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The Treatment of Hematologic Malignancies With Single or Double Umbilical Cord Blood Unit Transplantation Followed by Graft-Versus-Host Disease Prophylaxis With Tacrolimus and Mycophenolate Mofetil


Phase 2
1 Month
50 Years
Open (Enrolling)
Both
Cord Blood Stem Cell Transplantation

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Trial Information

The Treatment of Hematologic Malignancies With Single or Double Umbilical Cord Blood Unit Transplantation Followed by Graft-Versus-Host Disease Prophylaxis With Tacrolimus and Mycophenolate Mofetil


An increasing number of patients with fatal malignant and nonmalignant diseases are being
treated with SCT. Unfortunately only about 30% of patients who could benefit from this
procedure have a HLA-matched related donor (MRD), and only an additional 20% can find a
suitable HLA-matched unrelated donor (MUD) 1. This problem is magnified in patients of
minority groups who are often underrepresented in the donor pool. In an attempt to expand
the number of patients who could be helped by transplantation alternative donor sources has
been explored including UCB. Transplantation using UCB has numerous advantages including:
ease of procurement, lack of donor attrition, absence of risk to mothers and donors,
potential reduced risk of GVHD, and less stringent criteria for HLA matching 2. However
these benefits are limited by the delayed engraftment, extended post-transplant neutropenia
and thrombocytopenia, increased infection rate, and relative decreased cell dose of the
graft.

Pediatric Experience in UCB SCT (Related and Unrelated Donors) Related UCB SCT

By November 1996, 74 patients had been treated with a related UCB SCT and the data had been
reported to the International Cord Blood Transplant Registry (ICBTR) 3. Twenty patients
received HLA 1-3 antigen mismatched grafts. Pretransplant conditioning therapy,
post-transplant use of hematopoietic growth factors and prophylaxis for acute GVHD varied
between institutions.

For recipients of HLA-matched or HLA-1 antigen mismatched UCB grafts, the actuarial
probability of hematopoietic recovery at 60 days after transplantation was 91% ± 8%. Median
times to neutrophil recovery (defined as time to achieve an absolute neutrophil count [ANC]
> 0.5 x 109/L) and platelet recovery (defined as platelet count >50 x 109/L untransfused for
7 days) were 22 days (range, 9 to 46) and 51 days (range, 15 to 117) after transplantation,
respectively. Four patients never had signs of hematopoietic recovery and one patient had
early recovery but cells were entirely host in origin. Of the 5 patients without donor cell
engraftment, 4 had undergone UCB SCT for the treatment of a bone marrow failure syndrome and
one for the treatment of Hunter's syndrome.

Acute GVHD has occurred very infrequently in recipients of HLA-matched and HLA-1 antigen
mismatched UCB SCT. The actuarial probability of grade II-IV GVHD at 100 days after
transplantation was 3%. Notably, only one patient has been reported to have grade III-IV
aGVHD.

Of the 15 recipients of 2 and 3 antigen disparate haploidentical transplants, 12 were
evaluable for GVHD (3 died of graft failure). Moderate to severe GVHD occurred in 3
patients. As shown in Table 1, donor-recipient pairs mismatched at the maternal allele
appeared to be much less likely to develop grade II-IV GVHD than donor-recipient pairs
mismatched at the paternal allele. This observation supports the hypothesis that partial
tolerance may develop to the non-inherited maternal allele (NIMA) during gestation as
opposed to the non-inherited paternal allele (NIPA)


Inclusion Criteria:



Only one of the following should be present:

1. Acute leukemia (lymphocytic or myeloid or undifferentiated or biphenotypic)in
complete remission 2 or beyond

2. Acute lymphocytic leukemia, Philadelphia chromosome positive in complete remission 1
or beyond

3. Acute myeloid leukemia in complete remission 1 if it has evolved from myelodysplastic
syndrome (MDS) (there should be documented diagnosis of MDS at least 3 months prior
to diagnosis of acute myeloid leukemia)

4. Therapy related acute leukemia in complete remission 1 or beyond

5. Chronic myeloid leukemia (CML) chronic phase-1 (imatinib failures,imatinib
intolerance), or any CML beyond first chronic phase

6. Myelodysplastic syndromes (Intermediate -2 or high risk by IPSS)

7. Therapy related MDS (irrespective of IPSS)

For patients with acute leukemia-they must be in a remission (less than 5% leukemic marrow
blasts and no peripheral circulating leukemic blasts) at time of study entry.

