Ignite Creation Date:
2024-05-05 @ 5:32 PM
Last Modification Date:
2024-10-26 @ 9:33 AM
Study NCT ID:
NCT00479115
Status:
COMPLETED
Last Update Posted:
2020-10-30
First Post:
2007-05-23
Brief Title:
Mobilization and Collection of Peripheral Blood Stem Cells in Patients With Fanconi Anemia Using G-CSF and AMD3100
Sponsor:
Childrens Hospital Medical Center Cincinnati
Organization:
Childrens Hospital Medical Center Cincinnati
Study Overview
Official Title:
AMD3100 in Combination With G-CSF to Mobilize Peripheral Blood Stem Cells in Patients With Fanconi AnemiaFA A Phase III Study
Status:
COMPLETED
Status Verified Date:
2020-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this research study is to determine whether an experimental drug called AMD3100 used in combination with another medication called G-CSF is safe and can help to increase the amount of blood stem cells called CD34 stem cells found in the peripheral blood of patients with Fanconi anemia While AMD3100 has been used successfully in adult volunteers and cancer patients it has not been used in children or patients with Fanconi anemia and in only a few children with cancer
Fanconi anemia is a rare genetic disease Most Fanconi anemia patients eventually develop bone marrow failure a condition in which the bone marrow no longer produces red blood cells to carry oxygen white blood cells to fight infection and platelets to help blood clot The only successful treatment for patients with Fanconi anemia with bone marrow failure is bone marrow transplantation However this treatment has many risks and is not available to all patients with Fanconi anemia
CD34 cells include stem cells found in the bone marrow or peripheral blood which are capable of making the red blood cells white blood cells and platelets CD34 stem cells can be collected from bone marrow or peripheral blood and purified using an experimental device called the CliniMACS However most Fanconi anemia patients do not have enough CD34 stem cells in their bone marrow or peripheral blood to be collected using standard methods that work well in children and adults who dont have Fanconi anemia
Fanconi anemia is a rare genetic disease Most Fanconi anemia patients eventually develop bone marrow failure a condition in which the bone marrow no longer produces red blood cells to carry oxygen white blood cells to fight infection and platelets to help blood clot The only successful treatment for patients with Fanconi anemia with bone marrow failure is bone marrow transplantation However this treatment has many risks and is not available to all patients with Fanconi anemia
CD34 cells include stem cells found in the bone marrow or peripheral blood which are capable of making the red blood cells white blood cells and platelets CD34 stem cells can be collected from bone marrow or peripheral blood and purified using an experimental device called the CliniMACS However most Fanconi anemia patients do not have enough CD34 stem cells in their bone marrow or peripheral blood to be collected using standard methods that work well in children and adults who dont have Fanconi anemia
Detailed Description:
Fanconi anemia is a rare autosomal recessive syndrome comprised of progressive bone marrow failure congenital anomalies and a predisposition to malignancy The heterozygote rate in the United States may be as high as 1 in 300 The mean age for the onset of aplastic anemia is approximately eight years Although improved supportive care has prolonged the survival of these patients from only a few years from the diagnosis of bone marrow failure the mean age of death is still approximately 24 years of age Most patients die from complications of bone marrow failure including bleeding or infection or from malignancy or complications of stem cell transplantation In a recent 20 year review of patients in the Fanconi anemia registry the actual risk of developing leukemia or other cancers was approximately 30
The diagnosis of Fanconi anemia initially rested upon finding the combination of bone marrow failure with congenital anomalies These anomalies include cafe au lait spots andor hypo pigmentation of the skin short stature upper limb malformations often involving the thumb or radius renal and gastrointestinal abnormalities microcephaly and characteristic facies with a broad nasal base epicanthal folds narrow set and small eyes and micrognathia The bone marrow failure is characterized by slow progression to severe bone marrow aplasia and pancytopenia stress erythropoiesis with fetal features including macrocytosis elevated hemoglobin F and i antigen expression Attempts to culture bone marrow progenitors in vitro from patients with Fanconi anemia demonstrates decreased numbers of myeloid and erythroid colonies CFU consistent with clinical bone marrow failure
