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Co-Infusion of Umbilical Cord Blood and Haploidentical CD34+ Cells Following Nonmyeloablative Conditioning as Treatment for Severe Aplastic Anemia and MDS Associated With Severe Neutropenia Refractory to Immunosuppressive Therapy


Phase 2
4 Years
75 Years
Open (Enrolling)
Both
Myelodysplastic Syndrome (MDS), Severe Aplastic Anemia (SAA)

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Trial Information

Co-Infusion of Umbilical Cord Blood and Haploidentical CD34+ Cells Following Nonmyeloablative Conditioning as Treatment for Severe Aplastic Anemia and MDS Associated With Severe Neutropenia Refractory to Immunosuppressive Therapy


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 percent of responders will
relapse.

Allogeneic bone marrow transplantation from either HLA-matched sibling or matched unrelated
donor cures about 70 percent of patients with SAA and 30-60 percent of patients with MDS.
Unfortunately, most patients with these disorders are not suitable candidates for
hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a
histocompatible donor. For such patients, transplantation using unrelated cord blood (UCB)
has been shown to be a reasonable alternative transplant strategy. The advantage to UCB
transplant is the ease and rapidity of availability, requirement of less than perfect HLA
match, and lower rates of graft versus host disease compared to mismatched bone marrow or
peripheral blood stem cell transplants. The major disadvantage of UCB transplantation in
adults is the limited number of nucleated cells contained within the cord unit resulting in
prolonged neutropenia and failure of engraftment which contributes to infection and
transplant related mortality (TRM). In order to harness the advantage of UCB availability
and to overcome the disadvantage of delayed neutrophil recovery, we propose to test whether
co-administration of unrelated umbilical cord blood and a relatively low number of highly
purified haploidentical peripheral blood CD34+ cells from a related donor might promote
rapid engraftment and reduce TRM secondary to prolonged neutropenia associated with
conventional UCBT.

This research protocol is therefore designed to evaluate the safety and effectiveness of
co-infusion of unrelated umbilical cord blood and haploidentical CD34 plus cells from a
related donor following nonmyeloablative conditioning for neutropenic patients with SAA or
MDS that has proven to be refractory to medical therapy. Subjects will receive a novel
non-myeloablative immunosuppressive conditioning regimen of cyclophosphamide, fludarabine,
horse ATG and one dose of total body irradiation (200cGy) followed by an infusion of the
allografts. The haploidentical stem cell product will be T-cell depleted and enriched for
CD34 plus cells using the Miltenyi CliniMacs system. To reduce TRM secondary to prolonged
neutropenia associated with conventional UCB transplantation, haploidentical CD34+ stem
cells will be co-infused with a single UCB unit (serologically matched at greater than or
equal to 4/6 HLA loci).

The primary endpoint is donor engraftment by day 42 (defined as an ANC of greater than 500
from either the haplo donor, the cord, or both combined). Secondary endpoints will include
standard transplant outcome variables such as non-hematological toxicities, incidence and
severity of acute and chronic GVHD, and relapse of disease. We will also evaluate ANC
recovery (ANC greater than 500 cells/microl) at day 22, and 100 day and 200 day treatment
related mortality (TRM) of this novel transplant approach. Health related quality of life
will also be assessed pre-transplant 30 and 100 days poste transplant, and every 6 months
until 5 years post transplant.

Inclusion Criteria


- INCLUSION CRITERIA - RECIPIENT:

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

1. Bone marrow cellularity less than 30 percent (excluding lymphocytes)

2. Transfusion dependence for platelets and/or RBCs

3. Neutropenia (absolute neutrophil count less than 500 cells/microL) OR for
patients receiving granulocyte transfusions, absolute neutrophil count < 500
cells/microL before beginning granulocyte transfusions].)

