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| Name | Class |
|---|---|
| Memorial Sloan Kettering Cancer Center | OTHER |
| Fred Hutchinson Cancer Center | OTHER |
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The purpose of this study is to determine whether the use of lower doses of busulfan and the elimination of cyclosporine will further reduce transplant-related side effects for patients with Fanconi Anemia (FA). Patients will undergo a transplant utilizing mis-matched related or matched unrelated donors following a preparative regimen of busulfan, fludarabine, anti-thymocyte globulin and cyclophosphamide.
The trial proposed is a three arm phase II treatment protocol designed to investigate the safety and efficacy of risk-adjusted chemotherapy-based cytoreductive regimen plus a CD34+ selected T-cell depleted peripheral blood stem cell (PBSC) stem cell transplant for the treatment of patients with Fanconi anemia and severe hematologic disease. Candidates for this trial will include patients with Fanconi anemia presenting with severe marrow failure (transfusion dependent) or myelodysplastic syndrome, or acute myelogenous leukemia for whom an allogeneic stem cell transplant is indicated.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A: Good Risk Patients | Experimental | Patients 18 years old or younger with marrow aplasia or single lineage cytopenias will be receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days), as used in our most current study that led to > 90% survival rates . Busulfan pharmacokinetics will not be used. All patients will receive rabbit ATG (4 doses x 4 days) prior to and granulocyte-colony stimulating factor (G-CSF) after transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells for all patients will be peripheral blood stem cells mobilized by treatment of the donor with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). Enrollment on this arm will include up to 50 patients. |
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| Arm B: Intermediate Risk Patients | Experimental | Patients 18 years old or younger with MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). Busulfan pharmacokinetics will be used in this arm, as the dose of busulfan is higher. All patients will receive rabbit ATG (thymoglobulin) (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for prophylaxis against GVHD. The source of the stem cells for all patients will be peripheral blood stem cells induced and mobilized by treatment of the donor. T-cell will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled in this arm will be 10. |
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| Arm C: High Risk Patients |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Busulfan | Drug | A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A). A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control. A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity. |
| Measure | Description | Time Frame |
|---|---|---|
| Graft Failure or Rejection | Primary non-engraftment is diagnosed when the patient fails to achieve an ANC >=500/mm3 at any time in the first 28 days post-transplant. If (1) after achievement of an absolute neutrophil count (ANC) >=500/mm3, the ANC declines to <500/mm3 for more than 3 consecutive days in the absence of relapse, or, (2) there is absence of donor cells in the marrow and/or blood as demonstrated by chimerism assay in the absence of relapse, a diagnosis of secondary graft failure is made. The patient is not evaluable for graft failure or rejection if recurrence of host MDS is detected concurrently. | 5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Post-transplant severe morbidity and mortality | The occurrence of severe post-transplant regimen-related severe morbidity (grade IV toxicity) and/or mortality will be the second endpoint of this study. In the context of the agents or agent-combination used for cytoreduction used, particular attention will be given to toxicity involving (1) the liver, (2) the lungs, (3) the oral mucosa and gastrointestinal tract, and (4) the central nervous system. |
| Measure | Description | Time Frame |
|---|---|---|
| Graft Versus Host Disease | Patients will be observed for acute and/or chronic graft versus host disease (GvHD). Standard clinical criteria for the grading of acute and chronic GvHD will be done according to IBMTR guidelines. | One year |
| Leukemic Relapse |
Inclusion Criteria:
Patients must have a diagnosis of Fanconi anemia
Patients must have one of the following hematologic diagnoses:
Severe Aplastic Anemia (SAA), with bone marrow cellularity of <25% OR Severe Isolated Single Lineage Cytopenia and at least one of the following features:
Myelodysplastic Syndrome (MDS) (based on WHO or IPSS Classification
Acute Myelogenous Leukemia (untreated, in remission or with refractory or relapsed disease)
Donors will be either human leukocyte antigen (HLA) compatible unrelated or HLA-genotypically matched related donors (no fully matched sibling donor).
