Neoplasms

Blood and Lymph Conditions

All Conditions

Hematologic Neoplasms

Hematologic Diseases

Antineoplastic Agents

All Drugs and Chemicals

Fludarabine

Fludarabine phosphate

Thymoglobulin

Busulfan

Immunosuppressive Agents

Immunologic Factors

Alkylating Agents

Antineoplastic Agents, Alkylating

study :

* acute and/or chronic graft-versus-host reaction (incidence and severity) and immune reconstitution, post transplantation
* the effectiveness of the protocol on tumor response
* overall survival

Fludarabine, Busulfan, Thymoglobulin

Lacarin Patrick

Paillard Catherine, Dr

To assess the engraftment of hematopoietic stem cells following reduced-intensity conditioning in children presenting with solid tumors or hematological malignancy by evaluating post-transplantation chimerism and hematological reconstitution.

To study acute and/or chronic graft-versus-host reaction (incidence and severity) and immune reconstitution, post-transplantation To study the effectiveness of the protocol on tumor response.

To study overall survival.

Primary criterion

* Hematological reconstitution and chimerism post-transplantation

Secondary criteria

* Adverse effects, graft-related mortality at D90 and at 12 months, incidence and severity of acute and/or chronic GVH reactions
* Analysis of variations in post-transplantation immunological function profiles
* Median duration of response in therapy-responsive patients and median duration of stability in stabilized patients

Allogeneic Hematopoietic Stem Cell Transplantation

Feasibility Study on Allogeneic Hematopoietic Stem Cell Transplantation Following Fludarabine-Busulfan-ALS-based Reduced-intensity Conditioning in Children With Hematological Malignancy or Solid Tumor Not Responding to Standard Therapy or for Which the Indication for Allograft is Maintained But Cannot be Carried Out Due to the Toxicity Involved in Myeloablative Conditioning.

University Hospital, Clermont-Ferrand

Dr Catherine PAILLARD

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

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)

Hyo Seop Ahn, M.D, Ph. D

Cord blood transplantation (CBT) is an alternative option for patients with pediatric acute leukemia that indicated stem cell transplantation. Although CBT is as affective as unrelated bone marrow transplantation with lower graft versus host disease (GVHD) severity and incidence, transplantation related mortality (TRM) has been major problems after myeloablative conditioning. To reduce TRM, CBT with non-myeloablative conditionings have been performed but not so satisfactory especially for engraftment rate. Recently reduced toxicity myeloablative conditioning regimen was developed with promising result in adult bone marrow or mobilized peripheral blood transplantation. To increase the engraftment potential with low TRM rate, reduced toxicity myeloablative conditioning composed of fludarabine, intravenous busulfan plus thymoglobulin is planned for pediatric patients with 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.

Study of Reduced Toxicity Myeloablative Conditioning Regimen for Cord Blood Transplantation in Pediatric AML

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

The Korean Society of Pediatric Hematology Oncology

The Korean Society of Hematology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Allogeneic Hematopoietic Stem Cell Transplantation	NCT00750126	Solid Tumors Hematologic Neo...	Fludarabine, Bu...	- 20 Years	University Hospital, Clermont-Ferrand
Study of Reduced Toxicity Myeloablative Conditioning Regimen for Cord Blood Transplantation in Pediatric AML	NCT00887042	Acute Myeloid L...	Fludarabine, Bu...	1 Year - 21 Years	The Korean Society of Pediatric Hematology Oncology
Study of Reduced Toxicity Myeloablative Conditioning Regimen for Cord Blood Transplantation in Pediatric AML	NCT00887042	Acute Myeloid L...	Fludarabine, Bu...	1 Year - 21 Years	The Korean Society of Pediatric Hematology Oncology

Spots Global Cancer Trial Database for fludarabine, busulfan, thymoglobulin