OR

- Diagnosed with myelodysplastic syndrome characterized by Refractory Cytopenia with
Unilineage Dysplasia (RCUD) or (Refractory anemia with ringed sideroblasts (RARS), or
Refractory cytopenia with multi-lineage dysplasia (RCMD) or refractory anemia with
excess blasts (RAEB) type I or type II, MDS-imc;assofoed (MDS-U) and at least one of
the following:

1. Neutropenia [(absolute neutrophil count < 500 cells/microL) OR for patients
receiving granulocyte transfusions, absolute neutrophil count < 500
cells/microL before beginning granulocyte transfusions]) and history of 1 or
more opportunistic infections related to neutropenia. OR

2. History of severe aplastic anemia transformed to MDS

- Intolerance of or failure to respond standard immunosuppressive therapy.

- Availability 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 DO
loci) who is available to donate CD34+ cells (6-75 years old).

- Availability of at least one 4/6 HLA-matched (HLA-A, B, and DR loci) cord blood unit
from the National Marrow Donor Program (NMDP). The cord blood unit must contain a
minimum TNC (prior to thawing) of at least 1.5 x 10(7) cells per kilogram of
recipient body weight with the following exception: if the minimum criterion of TNC
is not met the cord unit must contain at least 1.7 x 10(5) CD34 plus cells/kg (prior
to thawing).

- Ages 4-55 years inclusive.

- 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:

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

- The patient is deemed to be a candidate for a 6/6 HLA matched unrelated stem cell
transplant (availability of a donor and resources required for such a transplant).

- ECOG performance status of 2 or more.

- Major anticipated illness or organ failure incompatible with survival from transplant

- Severe psychiatric illness. Mental deficiency sufficiently severe as to make
compliance with the transplant treatment unlikely and making informed consent
impossible.

- Positive pregnancy test for women of childbearing age.

- HIV positive

- Diagnosis of Fanconi's anemia or dyskeratosis congenita.

- Diffusion capacity of carbon monoxide (DLCO) less than 40 percent predicted (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).

- Left ventricular ejection fraction less than 40 percent (evaluated by ECHO) or less
than 30 percent (evaluated by MUGA)

- Transaminases greater than 5x upper limit of normal (when transaminases are elevated,
the subject may be excluded at the discretion of the PI).

- Serum bilirubin greater than 4 mg/dl

- Creatinine clearance less than 50 cc/min by 24 hr urine collection (adjusted for body
surface area, i.e.50 ml/min/1.73m(2))

- Failure to collect an adequate number of CD34+ cells (i.e. greater than or equal 2 x
10(6) CD34+ cells/kg) for transplantation from the subject's haploidentical relative.

- Presence of an active infection not adequately responding to appropriate therapy

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

INCLUSION CRITERIA - RELATED HAPLOIDENTICAL DONOR DONATING PURIFIED CD34 PLUS CELLS:

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

- Ages 6-75 inclusive

- Weight greater than or equal to 18 kg.

- 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.

EXCLUSION CRITERIA - RELATED DONOR (ANY OF THE FOLLOWING):

- Pregnant or lactating.

- A pediatric haploidentical donor will be excluded if a suitable adult haploidentical
donor is available.

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

- 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).

- Sickling hemoglobinopathies including HbSS, HbAS, HbSC

- Severe psychiatric illness. Mental deficiency sufficiently severe as to make
compliance with the BMT treatment unlikely and making informed consent impossible.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Day 42 cord engraftment

Outcome Time Frame:

Day 42

Safety Issue:

No

Principal Investigator

Richard W Childs, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Heart, Lung, and Blood Institute (NHLBI)

Authority:

United States: Federal Government

Study ID:

080046

NCT ID:

NCT00604201

Start Date:

January 2008

Completion Date:

December 2015

Related Keywords:

  • Myelodysplastic Syndrome (MDS)
  • Severe Aplastic Anemia (SAA)
  • Myelodyplastic Syndrome (MDS)
  • Severe Aplastic Anemia (SAA)
  • Stem Cell Transplant
  • Haploidentical Stem Cells
  • Umbilical Cord Blood
  • Severe Aplastic Anemia
  • Myelodysplastic Syndrome
  • MDS
  • Anemia
  • Anemia, Aplastic
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892