Study of Reduced Toxicity Myeloablative Conditioning Regimen for Cord Blood Transplantation in Pediatric AML
Recruitment status was: Active, not recruiting
|Acute Myeloid Leukemia||Drug: Fludarabine, Busulfan, Thymoglobulin||Phase 1 Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Study of Reduced Toxicity Myeloablative Conditioning Regimen for Cord Blood Transplantation in Pediatric Acute Myeloid Leukemia|
- To evaluate the engraftment potential of fludarabine, busulfan plus thymoglobulin conditioning regimen for CBT in AML. [ Time Frame: From June 2006 to May 2010 ]
- To evaluate the incidence and severity of toxicity and treatment related mortality. [ Time Frame: From June 2006 to May 2010 ]
- To evaluate overall and event free survival rate. [ Time Frame: From June 2006 to May 2010 ]
- To evaluate acute and chronic GVHD. [ Time Frame: From June 2006 to May 2010 ]
- To evaluate immunologic recovery after CBT. [ Time Frame: From June 2006 to May 2010 ]
|Study Start Date:||June 2006|
|Estimated Study Completion Date:||May 2012|
|Estimated Primary Completion Date:||May 2012 (Final data collection date for primary outcome measure)|
Drug: Fludarabine, Busulfan, Thymoglobulin
fludarabine (40 mg/m2 once daily i.v. on days -8, -7, -6, -5, -4 & -3) busulfan (0.8 mg/kg every 6 hours i.v. on days -6, -5, -4, & -3) thymoglobulin (2.5 mg/kg once daily i.v. on days -8, -7, & -6)
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00887042
|Korea, Republic of|
|Seoul National University Hospital|
|Seoul, Chongno-gu, Korea, Republic of, 110-744|
|Principal Investigator:||Hyo Seop Ahn, M.D, Ph. D||The Korean Society of Pediatric Hematology Oncology|