Fanconi anemia cells appear to have a defect in DNA repair that leads to increased spontaneous chromosomal breakage This feature increases the susceptibility of Fanconi anemia cells to DNA bifunctional cross-linking agents such as mitomycin C and diepoxybutane DEB The diagnosis of Fanconi anemia now relies upon detecting increased chromosomal breakage after in vitro treatment with DEB 11 Similarly cells cultured from patients with Fanconi anemia display increased susceptibility to the cytotoxicity of mitomycin C More recently cells from patients with Fanconi anemia have been demonstrated to display G2 phase prolongationarrest increased sensitivity to toxicity by oxygen defective p53 induction and increased apoptosis
Fanconi anemia can be classified into at least thirteen complementation groups by somatic cell hybrids The complementation is based upon correction of the chromosomal sensitivity to cross-linking agents in hybrid cells Twelve independent genes have been cloned and characterized within these 13 complementation groups A loss of function in any of these genes including FANC A B C D2 E F G J L M N and FANC D1 which is BRCA2 can cause Fanconi anemia However complementation groups A C and G account for approximately 80-85 of patients with Fanconi anemia in the United States Discrete mutations in these genes have been identified in families with the disorder Expression of the complementary cDNA gene in the respective Fanconi anemia cells in vitro corrects the increased chromosomal breakage from DEB and the increased sensitivity to mitomycin C Expression of gene products in bone marrow progenitors from patients with Fanconi anemia increases survival in in vitro assays
The current treatment for Fanconi anemia relies upon hematological support in the form of red blood cell and platelet transfusions Aplastic anemia will transiently respond to androgen therapy in 50 of children G-CSF has also been utilized in published studies from our own group to improve the number of myeloid cells in the peripheral circulation Bone marrow transplantation has cured some patients of their bone marrow failure however there appears to be more toxicity to the conditioning regimens and there may be increased numbers of solid tumors post transplant compared to patients without the disorder Survival five years after a matched sibling transplant now exceeds 65 and after an unrelated donor transplant 30 More recent studies in unrelated donor transplant for Fanconi anemia at Cincinnati Childrens Hospital and the University of Minnesota have reported survival rates approaching those observed in matched sibling donor transplants However graft failure resulting in death remains a major obstacle The availability of sufficient numbers of previously purified and cryopreserved autologous HSC for re-infusion after graft failure may prevent this complication
Finally gene therapy approaches are being pursued but to date there is no evidence for cure with this approach in humans although correction has been reported in murine models These studies are hampered by the fact that mouse knockouts of FA genes do not develop spontaneous aplastic anemia and thus are not phenocopies of the human disease Thus in previously reported mouse-studies gene therapy approaches required ablative total body irradiation of the recipient mice to ensure engraftment of the gene corrected stem cells
An obvious limitation of Fanconi anemia hematopoietic stem cell gene transfer is that the necessary target for genetic manipulation the hematopoietic stem cell or its surrogate CD34 cell is progressively lost during the development of aplastic anemia Thus at the time of severe aplasia and the greatest need for treatment target stem cells for genetic modification are deficient Collection of a meaningful number of HSC prior to the onset of aplastic anemia for eventual use in a therapeutic gene therapy trial will be explored in the study outlined here Key questions remaining are whether corrected HSC from Fanconi anemia patients will engraft after autologous re-infusion without any cyto-reductive treatment of the recipient and if engrafted whether the corrected cells will demonstrate a proliferative advantage over uncorrected stem cells
The diagnosis of Fanconi anemia initially rested upon finding the combination of bone marrow failure with congenital anomalies These anomalies include cafe au lait spots andor hypo pigmentation of the skin short stature upper limb malformations often involving the thumb or radius renal and gastrointestinal abnormalities microcephaly and characteristic facies with a broad nasal base epicanthal folds narrow set and small eyes and micrognathia The bone marrow failure is characterized by slow progression to severe bone marrow aplasia and pancytopenia stress erythropoiesis with fetal features including macrocytosis elevated hemoglobin F and i antigen expression Attempts to culture bone marrow progenitors in vitro from patients with Fanconi anemia demonstrates decreased numbers of myeloid and erythroid colonies CFU consistent with clinical bone marrow failure
