and DQ loci) -
relative to serve as a stem cell donor.

2. The patient is deemed to be a candidate for a 10/10 HLA matched unrelated stem cell
transplant (availability of a donor and resources required for such a transplant).

3. ECOG performance status of 2 or more.

4. Major anticipated illness or organ failure incompatible with survival from transplant.

5. Current pregnancy, or unwillingness to take oral contraceptives or use a barrier
method of birth control or practice abstinence to refrain from pregnancy, if of
childbearing potential for one year.

6. HIV positive.

7. Diagnosis of Fanconi s anemia (by chromosome breakage study)

8. Diffusion capacity of carbon monoxide (DLCO) <40% predicted using DLCO corrected for
Hgb or lung volumes (patients under the age of 10 may be excluded from this criterion
if they have difficulty performing the test correctly and thus are unable to have
their DLCO assessed).

9. Left ventricular ejection fraction < 40% (evaluated by ECHO).

10. Transaminases > 5x upper limit of normal.

11. Serum bilirubin >4 mg/dl.

12. Creatinine clearance < 50 cc/min/BSAm^2 by 24-hour urine collection adjusted by body
surface area..

13. Serum creatinine > 2.5 mg/dl

14. Presence of an active infection not adequately responding to appropriate therapy.

15. History of a malignant disease liable to relapse or progress within 5 years.

16. Allergy to bovine, Gentamicin, or to any product which may interfere with the
treatment.

17. Presence of donor-specific antibodies (DSA) to the umbilical cord blood unit and for
cohort 1, to the haplo-identical donor.

INCLUSION CRITERIA - RELATED HAPLOIDENTICAL DONOR DONATING PURIFIED CD34+ CELLS (cohort 1
only):

1. HLA mismatched family donor ( greater than or equal to 5/10 and less than or equal to
8/10 HLA match (HLA-A, B, C, DR, and DQ loci)) who is available to donate CD34+ cells.

2. Ages 4-75 inclusive. Note: a pediatric family member will only be considered as a
donor if a suitable adult haplo-identical donor is not available.

3. Weight greater than or equal to 15 kg.

4. For adults: Ability to comprehend the investigational nature of the study and provide
informed consent. For minors: Written informed consent from one parent or guardian who
is not the recipient of the transplant and informed assent. The process will be
explained to the minor on a level of complexity appropriate for their age and ability
to comprehend.

5. Genetic testing for genes associated with bone marrow failure syndromes (BMFS)
perfomed at a CLIA-certified laboratory.If there is a suspicion of familial BMFS in
the recipient, then the haplo donor must have undergone genetic testing for genes
associated with BMFS - performed at a CLIA-certified laboratory, prior to enrolling in
this protocol (applies only to cohort 1).

EXCLUSION CRITERIA - RELATED DONOR (ANY OF THE FOLLOWING)

1. Pregnant or lactating.

2. A pediatric haplo-identical donor will be excluded if a suitable adult haplo-identical
donor is available.

3. Unfit to receive filgrastim (G-CSF) and undergo apheresis (history of stroke, MI,
unstable angina, uncontrolled hypertension, severe heart disease or palpable spleen).

4. HIV positive (Donors who are positive for HBV, HCV or HTLV-I/II, T.cruzi (Chagas) may
be used at the discretion of the investigator following counseling and approval from
the recipient).

5. Sickling hemoglobinopathies including HbSS or HbSC. Donors with HbAS are acceptable.

6. Psychiatric illness that would limit the patient s ability to tolerate and/or comply
with study requirements.