Patients and donors may be of either gender or any ethnic background.
Patients must have a Karnofsky adult, or Lansky pediatric performance scale status > 70%.
Patients must have adequate physical function measured by:
Each patient must be willing to participate as a research subject and must sign an informed consent form.
Female patients and donors must not be pregnant or breastfeeding at the time of signing consent. Women must be willing to undergo a pregnancy test prior to transplant and avoid becoming pregnant while on study.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jamie Wilhelm | Contact | (513)803-1102 | Jamie.Wilhelm@cchmc.org | |
| Sara Loveless, RN | Contact | (513)803-7656 | Sara.Loveless@cchmc.org |
| Name | Affiliation | Role |
|---|---|---|
| Parinda Mehta, MD | CCHMC | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Memorial Sloan Kettering Cancer Center | Completed | New York | New York | 10174 | United States | |
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| Experimental |
Patients 19 years old or older with marrow aplasia or MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). In this study, we will test whether outcomes can be improved, yet engraftment maintained, with a slightly reduced dose of busulfan. Patients will receive rabbit ATG (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells will be peripheral blood stem cells collected from donors treated with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled will be 10. |
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| Cyclophosphamide | Drug | Arms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients. |
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| Fludarabine | Drug | Arms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines. |
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| rabbit ATG | Drug | Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment. |
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| G-CSF | Drug | All patients will also receive G-CSF post-transplant to foster engraftment. |
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| Peripheral blood stem cell | Biological | The source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). |
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| 2 years post-transplant |
For patients with MDS or AML, relapse will be analyzed as to type and genetic origin of the MDS/leukemic cells.
| 5 years |
| Secondary malignancies | Patients will be followed for 5 years through annual contact with their treatment center in order to track the risk of developing a secondary malignancy. | 5 years |
| Cincinnati Children's Hospital Medical Center |
| Recruiting |
| Cincinnati |
| Ohio |
| 45229 |
| United States |
|
| Fred Hutchinson Cancer Research Center | Recruiting | Seattle | Washington | 98109 | United States |
|
| ID | Term |
|---|---|
| D005199 | Fanconi Anemia |
| D009190 | Myelodysplastic Syndromes |
| D015470 | Leukemia, Myeloid, Acute |
| D000095542 | Cytopenia |
| D000754 | Anemia, Refractory, with Excess of Blasts |
| ID | Term |
|---|---|
| D029502 | Anemia, Hypoplastic, Congenital |
| D000741 | Anemia, Aplastic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D000080984 | Congenital Bone Marrow Failure Syndromes |
| D000080983 | Bone Marrow Failure Disorders |
| D001855 | Bone Marrow Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D049914 | DNA Repair-Deficiency Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D000753 | Anemia, Refractory |
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| ID | Term |
|---|---|
| D002066 | Busulfan |
| D003520 | Cyclophosphamide |
| C024352 | fludarabine |
| C042382 | fludarabine phosphate |
| C512542 | thymoglobulin |
| D016179 | Granulocyte Colony-Stimulating Factor |
| D000069585 | Filgrastim |
| D036102 | Peripheral Blood Stem Cell Transplantation |
| ID | Term |
|---|---|
| D002072 | Butylene Glycols |
| D006018 | Glycols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D008698 | Mesylates |
| D000476 | Alkanesulfonates |
| D017738 | Alkanesulfonic Acids |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |
| D013451 | Sulfonic Acids |
| D013456 | Sulfur Acids |
| D013457 | Sulfur Compounds |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D003115 | Colony-Stimulating Factors |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D016298 | Hematopoietic Cell Growth Factors |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
| D018380 | Hematopoietic Stem Cell Transplantation |
| D033581 | Stem Cell Transplantation |
| D017690 | Cell Transplantation |
| D064987 | Cell- and Tissue-Based Therapy |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D014180 | Transplantation |
| D013514 | Surgical Procedures, Operative |
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