Inclusion Criteria:

Adult (defined as 18 years or greater) All of the criteria should be
present Karnofsky score of > or = to 70% Estimated Creatinine clearance of of > or = to 60
ml/min Left ventricular ejection fraction of > or = to 50% Pulmonary function test with
DLCO, FEV1 and FVC of > or = to 60% Total bilirubin and SGOT of < or = to 1.5 x upper
limits of normal As Per Adult Vanderbilt Stem Cell Transplant Standard Guidelines, except
Age 18- 40 years for adult myeloablative conditioning Age 41 -50 years for adult reduced
intensity conditioning

Inclusion Criteria:

Pediatric (defined as less than 18 years) All of the criteria should
be present Karnofsky or Lansky score of > or = to 70% Estimated Creatinine clearance of >
or = to 60 ml/min Left ventricular ejection fraction of > or = to 50% Pulmonary function
test with FEV1 and FVC of > or = to 60% (for patients >6 years of age) Total bilirubin and
SGOT of < or = to 1.5 x upper limits of normal As Per Vanderbilt Pediatric Stem Cell
Transplant Standard Guidelines All pediatric patients will receive myeloablative
conditioning

Inclusion Criteria:

Donor Issues

- No available HLA identical or 1 antigen/allele mismatched (Class I-A, B or Class II
DR locus) related donor

- No available HLA matched unrelated donor

Inclusion Criteria:

Umbilical Cord Blood Unit-HLA Typing

- At least a HLA 4/6 match (Class I-A,B by low resolution, Class II-DR by high
resolution) to recipient

- For double UCB SCT each unit should be at least a 4/6 match (Class I-A,B by low
resolution, Class II-DR by high resolution) to recipient, and should be at least a
4/6 match (Class I-A,B by low resolution, Class II-DR by high resolution) to each
other

Inclusion Criteria:

Umbilical Cord Blood Unit-Cell dose

For Single UCB SCT: the unit will have ≥ 3.5 X 10(7) NC/kg of recipient body weight (For
pediatric patients a cell dose ≥ 3.0 X 10(7) NC/kg of recipient body weight is
acceptable). Recipient body weight will be determined as per Vanderbilt Stem Cell
Transplant Standard Guidelines.

For Double UCB SCT: (done only if no single UCB unit ≥ 3.5 X 10(7) NC/kg of recipient body
weight is available for adults, and ≥ 3.0 X 10(7) NC/kg of recipient body weight is
available for pediatric patients )

The larger of the two units (UCB1) will have a minimum cell dose of 2.5 X 10(7) NC/kg of
recipient body weight. The smaller of the two units (UCB2) will have a minimum of 0.5 X
10(7) NC/kg of recipient body weight.

The total cell dose UCB1 + UCB2 will be ≥ 3.0 X 10(7) NC/kg of recipient body weight.

Adult patients eligible for a double UCB SCT but without an appropriate second UCB unit
will be enrolled in the study if their single UCB unit contains ≥ 3.0 x 10(7) NC/kg
recipient body weight.

Exclusion Criteria:

- Organ dysfunction as per Vanderbilt Stem Cell Transplant Standard Guidelines

- Unable to give informed consent (for adults only)

- Pregnant or lactating

- Sexually active individuals capable of becoming pregnant or causing a pregnancy who
are unable or unwilling to use appropriate contraceptives.

- Active use of illicit drugs as evidenced by a positive toxicology screen for a
substance not prescribed by a medical professional just prior to initiating the
preparative regimen

- Actively smoking as evidenced by a positive nicotine screen just prior to initiating
the preparative regimen

- HIV positive

- Patients with other unrelated malignancies will be excluded except:

- diagnosis of skin cancer (squamous cell or basal cell)

- diagnosis of cervical dysplasia (CIN I-III)

- any other malignancy which is currently in remission and was treated with
curative intent more than 5 years preceding study entry

- In patients with secondary MDS or secondary acute leukemias-the previous
non-hematopoietic neoplasm should be in remission but can be within 5 years of study
entry

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To determine the safety (as assessed by the day 100 non-relapse mortality) and feasibility of single or double UCB SCT in patients with hematological malignancies receiving GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).

Outcome Time Frame:

+100 days

Safety Issue:

Yes

Principal Investigator

Brian G. Engelhardt, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Vanderbilt University

Authority:

United States: Food and Drug Administration

Study ID:

BMT 050674

NCT ID:

NCT00244036

Start Date:

September 2005

Completion Date:

September 2009

Related Keywords:

  • Cord Blood Stem Cell Transplantation
  • Graft vs Host Disease

Name

Location

Vanderbilt University Medical CenterNashville, Tennessee  37232-2516