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
tissue.

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.