Fanconi anemia cells appear to have a defect in DNA repair that leads to increased spontaneous chromosomal breakage This feature increases the susceptibility of Fanconi anemia cells to DNA bifunctional cross-linking agents such as mitomycin C and diepoxybutane DEB The diagnosis of Fanconi anemia now relies upon detecting increased chromosomal breakage after in vitro treatment with DEB 11 Similarly cells cultured from patients with Fanconi anemia display increased susceptibility to the cytotoxicity of mitomycin C More recently cells from patients with Fanconi anemia have been demonstrated to display G2 phase prolongationarrest increased sensitivity to toxicity by oxygen defective p53 induction and increased apoptosis
Fanconi anemia can be classified into at least thirteen complementation groups by somatic cell hybrids The complementation is based upon correction of the chromosomal sensitivity to cross-linking agents in hybrid cells Twelve independent genes have been cloned and characterized within these 13 complementation groups A loss of function in any of these genes including FANC A B C D2 E F G J L M N and FANC D1 which is BRCA2 can cause Fanconi anemia However complementation groups A C and G account for approximately 80-85 of patients with Fanconi anemia in the United States Discrete mutations in these genes have been identified in families with the disorder Expression of the complementary cDNA gene in the respective Fanconi anemia cells in vitro corrects the increased chromosomal breakage from DEB and the increased sensitivity to mitomycin C Expression of gene products in bone marrow progenitors from patients with Fanconi anemia increases survival in in vitro assays
The current treatment for Fanconi anemia relies upon hematological support in the form of red blood cell and platelet transfusions Aplastic anemia will transiently respond to androgen therapy in 50 of children G-CSF has also been utilized in published studies from our own group to improve the number of myeloid cells in the peripheral circulation Bone marrow transplantation has cured some patients of their bone marrow failure however there appears to be more toxicity to the conditioning regimens and there may be increased numbers of solid tumors post transplant compared to patients without the disorder Survival five years after a matched sibling transplant now exceeds 65 and after an unrelated donor transplant 30 More recent studies in unrelated donor transplant for Fanconi anemia at Cincinnati Childrens Hospital and the University of Minnesota have reported survival rates approaching those observed in matched sibling donor transplants However graft failure resulting in death remains a major obstacle The availability of sufficient numbers of previously purified and cryopreserved autologous HSC for re-infusion after graft failure may prevent this complication
Finally gene therapy approaches are being pursued but to date there is no evidence for cure with this approach in humans although correction has been reported in murine models These studies are hampered by the fact that mouse knockouts of FA genes do not develop spontaneous aplastic anemia and thus are not phenocopies of the human disease Thus in previously reported mouse-studies gene therapy approaches required ablative total body irradiation of the recipient mice to ensure engraftment of the gene corrected stem cells
An obvious limitation of Fanconi anemia hematopoietic stem cell gene transfer is that the necessary target for genetic manipulation the hematopoietic stem cell or its surrogate CD34 cell is progressively lost during the development of aplastic anemia Thus at the time of severe aplasia and the greatest need for treatment target stem cells for genetic modification are deficient Collection of a meaningful number of HSC prior to the onset of aplastic anemia for eventual use in a therapeutic gene therapy trial will be explored in the study outlined here Key questions remaining are whether corrected HSC from Fanconi anemia patients will engraft after autologous re-infusion without any cyto-reductive treatment of the recipient and if engrafted whether the corrected cells will demonstrate a proliferative advantage over uncorrected stem cells
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01HL081499 | NIH | None | httpsreporternihgovquickSearchR01HL081499 |