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Phase II Study of Reduced Toxicity Myeloablative Conditioning Regimen for Cord Blood Transplantation in Pediatric Acute Myeloid Leukemia

Phase 1/Phase 2
1 Year
21 Years
Open (Enrolling)
Acute Myeloid Leukemia

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Trial Information

Phase II Study of Reduced Toxicity Myeloablative Conditioning Regimen for Cord Blood Transplantation in Pediatric Acute Myeloid Leukemia

Since the first successful transplantation using umbilical cord blood (UCB) to treat a
patient with Fanconi anemia in 1988 (Gluckman E, 1989), cord blood transplantation (CBT) has
become an alternative to bone marrow transplantation (BMT) to treat a variety of diseases.
Cord blood cells have many theoretical advantages as grafts for stem cell transplantation
because of the immaturity of newborn cells. Compared to adults, UCB stem cells produce
larger in vitro hematopoietic colonies, are able to expand in long-term culture in vitro
(Ahn HS, 2003). The properties of UCB cells should theoretically compensate for the
relatively low number of cells obtained in a single UCB unit and, through rapid expansion,
reconstitute myeloablated patients with fewer nucleated cells (by 1-2 logs) than bone marrow
(Barker JN, 2003-1).

Recent results of CBT revealed that HLA-matched and 1-antigen mismatched unrelated CBT had
similar survival as HLA-matched unrelated BMT and both the cell dose and HLA-disparity
influenced the outcome of CBT (CIBMTR data). But the major problems of CBT were engraftment
failure and transplantation related mortality (TRM) that compromised the outcomes of CBT. As
the numbers of stem cells are lower and immune cells are immature in cord blood than bone
marrow, the engraftment and immunologic recovery are delayed in CBT than BMT and these
properties of CBT result in higher rate of TRM up to 39% during 100 days after CBT (Rocha V,
2001). Early results of CBT also reported upto 50% of TRM (Gluckman E, 1997; Rubinstein P,
1998) and CIBMTR also reported that the cumulative incidence of TRM in pediatric study is
about 40%.

As the TRM is higher in CBT especially after conventional myeloablative conditioning,
non-myeloablative conditioning regimens are investigated especially for adult CBT (Barker
JN, 2003-2; Chao NJ, 2004). But studies about pediatric acute leukemia patients are not so
much and our pilot data suggested that CBT with non-myeloablative conditioning resulted in
lower engraftment rate and anti-leukemic effect although with low morbidity and mortality
(Ahn HS, 2004).

Recently, fludarabine based reduced toxicity myeloablative regimens were investigated with
promising result in adult transplant with bone marrow or mobilized peripheral blood (Russell
JA, 2002; Bornhauser M, 2003; de Lima M, 2004).

Purine-analog, in particular fludarabine, has some advantage over cyclophosphamide. It has
immunosuppressive property that allows the engraftment of hematopoietic stem cells with
minimal extramudullary toxicity. Fludarabine also inhibit the repair mechanism of alkylating
agent induced DNA damage, thus providing a synergistic effect if pre-exposed to the target

As the fludarabine plus myeloablative dose of busulfan allowed good engraftment and reduced
toxicity in transplant with bone marrow or mobilized peripheral blood, this combination
could be optimal for the conditioning regimen for CBT, which has high TRM and lower
engraftment rate with conventional myeloablative conditioning.

To increase the engraftment potential with low TRM rate, reduced toxicity myeloablative
conditioning composed of fludarabine, intravenous busulfan, thymoglobulin for CBT is planned
for pediatric patients with AML.

Inclusion Criteria:

1. Diagnosis of acute myeloid leukemia (FAB or WHO classification).

2. Indicated for hematopoietic stem cell transplantation.

3. Age: < 21 years old.

4. Performance status: ECOG 0-2.

5. Patients must be free of significant functional deficits in major organs, but the
following eligibility criteria may be modified in individual cases. 1. Heart: a
shortening fraction > 30%, ejection fraction > 45%. 2. Liver: total bilirubin < 2 ×
upper limit of normal; ALT < 3 × upper limit of normal. 3. Kidney: creatinine <2 ×
normal or a creatinine clearance (GFR) > 60 ml/min/1.73m2.

6. Patients must lack any active viral infections or active fungal infection.

7. Appropriate cord blood unit is available: accept HLA mismatch in two of six loci
(pairs of A, B, and DR). Allow 2 units cord transplantation.

8. One of parents should sign informed consent.

Exclusion Criteria:

1. Pregnant or nursing women.

2. Malignant (except acute myeloid leukemia) or nonmalignant illness that is
uncontrolled or whose control may be jeopardized by complications of study therapy.

3. Psychiatric disorder that would preclude compliance.

4. More than three HLA type mismatch.

5. T cell depleted or ex vivo expanded cord blood.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the engraftment potential of fludarabine, busulfan plus thymoglobulin conditioning regimen for CBT in AML.

Outcome Time Frame:

From June 2006 to May 2010

Safety Issue:


Principal Investigator

Hyo Seop Ahn, M.D, Ph. D

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Korean Society of Pediatric Hematology Oncology


Korea: Food and Drug Administration

Study ID:




Start Date:

June 2006

Completion Date:

May 2012

Related Keywords:

  • Acute Myeloid Leukemia
  • Acute myeloid leukemia
  • Cord blood transplantation
  • Pediatric
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid